Endocrine Abstracts May 2008 Volume 16 ISSN 1470-3947 (print) ISSN 1479-6848 (online)
10th European Congress of Endocrinology
3–7 May 2008, Berlin, Germany
Online version available at www.endocrine-abstracts.org
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d:g2 \dA ) !2 rBs g_ j 10th European Congress of Endocrinology, Berlin, Germany, 2008
Estrogens and cardiovascular disease The red wine hypothesis: resveratrol and human PL1 metabolism Estrogens and cardiovascular disease PL3 Michael Mendelsohn Central regulation of appetite and body weight: the role of peripheral Tufts Medical Center, Boston, Massachusetts, USA. signals Jens Bru¨ning In the 1990s, we learned that the same estrogen receptors that mediate Institute for Genetics, Cologne, Germany. hormonal effects in reproductive tissues also function in the heart and blood vessels, where they are required for normal cardiovascular physiology and The ever-growing obesity epidemic puts an enormous burden on our societies. for estrogen-mediated protection against vascular injury and atherosclerosis. The need for the development of novel therapeutic interventions necessitates the Great progress has been made in the past decade in understanding the exact understanding of the underlying regulatory principles in energy importance of ERa and ERb in cardiovascular physiology and disease. homeostasis. Over the last 10 years, the hormonal and nutritional factors In this presentation, data regarding the specific role of ERs in cardiovascular communicating the energy state of the body to the central nervous system to adapt physiology and pathophysiology will be reviewed and biological expla- caloric intake and energy expenditure have rapidly extended our understanding on nations for the WHI-generated controversy and confusion regarding hormone the mechanisms controlling energy homeostasis. The presentation will focus on replacement therapy (HRT) will be highlighted. Newer clinical evidence that insights into the primary neuronal target sites of such signals as well as molecular more firmly supports the beneficial cardiovascular effects of HRT for signaling mechanisms involved mainly obtained through the use of mice with menopausal women also will be reviewed and explained in the context of conditional inactivation of signaling components in specific neuronal populations. basic science and animal studies from the past 15 years that clearly support a central protective role for estrogen and ERs in cardiovascular disease. Molecular and cellular explanations for the controversy that arose from the Women’s Health Initiative (WHI) trials of the cardiovascular effects of HRT on CVD will be discussed and differences in the underlying vascular biology that exists between younger and older menopausal women that Berthold lecture of the German Endocrine Society support the importance of timing of HRT initiation will be reviewed. PL4 Several newer concepts in sex steroid hormone receptor action that have important implications for cardiovascular physiology and disease also will be discussed. These include the role of receptor co-regulatory proteins in Abstract unavailable cardiovascular cell biology, rapid (‘non-genomic’) activation of vascular endothelial cells by estrogen and ERs, ligand-independent ER activation in vascular cells, gender differences in regulation of metabolic pathways important to cardiovascular diseases by other NHR, and genetic ER variants associated with altered cardiovascular risk in both sexes. The ways in which these newer pathways can add substantial combinatorial complexity to the physiological effects of estrogen in target cardiovascular tissues will be discussed. Too little and too much insulin – lessons to learn from newborns PL5 Too little and too much insulin: lessons from newborns Andrew Hattersley Penisula Medical School, Exeter, UK. Let’s get older-lessons to learn from centenarians PL2 Insulin is a crucial growth factor in utero as well as the key post natal determinant Why did Moses live to be 120? of blood glucose. Mutations in beta-cell genes altering insulin secretion therefore Nir Barzilai present with both altered birth weight and also hyper or hypoglycaemia. Recent Albert Einstein College of Medicine, Bronx, New York, USA. advances in the genetics of neonatal diabetes and neonatal hyperinsulinism give key insights to beta-cell physiology as well as offering improved clinical management. Aging is associated with an increase in all the components of the metabolic In the genes encoding key beta-cell proteins Kir6.2, SUR1 and glucokinase syndrome and decline in the endocrine axis. We asked if healthy different mutations will result in both activating and inactivating mutations and centenarians are over-represented with phenotype and genotype for result in the opposing phenotypes of hypo and hyper glycaemia. Recently, we exceptional longevity that protects them from the endocrine causes of showed mutations in HNF4alpha the same loss of function mutations result in aging. For that, we recruited a genetically homogenous population of both transient neonatal hypoglycaemia and also latter beta-cell failure and unrelated ashkenazi jews with exceptional longevity (nw450). To validate diabetes. the genetic and physiological findings we also recruited the offspring of There have been major advances in the genetics of neonatal diabetes and a these subjects with exceptional longevity (nw400). We assessed their molecular genetic diagnosis is now possible most patients with transient or clinical (NCEPIII guidelines), their metabolic (lipoproteins, insulin), and permanent neonatal diabetes. In transient neonatal diabetes (TNDM) is now endocrine (IGF-1 and its bonding proteins, TSH) phenotype. We used a possible to give a diagnosis in over 95% of patients. The commonest cause are several method to genotype numerous SNPs in promoters, exons or introns abnormalities of imprinting in the region of the ZAC gene on 6q (71%) the of genes associated with this phenotype, and a method to discover new majority of other patients either have a mutation in SUR1 (14%) or Kir6.2 (12%). mutations. We show that centenarians have a unique liporotein profile that is KATP mutations like ZAC anomalies that cause TNDM may also relapse with inherited by their offspring. We demonstrate 3 genotypes in cholesterol ester permanent diabetes outside the neonatal period. transfer protein (CETP), apo-lipoprotein c-3 (APOC3), and adiponectin In permanent neonatal diabetes (PNDM), the commonest cause is Kir6.2 (ADIPOQ) that monotonically increase between ages 60–110 in unrelated mutations (30%) but SUR1and insulin mutations that may present as dominant individuals, and are over represented by 2–3 folds in the oldest old group, or recessive mutations are found in 12 and 14% of cases, respectively. suggesting that they may be necessary to assure exceptional survival. Neurological features which account for approximately 20% of Kir6.2 mutations Furthermore, we show that these genotypes are associated with changes in are seen in !5% in SUR1 patients and are not a feature of insulin mutations. their protein plasma levels and out come related to the metabolic syndrome. The major reason that genetics have been important in neonatal diabetes is We also demonstrate the role of IGF-1 receptor mutation in exceptional because it had altered treatment. Patients with SUR1 and Kir6.2 mutations, even if longevity and of length of telomeres in the metabolic syndrome. We will insulin dependent, can improve control by replacing insulin injections with support the notion that exceptional longevity is associated with enrichment sulphonylurea tablets. in the several genotypes, and significant measurable phenotype. These Neonatal diabetes is now an area where a molecular genetic diagnosis is not a genotypes and their associated phenotype may play a role in conferring luxury but a necessity. A molecular diagnostic service is provided by centres survival to exceptionally old age by providing protection from the metabolic throughout the world including our own on www.diabetesgenes.org and is having syndrome and other endocrine manifestation of aging. a positive impact on the care of patients with neonatal diabetes.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Graves’ ophthalmopathy – problems solved and new homeostasis. Insulin sensitivity decreases rapidly and markedly without adequate questions to be answered compensation in beta cell function, resulting in an elevated risk of diabetes. Multiple factors appear to mediate this adverse impact of sleep loss, including PL6 increased sympathetic nervous activity, decreased brain glucose uptake and Graves’ ophthalmopathy: problems solved and new questions to be elevated evening cortisol levels. Reduced sleep quality, without change in sleep answered duration, is also associated with an increased risk of diabetes. Indeed, selective Wilmar M Wiersinga suppression of slow-wave sleep, a highly heritable trait, rapidly results in a Academic Medical Center, Amsterdam, The Netherlands. marked reduction in insulin sensitivity and disposition index. Prospective epidemiologic studies in children and adults are consistent with a role for sleep disturbances in the increased risk of diabetes. Sleep curtailment is also associated Graves’ ophthalmopathy (GO) remains the most enigmatic presentation of with a dysregulation of the neuroendocrine control of appetite. Under conditions thyroid autoimmunity. Although many issues regarding its pathogenesis and of controlled caloric intake and energy expenditure, there is a negative management have been solved, they are still outnumbered by unresolved open relationship between leptin levels and sleep duration. In a randomized cross- questions. over design study (2 days of 4-h versus 8-h bedtimes), leptin levels were Pathogenesis decreased and ghrelin levels increased during the short sleep condition, and the Orbital fibroblasts (OF) have been recognized as the primary target cells of the change in the ghrelin to leptin ratio was strongly correlated with increased hunger. autoimmune attack. Cytokine-induced excessive secretion of glycosaminogly- Thus, sleep loss may alter the ability of leptin and ghrelin to accurately signal cans and differentiation of a subset of OF into adipocytes cause swelling of caloric need. Consistent with the laboratory evidence, epidemiologic studies have extraocular muscles and orbital fat, explaining in a mechanistic sense symptoms shown an association between short sleep and higher BMI after controlling for a and signs of GO. The nature of the autoantigen on OF remains elusive, although variety of possible confounders. Taken together, the current evidence suggest that the TSH receptor is favoured over others (like the IGF-1 receptor). Attempts to chronic partial sleep curtailment, a novel behavior that appears to have developed develop a suitable experimental animal model are still unsuccessful. with the advent of the 24-h society, and reduced sleep quality may be involved in Clinical presentation the current epidemic of obesity and diabetes. Graves’ hyperthyroidism (GH) and GO apparently belong to the same disease entity, as the majority of GH patients have subclinical GO and euthyroid GO patients have TSH receptor autoantibodies. Why not all GH patients develop overt GO remains (apart from smoking) poorly understood; also why not all euthyroid GO patients develop overt GH. Whereas unilateral GO frequently evolves into bilateral GO many cases remain strictly unilateral for unknown Central regulation of appetite and body weight – the role of reasons. Most patients have increased muscle and fat volumes, but some have peripheral signals only increased muscle or fat volume, probably indicating various phenotypes with PL8 different immunopathogenesis. Management A cofactor network that controls PGC-1a activity and energy It matters for the eyes whether the patient is euthyroid and how euthyroidism is homeostasis restored, although controversy continues on the benefit of total thyroid ablation. Johan Auwerx There is broad agreement that immunosuppression is indicated only in active GO, Institut de Ge´ne´tique et de Biologie Mole´culaire et Cellulaire and Institut and that iv pulses of methylprednisolone are most effective. Anticytokine Clinique de la Souris, Illkirch, France. treatment (rituximab) is promising, but in its early stages. Combination treatment might be more efficaceous than monotherapy. Dysfunctional mitochondrial oxidative phosphorylation and diminished aerobic Prevention capacity are associated with metabolic, cardiovascular and neurodegenerative Discontinuation of smoking constitutes primary, secondary and tertiary diseases that eventually alter life span. We will discuss two distinct signalling prevention. Determinants of progression from mild to more severe GO are pathways to control energy expenditure that converge on the coactivator PGC-1a. incompletely understood, and hamper effective intervention (with selenium?) to In a first study we focussed on the polyphenol resveratrol, an activator of the class halt progression. III HDAC SIRT1, the mammalian Sir2 homolog. Resveratrol significantly increased aerobic capacity as evidenced by the doubling of time that mice run on a treadmill and by the increased oxidative capacity in muscle fibers ex vivo. This enhanced muscle performance was associated with an increase in expression of genes encoding for oxidative phosphorylation and mitochondrial biogenesis. When and why do we wake up – the endocrine regulation of These molecular events were largely explained by the resveratrol-mediated increase in PGC-1a activity, both through an increase in its expression level and a sleep in humans decrease in PGC-1a acetylation, fitting with the fact that resveratrol activates PL7 SIRT1. Importantly, the improved mitochondrial activity induced by resveratrol Decreased sleep duration and quality: novel risk factors for obesity and treatment protected mice against diet induced obesity and insulin resistance. In a diabetes second study, we characterized the role of SRC-3 in energy metabolism. SRC-1 and -2, two members of the p160 cofactor family were previously shown by us to Eve Van Cauter K/K The University of Chicago, Chicago, Illinois, USA. affect energy homeostasis. Differently from SRC-1 and -2 KO mice, SRC-3 animals weigh less under basal conditions, an effect which is accentuated by a high fat diet. This lean phenotype of SRC-3K/K mice is associated with increased Sleep curtailment has become a common behavior in industrialized countries. energy expenditure in BAT and skeletal muscle subsequent to enhanced Simultaneously, the aging of the population is associated with an increased mitochondrial activity. The effect on energy expenditure in the SRC-3K/K prevalence of sleep disturbances. These trends for shorter sleep duration and mice is dependent on the increase in both PGC-1a expression and activity, poorer sleep quality have developed over the same time period as the dramatic subsequent to its decreased acetylation. In combination, these data suggest that increase in the prevalence of obesity and diabetes. There is recent evidence to SRC-3 and SIRT-1 are critical links in a complex cofactor network that is indicate that chronic partial sleep loss and decreased sleep quality may increase governed by PGC-1a and that controls energy homeostasis. This work opens up the risk of obesity and diabetes. Studies in healthy volunteers have shown that new perspectives for therapeutic and preventive strategies for metabolic diseases. sleep restriction (4–6 h bedtimes) is associated with an adverse impact on glucose
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d:g2 \dA ) !2 rBs g_ j 10th European Congress of Endocrinology, Berlin, Germany, 2008
P18 Impact of total cumulative glucocorticoid dose on bone mineral density Conclusion in patients with 21-hydroxylase deficiency Our data show an over-expression of all studied genes (VEGF, VEGFR1, VEGFR2, Chakhtoura Zeina1, Bachelot Anne1, Samara-Boustani Dinane2, Ruiz EG-VEGF and SSTR1) in AC and APA compared to NA. The SSTR1 over- Jean-Charles1, Donadille Bruno3, Dulon Je´rome1, Christin-Maitre Sophie3, expression both in AC and in APA suggests potential therapeutic utility for SSTR1 Bouvattier Claire4, Raux-Demay Marie-Charles5, Bouchard Philippe3, selective agonist in the proliferative diseases involving angiogenesis. Finally we Carel Jean-Claude6, Leger Juliane6, Kuttenn Fre´de´rique1, Polak Michel2 described, for the first time, a relevant EG-VEGF over-expression in AC compared to & Touraine Philippe1 APA and NA. It will be interesting to evaluate the effect on EG-VEGF of the new 1Pitie´-Salpe´trie`re Hospital, Paris, France; 2Necker Hospital, Paris, France; inhibitors of tyrosin kinase which are currently used in anti-VEGF strategies in 3Saint Antoine Hospital, Paris, France; 4Saint-Vincent de Paul Hospital, human tumors. Paris, France; 5Trousseau Hospital, Paris, France; 6Robert-Debre´ Hospital, Paris, France.
Introduction P20 There are contradictory results concerning bone mineral density status in adult patients with congenital adrenal hyperplasia. To resolve this issue, we hypothesized Diagnostic potential of GC–MS urinary steroid profiling in the diagnosis of CAH due to 21-OH deficiency in neonates and infants that there could be a correlation between BMD and a total cumulative glucocorticoid 1 2 1 dose from the diagnosis in early infancy to adulthood. We then conducted a Michaela Hartmann , Eniko¨ Felszeghy & Stefan Wudy 1Justus Liebig University of Giessen, Children’s Hospital, Giessen, retrospective in a referral centers for CAH. Thirty-eight adult patients (28 women, 10 2 men, aged 16–39 years) suffering from CAH and treated since early infancy (24 with Germany; Department of Pediatrics, University of Debrecen, Debrecen, the salt-wasting form, 5 with the simple virilizing form and 9 with the non-classical Hungary. form) were included in the study. BMD was measured in the lumbar spine and femoral neck. Total cumulative dose (TCG) and total average (TAG) glucocorticoid 21-hydroxylase deficiency is by far (O90%) the most common cause of dose were calculated from pediatric and adult files. congenital adrenal hyperplasia (CAH). Undiagnosed and untreated Results 21-hydoxylase deficiency bears the risk of salt loss, adrenal insufficiency and CAH patients showed a significant difference between final height and target height sex misassignment, therefore early diagnosis is very important. The most K G K G ! ( 0.82 0.92 S.D. for women and 1.31 0.84 S.D.formen;P 0.001). There common way to identify children affected by the enzyme defect is the was a discrepancy between the 28 women and the 10 men for lumbar T-score measurement of blood levels of adrenal hormones and precursor steroids, K G K G Z ( 0.26 0.23 S.D. versus 1.25 0.42 S.D.; P 0.04) and femoral T-score which is an invasive method and may lead to inaccuracy due to maternal-placental G K G Z (0.21 0.25 S.D. versus 1.08 0.35 S.D.; P 0.009). Non-classical women had and fetal steroid products. We analyzed the urinary steroid profiles in neonates G K G Z higher lumbar T-score (0.33 0.46 S.D.versus 0.36 0.23 S.D.; P 0.003) and and young infants by GC–MS at time of diagnosis. The aim of the study was to G G Z femoral T-score (0.62 0.43 S.D. versus 0.20 0.32 S.D.; P 0.01) than salt- determine the most specific and sensitive parameters of 21-hydroxylase wasting women. There was a strong correlation between BMI and femoral BMD in deficiency. Twenty-seven children diagnosed with classical form of 21-hydroxy- Z ! patients (R 0.67; P 0.001). We found negative correlations between TCG, TAG lase deficiency,(14 boys, 13 girls; average age 37 (2–125) days) were included in ZK Z ZK Z and lumbar (R 0.38; P 0.02 and R 0.50; P 0.001, respectively) and the study and were compared with 47 healthy children (25 boys, 22 girls; average ZK Z ZK ! femoral T-scores (R 0.43; P 0.006 and R 0.51; P 0.001, respectively). age 43 (0–144) days). Random urine samples were analyzed for steroid hormone Conclusion metabolites and precursor/product ratios were calculated. Fetal zone steroids and Adult CAH patients, especially men, have lower BMD and this was correlated with cortisone metabolites were not discriminating. Indicators for 21-hydroxylase TCG. These results should help us in improving the management and the follow-up deficiency were: 15b,17a-dihydroxy-pregnanolone (15b,17a-OH-Po), pregnane- of BMD in CAH patients from childhood to adulthood. triol (PT), 11-O-pregnanetriol (11-O-PT), 5a,3a-pregnanolone (Po-5a,3a), 5b,3a-pregnanolone (Po-5b,3a). All parameters discriminated between CAH patients and healthy children by 100%. Differences were most expressed regarding 11-O-pregnanetriol.
Conc. in CAH (mg/l) Conc. in healthy Cases Parameters median (range) (mg/l) median (range) detected P19 15b,17a-OH-Po 4177 (496–28 077) 22 (1–175) 27/27 (100%) PT 1770 (183–17 715) 23 (3–133) 27/27 (100%) Angiogenic status of human adrenocortical tumors 11-O-PT 3390 (251–17 035) 4 (0–27) 27/27 (100%) 1 1 1 1 Barbara Mariniello , Paola Sartorato , Isabella Finco , Anna Patalano , Po-5b,3a 1981 (186–17 677) 21 (0–63) 27/27 (100%) Maurizio Iacobone2 & Franco Mantero1 1Endocrinology Unit, University of Padua, Padua, Italy; 2Endocrine Surgery Precursor/product ratios did not give more information to detect affected Unit, University of Padua, Padua, Italy. children. The advantage of urinary GC–MS analysis is that it is non-invasive and that it permits rapid and definitive diagnosis of 21-hydroxylase deficiency. Introduction Angiogenesis plays a major role in cancer growth and metastasis. Differences in angiogenesis and the balance of angiogenic growth factors and inhibitors may play a role in determining the observed variations in tumor behaviour. VEGF overexpression in adrenocortical carcinomas (AC) has been recently shown. Moreover a new steroidogenic specific tissue angiogenic factor (EG-VEGF) has been described, and its role is presently unknown in adrenal tumors. Previous P21 evidence showed that somatostatin SST1 receptor (SSTR1) selective agonist inhibits VEGF and VEGFR2 expression. 11b-hydroxysteroid dehydrogenase 2 activity is elevated in extreme obese subjects and negatively associated with insulin sensitivity Objective of the study 1 2 1 1 The aim of this study was to evaluate the expression of VEGF, VEGFR1, Karsten Mu¨ssig , Thomas Remer , Axel Haupt , Baptist Gallwitz , Andreas Fritsche3, Hans-Ulrich Ha¨ring1 & Christiane Maser-Gluth4 VEGFR2, EG-VEGF and SSTR1 genes in AC compared to aldosterone producing 1 adenomas (APA) and normal adrenals (NA). Division of Endocrinology, Diabetes, Angiology, Nephrology, and Clinical Methods Chemistry, Department of Internal Medicine, University Hospital of Tu¨bingen, Tu¨bingen, Germany; 2Department of Nutrition and Health, We analyzed the mRNA expression by real-time PCR in 11 AC, 20 APA and 7 NA. 3 Results Research Institute of Child Nutrition, Dortmund, Germany; Nutritonal and Preventive Medicine, Department of Internal Medicine, University Hospital of Tu¨bingen, Tu¨bingen, Germany; 4Steroid Laboratory, Department of VEGF VEGFR1 VEGFR2 EG-VEGF SSTR1 Pharmacology, University of Heidelberg, Heidelberg, Germany.
AC 87/11; *3.6 86/11; *3.5 85/11; *4.5 87/11; *52 86/11; *19 APA 811/20; *3.9 812/20; *4.9 88/20; *2.5 89/20; *5.8 817/20;*11 Objectives Alterations in glucocorticoid (GC) metabolism may contribute to the 8positive /total samples; *fold-increase compared to controls (NA). development of obesity and insulin resistance. We aimed to study the role of
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
11b-hydroxysteroid dehydrogenase type 2 (11b-HSD2) in human adiposity, P23 paying special attention to the association between altered GC metabolism and Effects of free fatty acids on adrenocorticotropin secretion and insulin sensitivity. metabolic glucocorticoid pattern in healthy young women Design 1 1 1 1 G 2 Knut Mai , Franziska Reinecke , Thomas Bobbert , Janin Andres , In 24-h urine samples of 72 extremely obese (mean BMI 45.5 1.1 kg/m ), but Volker Ba¨hr1, Stefan Wudy2, Michaela Hartmann2, Christiane Maser- otherwise healthy patients urinary free cortisol (UFF) and cortisone (UFE), Gluth3, Sven Diederich4, Andreas Pfeiffer1 & Joachim Spranger1 tetrahydrocortisol, 5a-tetrahydrocortisol, and tetrahydrocortisone were quantified 1Department of Endocrinology, Diabetes and Nutrition, Charite – University by RIA. The sum of the three major tetrahydrometabolites is an estimate for daily Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany; 2Steroid GC secretion, and the sum of UFF and UFE represents potentially-bioactive-free- G 2 Research Unit, Center of Child and Adolescent Medicine, Justus Liebig GCs. Thirty healthy lean subjects (BMI 22.3 0.3 kg/m ) served as controls. University, Giessen, Germany; 3Steroid Laboratory, Department of Results Pharmacology, Ruprecht-Karls-University of Heidelberg, Heidelberg, In obese subjects, absolute daily GC secretion and the potentially-bioactive-free- Germany; 4Endokrinologikum Berlin, Berlin, Germany. GCs were significantly (P!0.005) higher than in lean controls (11.8G0.7 vs 8.0G0.6 mg/d; and 171.8G11.2 vs 117.6G9.2 mg/d, respectively). However, when these values were corrected for body surface area (BSA), significant Introduction differences were no longer detectable. While enzyme activity indices for Free fatty acids (FFAs) affect pituitary function. While no effect of FFAs on 5a-reductase and 11b-HSD1 were similar in lean and obese subjects, 11b-HSD2 ACTH and cortisol seems to exist in men, data in women are somewhat was markedly elevated in adiposity (3.7G0.2 vs 2.1G0.1; P!0.0001). This controversial. Therefore, we aimed to assess the effect of an acute increase of increase was accompanied by a significant reduction of UFF excretion corrected circulating FFA levels induced by the infusion of a lipid-heparin infusion on for BSA (16.5G1.2 vs 21.7G2.0 mg/d per m2; PZ0.0222). Besides, 11b-HSD2 ACTH and cortisol secretion in healthy young women. activity was significantly correlated with insulin sensitivity (PZ0.0262). Methods Conclusions Following a 10-h overnight fast 13 healthy female volunteers were investigated in When body size is accounted for, both adrenal GC secretion and potentially- a randomised controlled cross-over trial. A 20% lipid/heparin (LHI) or bioactive-free-GCs are indistinguishable between lean and extremely obese saline/heparin (SHI) infusion was administered at a rate of 1.5 ml/min for 6 h. subjects. However, in obesity the kidney appears to intensify its supply of the ACTH, cortisol and 24 h urinary excretion of glucocorticoids were measured to direct substrate cortisone for extra-renal 11b-HSD1 which may fuel visceral assess steroid metabolism, the overall daily cortisol secretion and the enzyme adiposity and insulin resistance. activities of 5a-reductase, 21-hydroxylase and 11b-hydroxysteroid dehydro- genase Type 1 and 2. Results During SHI, both serum cortisol and plasma ACTH showed a progressive decline according to the circadian rhythm. The cortisol levels were not altered by LHI, resulting in higher levels compared to SHI, while the decrease in plasma ACTH P22 during LHI was comparable to the decline observed during SHI. No effects were found on daily urinary excretion rates of adrenal glucocorticoids, glucocorticoid Free fatty acids affect urinary excretion of androgen precursors thereby precursors or calculated activity of 5a-reductase, 21-hydroxylase and 11b-HSD1 linking metabolism and hyperandrogenemia in vivo: results of a and 2. randomized, controlled trial 1 1 1 1 Conclusion Knut Mai , Thomas Bobbert , Franziska Reinecke , Janin Andres , FFAs seem to have no effect on ACTH secretion in normal weight young women. ¨ 1 4 5 Volker Bahr , Christiane Maser-Gluth , Stefan Wudy , However the adrenal sensitivity to ACTH seems to be increased during LHI in 5 ¨ 1 2 Michaela Hartmann , Matthias Mohlig , Martin O Weickert , women, as no change in neither in 21-hydroxylase activity nor in cortisol Heinrich Schulte3, Sven Diederich3, Andreas Pfeiffer1 & Joachim Spranger1 1 degradation, excretion or in peripheral conversion exists. This effect may have Department of Endocrinology, Diabetes and Nutrition, Charite – University role in the development of obesity-associated complication. Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany; 2Depart- ment of Clinical Nutrition, German Institute of Human Nutrition Potsdam- Rehbru¨cke, Nuthetal, Germany; 3Endokrinologikum Berlin, Berlin, Germany; 4Steroid Laboratory, Department of Pharmacology, Ruprecht- Karls-University of Heidelberg, Heidelberg, Germany; 5Steroid Research Unit, Center of Child and Adolescent Medicine, Justus Liebig University, Giessen, Germany. P24 Association of diabetes mellitus and arterial hypertension in adrenal Context incidentaloma The polycystic ovarian syndrome (PCOS) is characterized by hyperandrogenism Milos Zarkovic, Jasmina Ciric, Biljana Beleslin, Slavica Savic, and associated with obesity and impaired glucose metabolism. Despite the high Mirjana Stojkovic, Djordje Marina & Bozo Trbojevic prevalence of PCOS and the considerable clinical impact, the precise interplay Institute of Endocrinology, Belgrade, Serbia. between metabolism and hyperandrogenemia is not entirely clear. We therefore aimed to analyse the relation between circulating free fatty acids (FFAs) and androgen metabolism in vivo in women. Background/objectives Design and participants The aim of the study was to assess association between diabetes mellitus (DM) Twelve healthy young women during the early follicular phase of two subsequent and arterial hypertension (AH) in patients with adrenal incidentaloma. cycles were investigated. A randomized controlled cross-over trial was Design and methods performed. Following a 10-h overnight fast, 20% lipid/heparin or saline/heparin One hundred and eleven consecutive patients with incidentally discovered adrenal infusion was administered at a rate of 1.5 ml/min for 5 h. tumours were included in the study. OGTT was done and 24 h urinary Main outcome measures catecholamines were measured. Aldosterone and plasma renine activity (PRA) Circulating androgens and their precursors as well as 24 h-urinary excretion of were determined, and 1 mg dexametasone test was performed. Insulin sensitivity free DHEA, DHEAS, androstenedione, androsterone (An), etiocholanolone (Et), (Si) was calculated using BIGTT test. Data are presented as meanGS.D. 5-androstene-3b,17a-diol, 5-androstene-3b,17b-diol, DHEA, 16a-hydroxy- Results DHEA, and 5-androstene-3b,16a,17b-triol) were measured. In our study group, there was significant association between DM and AH. Out of Results 13 DM subjects, 12 were also hypertensive. Out of 98 non-diabetic subjects 38 FFAs induced elevated circulating levels of androstenedione, DHEA, DHEAS, were normotensive and 60 hypertensive (Fisher exact test PZ0.031). As there testosterone, DHT, estrone and 17b-estradiol. Urinary excretion of DHEA, free was only one normotensive diabetic patient two-way analysis was not feasible. DHEAS, 5-androstene-3b,17a-diol and sum of urinary excreted DHEA and its Subjects with diabetes mellitus had significantly lower Si (7.32G3.05 vs 3.58G 16-hydroxylated downstream metabolites 16a-hydroxy-DHEA and 5-androstene- 0.84!10K5 (min!pmol)K1, PZ0.21) and higher cortisol after 1 mg dexame- 3b,16a,17b-triol were reduced by FFAs. tasone (86.7G90.4 vs 155.0G192.5 nmol/l, PZ0.05). Subjects with arterial Conclusions hypertension were older (57.6G8.6 vs 52.7G9.9 years) and had significantly Elevation of FFAs increases adrenal androgen precursors DHEA and DHEAS by lower PRA (1.84G1.59 vs 3.85G3.52 ng/ml per h) compared to normotensive lowering their urinary excretion in vivo in healthy young women. The here subjects. described mechanism might contribute to the development of hyperandrogenism Conclusions in women with PCOS and suggests novel therapeutic targets to treat those In adrenal incidentaloma subjects significant association exists between DM and patients. AH, probably caused by subclinical form of the Cushing’s syndrome.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P25 polymorphism and GC sensitivity in subjects with Cushing’s syndrome Dehydroepiandrosterone (DHEA) exerts a prominent effect on suggesting that this polymorphism might be associated with lower bone chromaffin PC12 cell differentiation processes mineral density. Christian G Ziegler, Heike Langbein, Vladimir Vukicevic, Stefan R Bornstein, Monika Ehrhart-Bornstein & Alexander W Krug Medical Clinic III, Dresden, Germany.
Within the adrenal gland, chromaffin cells and their progenitors are exposed to a wide variety of growth factors and hormones, including adrenal androgens such as DHEA. The DHEA producing-zona reticularis of the P27 adrenal cortex is in close proximity to the neural crest-derived catecholamine- Modulation of adrenocortical aldosterone and cortisol synthesis by producing chromaffin cells of the medulla, enabling strong paracrine in vitro oxidized low density lipoprotein interactions. In vivo studies in humans revealed that congenital adrenal Steffi Kopprasch, Ishrath Ansurudeen, Juergen Graessler, Stefan hyperplasia due to 21-hydroxylase (OH) deficiency results in androgen excess R Bornstein & Jens Pietzsch accompanied by severe adrenomedullary dysplasia and chromaffin cell 1Department of Internal Medicine 3, CG Carus Medical School, Dresden, dysfunction. Based on this evidence our in vitro study now aimed at further Germany; 2Department of Radiopharmaceutical Biology, Institute of elucidating the effect of DHEA on chromaffin PC12 cells on a molecular Radiopharmacy, Dresden-Rossendorf, Germany. level, focussing on cell survival and differentiation processes. We could show that DHEA significantly reduced nerve growth factor (NGF)- induced cell survival as well as neuronal markers, such as neurite outgrowth Objectives and expression of neuronal marker proteins, like SNAP-25 and VAMP-2. Oxidative stress is of critical importance in the pathogenesis of endocrinopathies. Accordingly, DHEA was found to stimulate the NGF-stimulated cells towards Since cholesterol serves as a major source of steroid hormone synthesis we a more neuroendocrine phenotype. Thus, DHEA largely elevated catechol- investigated the effect of hypochlorite-modified low density lipoprotein (LDL) on amine release from NGF-induced PC12 cells and enhanced expression of the aldosterone and cortisol release from human adrenocortical NCI-H295R cells. neuroendocrine marker chromogranin A. In a next step, we explored the Methods molecular mechanisms of DHEA and NGF interaction in more detail. We Native LDL obtained from healthy volunteers was oxidized to varying degrees by could further demonstrate that DHEA significantly reduced NGF-mediated sodium hypochlorite. The resulting modified LDL was biochemically charac- ERK1/2 MAPK activation. Differentiation as well as proliferation processes terized by gas chromatography–mass spectrometry (GC–MS) analysis. Human in PC12 cells are accompanied by ERK 1/2 activation. NCI-H295R cells were cultured in DMEM/F12. Aldosterone release in In summary, our data demonstrate that DHEA influences differentiation supernatants was measured by RIA and cortisol secretion was determined by processes in PC12 pheochromocytoma cells. DHEA drives the cells in the competitive luminometric assay. presence, but not in the absence, of NGF towards a more neuroendocrine Results phenotype. Our studies further suggest that this effect might be due to Incubation of LDL with sodium hypochlorite resulted in increasing concen- interference of DHEA with NGF-induced ERK1/2 activation by a rapid, so trations of the apolipoprotein B-100 oxidation markers HAVA, HACA, and called non-genomic signalling mechanism. 3-chlorotyrosine in dependence on the degree of oxidation. Incubation of adrenocortical cells with 10–100 mg/ml native or oxidized LDL for 24 h stimulated hormone release dose-dependently up to 3-fold. Subsequent stimulation of NCI-H295R cells with the physiological stimulus angiotensin II induced an additional hormone secretion up to 2.9-fold in LDL-pretreated samples. Compared to native LDL, oxidized LDL induced a smaller stimulation of hormone secretion that decreased with increasing degree of oxidation. Conclusion Oxidation of LDL may contribute to endocrine dysfunction by decreasing P26 adrenocortical aldosterone and cortisol release. Glucocorticoid receptor gene polymorphisms and bone mineral density in hpa axis disorders Giorgio Arnaldi, Gloria Appolloni, Paola Romagni, Marina Cardinaletti, Laura Trementino, Barbara Polenta, Carolina Concettoni & Marco Boscaro Division of Endocrinology, Marche Region, Ancona, Italy. P28 Glucocorticoid receptor (GR) gene polymorphisms have been associated with Establishment of a mutagenesis screen to identify mice with high interindividual variations in glucocorticoid sensitivity in healthy individuals. aldosterone levels Aim Ariadni Spyroglou1, Sibylle Wagner2, Jenny Manolopoulou1, Aim of this study was to investigate whether there was an association with Constanze Hantel1, Martin Reincke1, Martin Bidlingmaier1, Martin sensitivity to glucocorticoids and bone mineral density in HPA axis disorders. Hrabe´ de Angelis2 & Felix Beuschlein1 Methods 1Medizinische Klinik Innenstadt, Ludwig-Maximilians-University, Munich, We analyzed 3 polymorphisms of the GR gene (Bcl1, N363S, ER22/23EK) Germany; 2Institute of Experimental Genetics, GSF-National Research in 185 subjects: 52 patients with Cushing’s Syndrome (CS), 32 patients with Centre for Environment and Health, Munich, Germany. adrenal incidentaloma (AI), 101 healthy subjects (C). The patients were compared by anthropometric and clinical indices and bone mineral density (BMD) at spine and femoral neck levels. Genotype frequencies were According to recent studies, primary aldosteronism is considered to be assessed for each polymorphism. responsible for almost 10% of all cases of arterial hypertension. The genetic Results background of this common disease, however, has been elucidated only for The groups did not differ for age, sex, and BMI. Lumbar BMD was the rare familial types whereas in the large majority of sporadic cases it still significantly lower in CS and AI compared to C, while there were no remains unclear. In an attempt to define novel genetic mechanisms of differences in femoral neck BMD. Lumbar and femoral neck z-score was hyperaldosteronism we utilized a random mutagenesis screen after treatment significantly lower in CS compared to both AI and C. For N363S and with the alkylating agent N-ethylnitrosourea (ENU) and phenotypically ER22/23EK polymorphisms the allelic frequency was 1.89% and 0.81% characterized affected mice for their plasma aldosterone levels. As the respectively, so no associations with hormonal and bone parameters was detection method we used a time resolved fluorescence immunoassay, which evaluated. For BclI polymorphism, allelic frequencies were 28.1% in CS, allows the measurement of aldosterone in very small murine sample 27.8% in AI, 41.2% in C. Heterozygous C/G was more prevalent (P!0.03) volumes. Using this assay we determined the normal aldosterone values for in CS and AI (nZ16/32; P!0.03) than in C. After dexamethasone C3HeB/FeJ wild type mice under baseline conditions (meanGS.D.; 92G suppression test, CG carriers had lower cortisol levels than C/C carriers in 53 pg/ml for females (nZ69) and 173G114 pg/ml for males (nZ55)) and CS, while no significant differences were found in AI and CG. Only in the following specific stimulation and suppression tests. Subsequently, aldoster- lumbar spine a tendency towards lower BMD in CG carriers was found in one measurement was carried out in more than 2000 male and female F1 AI, while no differences were found in femoral neck BMD and z-score. offspring of chemically mutated inbred C3HeB/FeJ mice. Upon repeated Lumbar and femoral neck BMD and z-score did not differ in C/G carriers measurement, 7 female animals of the tested F1 offspring had consistently with CS. In conclusion, we found an association between Bcl I elevated aldosterone levels (defined as 3 S.D.’s above the mean of untreated
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 animals) measured at a mean of 456G104 pg/ml at initial time point. So far, pts, ACTH was inhibited in 8 pts, while UFC, cortisol, DHEAS and 17OHP no affected male mice have been detected. Further breeding of affected levels were in the normal range in all pts. In 39 pts (57%) cortisol levels after female animals gave rise to F2 pedigrees from which one established line Nugent test were!1.8 mg/dl and no further hormonal evaluation was displays high aldosterone values in 50% of littermates as would be expected performed. In 7 pts (10%) post-Nugent cortisol levels wereO5.0 mg/dl and from an autosomal dominant trait of inheritance. These animals will serve in 5 cases Liddle I test confirmed the existence of SCS. In 23 pts (33%) post- for detailed phenotypic and genetic characterization in the future. Taken Nugent cortisol levels were between 1.8 and 5.0 mg/dl and Liddle I test in 13 together our data demonstrate the feasibility of a phenotype-driven cases confirmed the existence of SCS. The hormonal work-up demonstrated mutagenesis screen to detect and establish mutant mouse lines with a that 70% (51/73) of the masses were non-hypersecretory, 5% (4/73) were high aldosterone phenotype. pheocromocytoma, 25% (18/73) were SCS. No significant difference was found in mass size, while a slight higher percentage of patients in the SCS group showed impairment in blood pressure, glucose tolerance, lipid profile and bone metabolism. Four SCS pts were operated, without a significant clinical improvement, while, in the other SCS pts, no significant progression P29 of the disease was observed. Further studies on large populations are needed to clarify the clinical impact of SCS as well as the effects of adrenal mass Late night salivary cortisol in the diagnosis of Cushing’s syndrome removal. Jeyaraman Kanakamani, Gupta Nandita & AC Ammini All India Institute of Mediacl Sciences, New Delhi, India.
Introduction Late night salivary cortisol appears to be promising as a simple stress-free P31 screening test for Cushing’s syndrome (CS). But there is no consensus on the cut- Follow-up in a group of 166 adrenal incidentaloma patients off value because of the lack of availability larger studies and of standardization Anna Bohdanowicz-Pawlak, Jadwiga Szymczak & Ewa Waszczuk of assays. The normal reference ranges are assay-dependent and should be Department of Endocrinology, Diabetology and Isotope Therapy, Medical validated for each laboratory. University Wrocław, Wrocław, Poland. Objective The purpose of this study was to evaluate the usefulness of late-night salivary cortisol in the diagnosis of CS. The adrenal incidentalomas have become a common clinical problem. In the vast Methods majority of cases these masses are non- secreting adrenocrotical adenomas. We studied 49 normal subjects and 52 patients with suspected hypercortisolism. However, some may show minor endocrine abnormalities with a subclinical Salivary cortisol was collected at 0800 h and 2300 h using a commercially- hyperfunction or represent malignancies. available salivette and measured by an automated chemiluminescence assay. The Objectives study was approved by the Institute’s ethical committee. The aim of the study was to analyze and follow-up of incidentalomas and to Results establish the risk factors for mass enlargement and/or hormonal disturbances. Out of 52 patients 20 were confirmed to have CS and in the remaining CS was Material and methods excluded by dexamethasone suppression test. The 2300-h salivary cortisol of One hundred and sixty-six patients, mean age 56, with adrenal incidentalomas patients with CS was significantly higher (1.24G0.86 mg/dl), as compared with were investigated in our Department in 1995–2006 years. Endocrine evaluation patients in whom CS was excluded (0.109G0.076 mg/dl). The 0800-h cortisol consisted of serum cortisol profile, ACTH, DHEA-S, aldosterone and plasma was also significantly higher in CS (1.70G1.40 vs 0.240G0.132 mg/dl). The loss renin activity as well as 24 h urinary free cortisol, aldosterone and metanefrines of circadian rhythm highlighted by 0800-h to 2300-h cortisol of ! 2 was found in excretion. 17 of 20 CS patients. The upper limit of the reference range for 2300 h salivary The adrenal tumors were revealed by ultrasound scan, MRI or CT scan of the cortisol was calculated nonparametrically as 0.311 mg/dl, from the data on normal abdomen performed for unrelated reasons. Body mass index and blood pressure subjects. Two of 20 patients with proven CS had 2300-h salivary cortisol less than were investigated. The follow-up period was in range of 1–10 years. the calculated upper limit of the reference range, yielding a sensitivity of 90%; Results one of these 2 patients had intermittent hypercortisolism. Unilateral adrenal masses were found in 147 patients (right – 89, left – 58), while Conclusion bilateral masses were present in 19 patients. Mean diameter of the adrenal Late-night salivary cortisol measurement is a simple and reliable screening mass was 3.6 cm (range 0.5–9). Ninety-four patients were overweight/obese test for Cushing’s syndrome. A cut-off value of 0.311 mg/dl gives a sensitivity of (BMIO25), 99 patients had hypertension. 90% and specificity of 96.8%. Larger studies and wider availability of In 133 patients the endocrine function was normal initially. Thirty-five persons validated commercial assays are needed before it could be used as first line demonstrated hormonal disturbances without clinical symptoms: 26 persons screening test. developed subclinical hypercortisolism, 5 showed increased 24 h urinary level of metanefrines and 2 exhibited hyperaldosteronism. In 21 patients we observed enlargement of adrenal masses during follow-up. The operation because of tumor size or hormonal function was performed in 83 patients. The adrenal cancer was diagnosed in 3 patients and bilateral metastases into adrenals in 3 persons. Conclusions A careful biochemical and imaging follow-up is advisable in all patients with adrenal incidentaloma because in some of them the hormonal hyperfunction or P30 malignancy development is likely. Hormonal, metabolic and bone evaluation in a series of adrenal incidentalomas Lorenza Bonelli, Roberta Giordano, Marcella Balbo, Rita Berardelli, Elisa Marinazzo, Ezio Ghigo & Emanuela Arvat University of Turin, Turin, Italy. P32 Assessment of left ventricular functions by tissue Doppler echocardio- graphy in patients with Cushing’s disease Clinically silent adrenal masses discovered by abdominal imaging procedures Nihal Akar Bayram1, Reyhan Ersoy2, Cevdet Aydin2, Kamile Gul2, performed for non-adrenal disorders, i.e. adrenal incidentalomas, have Telat Keles1, Oya Topaloglu2, Tahir Durmaz1, Engin Bozkurt1 & become a common finding in clinical practice and they represent a clinical Bekir Cakir2 concern because of the risk not only of malignancy but also of subclinical 1Department of Cardiology, Ankara Ataturk Education and Research hormonal hypersecretion (SCS) that represents a new risk factor for Hospital, Ankara, Turkey; 2Department of Endocrinology and Metabolism, cardiovascular diseases and/or osteoporosis. We studied 73 patients (39F, Ankara Ataturk Education and Research Hospital, Ankara, Turkey. 34M; meanGS.E.M.: 61.6G1.3 year) with incidentalomas. In all patients the following measures were performed: urinary metanephrines, aldosterone/PRA ratio, UFC, cortisol, ACTH, DHEAS, 17OHP levels, Nugent and Liddle I Objective tests. BMI, blood pressure, OGTT, serum lipids and DEXA were also To verify whether tissue Doppler imaging (TDI) could contribute to a measured. In 4 pts a biochemical diagnosis of pheocromocytoma was made. better understanding of the natural history of cardiomyopathy in active No case of primary hyperaldosteronism was demonstrated. In the others 69 Cushing’s disease (CD), through its enhanced sensitivity to diastolic dysfunction,
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 and identifying preliminary regional signs of systolic dysfunction, before the P34 appearance of clinical symptoms of cardiac pathologies. Renal excretion rates of free cortisol, free cortisone and dehydroe- Methods piandrosterone metabolites, but not renal indices of cortisol secretion Eleven women with newly diagnosed CD, and 15 control cases, purposely are associated with urinary volume in healthy children matched for gender, age, body mass index and co-incidental diseases were Lije Shi1, Stefan A Wudy2, Christiane Maser-Gluth3, Michaela F Hartmann2 enrolled in this study. Conventional echocardiography and TDI examinations & Thomas Remer1 were performed with Vingmed System 7 (Vivid 7 Pro; Horten, Norway) using a 1Research Institute of Child Nutrition, Dortmund, Germany; 2Steroid 2.5-to 3.5-Mz transducer, and carried out by a single experienced cardiologist. Research Unit, University of Giessen, Giessen, Germany; 3Department of The peak systolic velocity (S’m), early diastolic myocardial peak velocity (E’m), Pharmacology, University of Heidelberg, Heidelberg, Germany. late diastolic myocardial peak velocity (A’m), isovolumic acceleration (IVA), myocardial pre-contraction time (PCT’m), myocardial contraction time (CT’m) Background and myocardial relaxation time (RT’m) were measured at septal (S) and lateral In experimental studies, a high fluid intake and a corresponding high urine volume (L) mitral anulus. have been shown to increase renal excretion rates of urinary free cortisol (UFF) Results and cortisone (UFE) in adults. We aimed to examine whether 24-h urinary steroid In TDI, E’mL, E’mS, E’mL/A’mL ratio, and E’mS/A’mS ratio were significantly excretion rates are also affected by urine volume in children. lower (P!0.05), and PCT’mL/CT’mL ratio and PCT’mS/CT’mS ratio were Methods higher (P!0.05), S’mL, S’mS, A’mL, A’mS, PCT’mL, PCT’mS, CT’mL, In 24-h urine samples of 100 prepubertal and 100 pubertal healthy children IVRT’mL and IVRT’mS values were similar in patients with CD than controls UFF, UFE, tetrahydrocortisol, 5a-tetrahydrocortisol, and tetrahydrocortisone (PO0.05). Lateral and septal annulus IVA were significantly lower in patients were quantified by RIA. Urinary dehydroepiandrosterone and its 16a- with CD than the control group (P!0.05). Correlation analysis showed that IVA- hydroxylated downstream metabolites (DHEA&M) were analyzed along with L correlated positively with S’mL (rZ0.58; PZ0.002) and IVA-S correlated the above three glucocorticoid tetrahydrometabolites using GC–MS in two positively with S’mS (rZ0.51; PZ0.008). additional groups of prepubertal (nZ100) and pubertal (nZ100) children. Conclusion The sum of the 3 primarily glucuronidated tetrahydrometabolites (GC3) The present study is the first study evaluating left ventricular functions in patients reflects daily cortisol secretion and DHEA&M represents an index of with active CD by TDI. We recommend using TDI, in addition to conventional adrenarchal androgen secretion. Associations of urine volume with outcome echocardiography parameters for the cardiovascular risk assessment of patients variables UFF, UFE, GC3, and DHEA&M were examined in each with Cushing’ syndrome. developmental group using multiple regression models adjusted for sex, body weight, height, and total energy intake. Results Significant positive associations were observed between 24-h urine volume and UFF, UFE and DHEA&M in the respective prepupertal and pubertal groups with the highest explained variation for UFE, especially in puberty (R2Z0.24). However, GC3 was not significant in any of the groups. P33 Conclusion Urinary 24-h excretion rates of UFF, UFE, and DHEA&M, but not Salt wasting form of classic congenital adrenal hyperplasia (cah) due to glucocorticoid secretion parameters are affected by daily urine volume in 21-hydroxylase deficiency: an overview in adult life healthy free-living children. For a more specific assessment of associations of Anna Castera`s Roma´n, M Concepcio´nPa´ramo Ferna´ndez, Laura UFF, UFE, or DHEA&M with (patho)physiologically relevant factors, urine Fajar Rodrı´guez, Beatriz Mantin˜a´n Gil, Paula Sa´nchez Sobrino, Reyes volume should be considered as a confounder. Luna Cano & Ricardo Vı´ctor Garcı´a-Mayor This work was supported by a grant from European Chemical Industry Council Hospital Xeral, Vigo, Spain. (Cefic).
Background Classic 21-hydroxylase deficiency, due to severe mutations in CYP21B gene, is an uncommon disease (1/ 150 000). Salt-wasting form accounts for 75% of the cases and turns up with gluco- and mineralocorticoid deficiency as well as feminine hermaphroditism. Although wide psycho-social repercussion especially in women is known, the rarity of the disease and losses in follow-up may lead to a P35 scarce clinical experience. We present 3 adult patients with CAH- SW followed regularly at our outpatient clinic. Glucocorticoids and body fat are associated with urinary excretion rates of uric acid and oxalate, but not of calcium in healthy children Case 1. 21-year male 1 1 1 2 Mutation in CYP21B: G656// Q318X/ R235W. Salt-wasting crisis in neonatal Lijie Shi , Shoma Berkemeyer , Annette Buyken , Christiane Maser-Gluth & Thomas Remer1 period. Frequent descompensations in childhood with banal infections. 1 2 Phaco-emulsification of bilateral steroidal cataract at 16 years. Psycho-social: Research Institute of Child Nutrition, Dortmund, Germany; Department of low academic performance, but he’s working and leads an adequate social life. Pharmacology, University of Heidelberg, Heidelberg, Germany. Height: 1.64 m, weight: 65 kg. Pectum excavatum. Low extremities’ lymphe- dema. Current hormonal study: 17OHProgesterone: 20.8 ng/ml, plasma renin Background activity: 2.92 ng/ml per h, total testosterone: 6.75 ng/dl, free testosterone: In patients with hypercortisolism, who are frequently obese, the prevalence of 16.3 pg/ml. urolithiasis is increased and urinary excretion rates of calcium (Ca), oxalate (Ox), Case 2. 18 year woman (sister of 1) and uric acid (UA) are regularly elevated. In the present study, we examined G656// Q318X/ R235W. Neonatal genital ambiguity. Clitoroplasty at 2 years old. whether these lithogenic factors are already associated with dietary intakes, body Periodic vaginal dilatation. Frequent descompensations in childhood with banal fat, and cortisol metabolites in free-living children. infections. Menarche at 13 years, regular menses. Low academic performance, Methods mutism, few and poor affective extrafamiliar relationships. 1.43 m, 66.5 kg. Low In 24-h urine samples of healthy children (150 boys, 150 girls, aged 4–14 years) extremities lymphedema. 17OHP: 74.7, PRA: 3.27, androstendione: 2.9 ng/ml. urinary free cortisol (UFF), cortisone (UFE), the sum of 3 major glucocorticoid Case 3. 30 year woman metabolites (GC3) as well as Ca, Ox, UA and net acid excretion (NAE) were Delection CYP21B/del8pb. Neonatal genital ambiguity. Clitoroplasty and determined cross-sectionally along with relevant nutritional and anthropometric vaginoplasty at 2 and 4 years. Permanent urinary incontinence. Epilepsy. parameters. Potentially-bioactive-free-glucocorticoids were assessed as UFFC Multiple hospital admissions in child and adulthood. Osteoporosis. Menarche at UFE and adrenal glucocorticoid secretion as GC3. Associations of diet, percent 11 years, amenorreic periods. Personality disorder, uninhibited behaviour, body fat (%BF) and glucocorticoids with outcome variables were examined in hypersexuality, neglected hygiene, family dependence. 1.58 m, 75 kg. Severe multiple regression models adjusted for sex, age, height, growth velocity and total hirsutism, red-wine striae, hyperpigmentation. 17OHProgesterone: 200, PRA: 20, energy intake. androstendione: 8. Results Comments Positive associations with the urinary outcomes Ca, Ox, and UA were Management of adult patients with classic CAH needs to be tight, multi- observed for the nutritional factors Ca, fiber, and protein intake, disciplinary and specialized, having particular care for psychosocial adaptative respectively, for sodium intake (outcomes: Ca, UA), and for the indicator disorders. Interaction of chronic steroid treatment and androgenic excess of dietary acid load NAE (outcomes: Ca, Ox, UA). %BF and cortisol determines high morbidity mainly in affected women. secretion (GC3) were both positive predictors of UA and Ox. Of all dietary and hormonal variables, UFFCUFE explained most of the variation (partial
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
R2Z0.08, P!0.0001) of urinary UA and also part of the variation of Ox studies. Long term outcome and health care costs of hypo- and normokalemic (partial R2Z0.02, P!0.05), but none of Ca. variants are largely unknown. The National Conn’s Registry is an initiative to Conclusion create a national database of sufficient epidemiological strength to investigate Apart from the known nutritional determinants, such as protein and sodium co-morbidity and mortality in these patients. intake, also dietary acid load and increased body fatness appear to affect urinary Methods Ca, Ox and UA. Additionally, higher potentially-bioactive-free-glucocorticoids, The registry has at present 7 participating centres in 5 locations and uses an even in the physiological range, may contribute to stone forming risk via electronic database to assure comparison of different centres. Since 07/2006 elevations in UA and Ox, but not Ca. retrospective data were included in the database from patients with Conn’s syndrome diagnosed between 1990 and 2007. Results Evaluation of the retrospective data entry provide the following results: Of the 726 patients (60.4G13.7 years, range 6–96 years), 54.3% had the hypokalemic P36 variant of the disease. The mean RR was 158G29 mmHg systolic and 94G Aberrant cortisol responses in adrenal incidentalomas: a study on 16 mmHg diastolic. Morbidity of cerebrovascular events (TIA, PRIND, stroke) in evaluation and management of 20 patients the overall cohort was high with 9.6% of patients. The prevalence of Me´lanie Priou1, Catherine Draunet Busson1, Fre´de´ric Illouz1, cardiovascular morbidity (angina pectoris, myocardial infarction, coronary Antoine Hamy2, Elsa Parot Schinkel3, Patrice Rodien1 & Vincent Rohmer1 angioplasty) was 13.5% in our cohort. Atrial fibrillation occurred in 8.4% of 1Department of Endocrinology, University Hospital of Angers, Angers, the patients and other atrial or ventricular dysrhythmia in 5.5% of the patients. France; 2Department of Surgery, University Hospital of Angers, Angers, Chronic renal failure was present in 10.9% of patients, and sleep apnea in 8.1% of France; 3Clinical Research Center, University Hospital of Angers, Angers, patients. Overall co-morbidities were more frequent in hypokalemic than in France. normokalemic individuals. Conclusion Our data show high proportion co-morbidites for Conn’s syndrome, which In overt or subclinical ACTH-independant Cushing’s syndrome (CS), aberrant is endorsed by previous results from France describing a 3–4 fold higher adrenal receptors may control cortisol secretion. prevalence of stroke, myocardial infarction and atrial fibrillation in a small cohort We systematically studied the 20 patients with adrenal incidentaloma screened in of primary aldosteronism (nZ124) compared to patients with essential our department for illegitimate adrenal receptors between 2000 and 2006. We hypertension (nZ465). In addition, our data demonstrate evidence that the investigated plasma cortisol level during successive stimulation tests performed hypokalemic variant of Conn’s syndrome has a higher morbidity than the while dexamethasone was given orally every 8 h (upright posture, meal, normokalemic variant. hypothalamic hormones, terlipressin, angiotensin II, metoclopramide and/or octreotide). Subjects were considered as responders if their plasma cortisol level increased at least by 25% after one or several tests without any parallel elevation of ACTH. Fourteen patients were responders, 11 of them responded to several tests. The most constant responses occurred after terlipressin (85% of explored subjects), suggesting aberrant vasopressin receptors in these patients. Neither clinical, biological or hormonal features nor adrenal tumour dimension nor noriodocho- P38 lesterol uptake were predictive of illegitimate cortisol response. The responders Retrospective clinical data on more than 160 pheochromocytoma in rate did not differ significantly between unilateral adrenal adenomas (69.2%, Z Z three east german endocrine centers n 13) and bilateral macronodular adrenal hyperplasias (71.4%, n 7). Ten Robert Kopetschke1, Aylin Kilisli1, U Tuschy2, Henri Wallaschofski3, patients with features of subclinical CS, including eight responders, underwent Wolfgang Oelkers4, Manfred Ventz1 & Marcus Quinkler1 adrenal surgery. Metabolism abnormalities and bone mineral density did not 1Klinische Endokrinologie, Charite´ Campus Mitte, Charite Universita¨ts- improve clearly afterwards. medizin Berlin, Berlin, Germany; 2Bereich Endokrinologie, 2. Medizinische In 3 prospective studies evaluating aberrant adrenal receptors in subclinical Klinik, Helios Klinikum Erfurt, Erfurt, Germany; 3Klinik fu¨r Innere CS, each patient presented with illicit cortisol response(s). In accordance Medizin A, Ernst-Moritz-Arndt-Universita¨t, Greifswald, Germany; with our results, vasopressin and its analogues induced the most constant 4Endokrinologikum Berlin, Berlin, Germany. responses in these studies. They differed from our procedure in 2 points: dexamethasone was administered during explorations in only two of these studies and cortisol responses mediated through an elevation of plasma Objective ACTH were excluded in none of them. Adrenalectomy is still controversial Pheochromocytoma is a rare disease with an incidence of 2–6 per million, and a in the management of subclinical CS. In our study, it resulted in no obvious prevalence of 0.1–0.6% in patients with hypertension. Pheochromocytoma may metabolic or bone benefit. In the future, medications targeting aberrant occur sporadically or as part of hereditary syndrome. According to the latest responses may be an alternative for these patients. studies, among patients with non-syndromic pheochromocytoma, up to 24% of tumors may be inherited. However, genetic testing was not generally performed until recently. There is still a debate which pheochromocytoma patient should be tested for hereditary syndrome. We started an initiative to create a database of sufficient epidemiological strength to investigate pheochromocytoma in P37 more detail. The German Conn’s registry: comorbidities in over 700 patients with Methods primary hyperaldosteronism The preliminary registry has at present 3 participating centres in 3 locations and Eric Born-Frontsberg1, Caroline Schirpenbach2, Stefanie Hahner3, uses an electronic database to assure comparison of different centres. Since Felix Beuschlein2, Martin Bidlingmaier2, Sven Diederich4, R Lorenz5, 07/2006 retrospective data was included in the database from patients with Lars Rump6, Jochen Seufert7, Stefan Endres2, Marcus Quinkler1 & pheochromocytoma between 1973 and 2007. Martin Reincke2 Results 1Klinische Endokrinologie, Charite´ Campus Mitte, Charite Universi- Evaluation of the retrospective data entry shows the following results: Of the 166 ta¨tsmedizin Berlin, Berlin, Germany; 2Medizinische Klinik Innenstadt, patients (49.3G14.4 years, range 12–81 years, 49.4% males), 115 pheochromo- Ludwig-Maximilians-Universita¨tMu¨nchen, Mu¨nchen, Germany; cytomas were unilateral (64 right, 53 left), 19 bilateral, and 4 extraadrenal (no 3Medizinische Klinik und Poliklinik I, Julius-Maximilians-Universita¨t, information in 28 patients). The mean size of unilateral pheochromocytoma was Wu¨rzburg, Germany; 4Endokrinologikum Berlin, Berlin, Germany; 64G25 mm. Fourteen pheochromocytoma were diagnosed as malignant, with 5Institut fu¨r Prophylaxe und Epidemiologie der Kreislaufkrankheiten, only 10 patients showing evidence of metastasis. Genetic testing was performed Ludwig-Maximilians-Universita¨tMu¨nchen, Mu¨nchen, Germany; in only 31 patients revealing a hereditary syndrome in 13 patients (8 RET, 3 VHL, 6Marienhospital, Ruhr-Universita¨t Bochum, Herne, Germany; 2 NF1). In addition, a hereditary syndrome was diagnosed clinically in 21 patients 7Medizinische Klinik II, Albert-Ludwigs-Universita¨t, Freiburg, (14 MEN, 4 VHL, 3 NF1). Germany. Conclusion In general, documentation and follow-up of patients with pheochromocytoma was insufficient over the recent years. This emphasizes the need for a clinical national Objective registry including follow-up information of the patients. In our cohort 34 patients Hypokalemic Conn’s syndrome is a rare disease with a prevalence of 0.5% in (20.5%) had a hereditary form of pheocromocytoma, which is in accordance to unselected hypertensive populations. However, recent studies indicate a higher previous studies. prevalence of a milder variant of Conn’s syndrome, reaching 10% in some
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P39 was documented in 81.4% of patients, but used as first diagnostic step in only Impaired endothelial morphology and function in patients with 64.7% (range 43.3–79.1% depending on centre). In 35.3% (range 20.9–56.7%) of subclinical Cushing’s syndrome due to single adrenocortical adenomas patients, the first documented biochemical result was obtained already during a Ioannis Androulakis1, Georgios Kollias2, Athina Markou1, Aggeliki Gouli1, confirmatory or differential diagnostic test (salt load, posture test, lasix-renin test, Tilemachos Anagnostou1, Kimon Stamatelopoulos2, Christos Papamichael2, adrenal vein sampling). Urinary aldosterone was analysed in only 4.6% of Georgios Piaditis1 & Gregory Kaltsas3 patients. ARR was documented in 66.7% (range 89.4–43.6%) during the first 1Department of Endocrinology and Diabetes Center, General Hospital of week of diagnosis. Documentation of variables potentially influencing ARR was Athens ‘G Gennimatas’, Athens, Greece; 2Vascular Laboratory, Department poor (medication 70%, K 42.5%). Medication was adequately paused in 93.2% of Clinical Therapeutics, Alexandra University Hospital, Athens, Greece; (mineralocorticoid receptor antagonists) and 59.4% (beta blocker). About 67% of 3Endocrine Unit, Department of Pathophysiology, University of Athens, patients were normokaliaemic at ARR determination. ARR values were Athens, Greece. calculated from 8 different combinations of assays (A plus RA or RC), with one or more changes in methods during the observational period in 6 of 7 centres. Mean A, RC and RA concentrations differed significantly between methods, as Background did the corresponding ARR. The highest ARR was observed for the combination Subclinical Cushing’s syndrome (SCS) due to incidentally discovered adrenal Adalits A/Adaltis RA and DPC A/Nichols RC. In conclusion, diagnostic adenomas (AI) has been associated with increased prevalence of hypertension, strategies differed between centres, which might also be reflected in a different obesity, and impaired glucose tolerance which are established risk factors for composition of patient’s populations. cardiovascular morbidity. Although functional and morphological (structural) changes of endothelium have been correlated with cardiovascular morbidity this has not been looked into detail in patients with adrenal incidentalomas. Subjects and methods Endothelial morphology and function was studied using high resolution linear P41 array ultrasound by measurement of carotid artery intima-media-thickness (IMT) and brachial artery flow-mediated dilation (FMD) in 15 patients with SCS due to Addison’s disease: aetiological role of oncological factors 2 AI (54.8G2.3 years, BMI 27.9G1.07 kg/m ) (meanGS.E.M). Twenty age, gender Anna Kasperlik-Załuska, Barbara Czarnocka, Lucyna Bednarek-Papierska and BMI matched patients with non functioning AI (NFAI) (53.1G2.2 years, & Wojciech Zgliczyn´ski BMI 27.3G0.6) were also studied and served as controls. Patients with SCS had Medical Center of Postgraduate Education, Warsaw, Poland. incomplete inhibition of serum cortisol levels after a formal low dose 2 days 2-mg DXM suppression test. All subjects had no evidence of cardiovascular disease Autoimmune destruction of the adrenocortical cells is the most frequent form of and/or diabetes mellitus and had normal 24 h urine catecholamine levels and no Addi-son’s disease, however modern imaging methods make possible to discover evidence of autonous aldosterone secretion. Systolic and diastolic blood pressure bilateral neoplastic laesions resulting in adrenal insufficiency more frequently and the following fasting concentrations were measured: glucose, insulin, than about twenty years ago. In our group of 315 patients with Addison’s disease triglycerides, total cholesterol, high and low density lipoproteins, fibrinogen, we diagnosed metastatic infiltrations of the adrenals in 18 cases and lymphoma of homocysteine. Insulin sensitivity was assessed by the homeostasis model both adrenals in four cases (in sum 7%). Typical clinical signs, biochemical assessment index (HOMA). abnormalities and results of hormonal examinations (low cortisol, high ACTH Results levels, lack of adrenal reserve during ACTH stimulation) were present in majority G Patients with SCS had higher IMT values than patients with NFAI (0.99 of them. In six cases pre-Addison’s disease was diagnosed, presenting with G Z G G 0.07 mm vs 0.83 0.03, P 0.038) and lower FMD levels (3.1 0.44% vs 4.3 fatigability and increased ACTH concentrations. Z 0.38, P 0.039) suggesting both functional and morphological endothelial A specific form of adrenal insufficiency has been observed in patients with G G dysfunction. HOMA index was significantly lower in SCS (1.94 0.34 vs 3.05 adrenal cancer, treated with mitotane, an adrenolytic agent. In such cases higher Z 0.33 mmol/mU per l, P 0.039) reflecting a significant reduction in insulin replacement doses of hydrocortisone, than in classic Addison’s disease, were sensitivity. No differences were found in fasting glucose levels, lipid profile and necessary (quick conversion to inactive forms of steroids, increased transcortin blood pressure. levels). In our material of 194 patients with adrenal cancer mitotane was Conclusion administered in a long-term therapy in 168 cases. In 18 out of 50 survivors it was Patients with mild subclinical autonomous cortisol excess due to AI exhibit possible to withdraw mitotane within four to five years of therapy, however in two impaired endothelial function and morphology. This could be linked to patients a continuous adrenal insufficiency has been observed. subsequently increased risk for cardiovascular diseases. Conclusions A relationship of adrenal insufficiency with oncology is evident however it is not a frequent finding.
P40 Comparison of strategies for biochemical diagnosis of primary aldosteronism in German academic centres S Reuschl1, C Schirpenbach1, S Hahner3, F Beuschlein1, S Diederich4, P42 R Lorenz5, LC Rump6, J Seufert7, S Endres1, M Quinckler2, M Reincke1 & Diurnal salivary cortisol in young adult-onset diabetes mellitus Type 1 M Bidlingmaier1 patients 1Medizinische Klinik Innenstadt; Ludwig-Maximilians-Universita¨t, Katerina Simunkova1, Karel Vondra1, Martin Hill1, Lubomir Kriz1, Munich, Germany; 2Klinische Endokrinologie, Charite´ Campus Mitte, Vaclav Zamrazil2, Hana Kvasnickova1, Denisa Janickova-Zdarska2 & Charite Universita¨tsmedizin, Berlin, Germany; 3Medizinische Klinik und Richard Hampl1 Poliklinik I, Julius-Maximilians-Universita¨t, Wu¨rzburg, Germany; 1Institute of Endocrinology, Prague, Czech Republic; 2Universitity Hospital 4Endokrinologikum, Berlin, Germany; 5Institut fu¨r Prophylaxe und Motol, Department of Diabetology, Prague, Czech Republic. Epidemiologie der Kreislaufkrankheiten, Ludwig-Maximilians-Universita¨t, Munich, Germany; 6Marienhospital, Ruhr-Universita¨t Bochum, Herne, Germany; 7Medizinische Klinik II, Albert-Ludwigs-Universita¨t, Freiburg, Detailed information on adrenal function in autoimmune Type 1 diabetes with Germany. onset in adult age is still missing. This work compared diabetics with low response (LR) to diabetics with normal response (NR) to low dose ACTH test and control group (C). Recent studies indicating that normokaliemic primary aldosteronism (PA) is a Thirty-two diabetics were investigated; LR (nZ16), NR (nZ16), age 44G10 more frequent cause of hypertension than previously expected led to an increased years (meanGS.D.), age at diagnosis 28.5G10 years, disease duration 15G8 interest in biochemical screening strategies. We investigated biochemical years, BMI 24.5G2.7 kg/cm2, HbA1c 7.2G1.2%. Control group consisted of 16 diagnostic strategies used in different academic centres for patients documented healthy subjects; age 27G6 years, BMI 21.7G2.3 kg/cm2. Neither group showed in the German National Conn’s Registry. Data from 7 centres in 5 cities have been any clinical signs of adrenal disorders or adrenal laboratory autoimmunity. The entered into a database by trained personnel. For analysis, results from 522 study was approved by local Ethical Committee. Adrenal reserve was tested by patients with documented results of measurements of aldosterone (A) in plasma or low dose ACTH test. Adrenal autoantibodies, plasma renin activity, transcortin urine, renin concentration (RC) or renin acitivity (RA) were used, 85% of the (CBG) were determined. Diurnal rhythm of salivary cortisol was investigated at results being obtained between 1997 and 2006. Aldosterone to renin ratio (ARR) 8 am, 12 am, 5 pm and 10 pm.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Basal and stimulated serum and salivary cortisol levels in NR did not differ (CPA), 20 pheochromocytomas (PHEO), and 20 non-functional adenomas significantly from those in C. Diurnal rhythm of salivary cortisol in NR did not (NFA) was obtained following laparoscopic surgery. The diagnosis was differ from C. In LR, basal and stimulated levels of serum and salivary cortisol confirmed by various biochemical tests, histological investigation, and clinical were significantly lower than C and NR, P!0.001 for all times. Diurnal rhythm follow-up. Extracted RNA underwent Real Time RT-PCR using CYP11B2 was changed, the levels of salivary cortisol were lower than NR and C, at 8 am specific primers and probe (detection limit 5!101 copies/mg RNA (cp)). mRNA and at 12 am P!0.05. LR did not differ from NR and C in either basal ACTH levels were normalized to GAPDH mRNA levels. ROC analysis was performed to value, or basal plasma renin activity, but levels of CBG was significantly lower established cut-offs with specificity of at least 95%. than NR, P!0.005. Results In conclusion, low response to low dose ACHT test was associated with changes APA demonstrated high CYP11B2 expression with a median of 1.4!108 cp in diurnal rhythm of salivary cortisol and lower levels of CBG. These changes (range 6.1!105–1.9!1011 cp). In contrast, expression was significantly lower support the conclusion that a portion of diabetics even without adrenal (P!0.001) in CPA, PHEO, and NFA with 5!101 cp (5!101–8.9!106 cp), autoimmunity show adrenal function impairment. The clinical significance 4.7!102 cp (5!101–2.3!107 cp), and 5!101 cp (5!101–2.5!106 cp), remains to be evaluated. The study was supported by grant No.NR/9154-3 respectively. ROC analysis suggested a threshold of 1!107 cp with a sensitivity IGAMZCR. of 90% and specificity of 97%. In H, CYP11B2 expression levels ranged from 5!101 to 2.7!109 with a median of 1.9!105 cp. Inclusion of H to the ROC analysis led to an identical cut-off with lower sensitivity (69%) and similar specificity (97%). Conclusion Characterization of CYP11B2 expression may serve as a molecular marker to distinguish aldosterone-producing adenomas and bilateral hyperplasia from other P43 adrenal neoplasms. Such criteria could be used to evaluate biochemical tests for the diagnosis of hyperaldosteronism. Diffuse hyperplasia of both adrenals in Insulin sensitivity calucated by HOMA, QUIQI and G/IR in patients H may lead to hyperaldosteronism even in the presence of low expression with adrenal incidentaloma of CYP11B. Miomira Ivovic, Svetlana Vujovic, Milos Stojanovic, Milina Tancic-Gajic, Ljiljana Marina, Marija Barac & Milka Drezgic Institute of Endocrinology, Diabetes and Metabolic Diseases, Belgrade, Serbia.
Many studies have shown insulin resistance (IR) in majority of patients with adrenal incidentaloma. The euglycaemic hyperinsulinaemic glucose clamp technique is still considered as ‘golden standard’ for evaluation of insuline sensitivity. These methods are also complicated, labor-intensive procedure better P45 for small research studies. Today, several surrogate indexes for insulin sensitivity Renal function in patients with primary aldosteronism: comparison were introduced such as: HOMA, QUIQI or G/IR. Some studies showed with essential hypertension that QUIQI had significantly better linear correlation with reference glucose Martin Reincke1, Caroline Schirpenbach1, Stephanie Hahner2, clamp method. Felix Beuschlein1, Martin Bidlingmaier1, Sven Diederich3, The aim of our study was to analyze insulin sensitivity and compared results and Reinhard Lorenz1, Lars Christian Rump4, Jochen Seufert5, prevalence of insuline resistance by various methods. Christa Meisinger6, Rolf Holle6 & Marcus Quinkler7 About 208 patients (148 women and 60 men, mean age 55.08G11.02 years and 1 G 2 Medizinische Klinik Innenstadt and Institut fu¨r Prophylaxe und Epide- mean BMI: 27.91 4.6 kg/m ) with adrenal incidentaloma were admitted to miologie der Kreislaufkrankheiten, Ludwig-Maximilians-Universita¨t hospital. Insulin sensitivity was calculated by HOMA, QUIQI and G/IR method. 2 G G Mu¨nchen, Mu¨nchen, Germany; Medizinische Klinik und Poliklinik I, Mean insulin sensitivity: HOMA 3.61 6.61; QUIQI 0.34 0.04 and G/IR Julius-Maximilians-Universita¨t, Wu¨rzburg, Germany; 3Endokrinologikum, 10.59G17.15. According to criteria insulin !12 mU/ml, glucose/insulin O6.4, 4 ! O Berlin, Germany; Klinik fu¨r Nephrologie, Universita¨tsklinikum Du¨ssel- HOMA 4.7, and QUICKI 0.333, insulin resistance was present in 56.84% of dorf, Du¨sseldorf, Germany; 5Medizinische Klinik II, Albert-Ludwigs- patients calculated by HOMA and QUIQI and 43.16% of patients calculated by Universita¨t, Freiburg, Germany; 6Institute of Health Economics and Health G/IR method. Care Management, GSF-National Research Center for Environment and No statistically difference was found comparing these methods in insulin 7 Z Z Health, Neuherberg, Germany; Klinische Endokrinologie, Charite´ Campus sensitivity (Mann Whitney Test: W 830; P 0.626), and in prevalence of IR Mitte, Charite Universita¨tsmedizin Berlin, Berlin, Germany. (Person X2 testZ0.772, dfZ1; PZ0.782) among patients with adrenal incidentaloma. Our study shows significant prevalence of IR in patients with adrenal Objective incidentaloma. Prevalence of IR with G/IR was smaller than with HOMA and Primary aldosteronism (PA) is associated with vascular end organ damage. We QUIQI methods but not statistically significant. evaluated the newly established German Conn’s Register for evidence of renal impairment and compared the data with renal function from hypertensive subjects from an epidemiologic cohort. Methods The registry was founded in 2006 and has at present 7 participating centres in 5 locations. Data are entered in a central electronic database. Up to July 2007 555 patients were enrolled and matched for age, sex and BMI in a 1:1 ratio with P44 hypertensive control subjects form the epidemiologic F3 survey of the Quantitative real time RT-PCR of CYP11B2 (aldosterone synthase) to Kooperative Gesundheitsforschung in the region of Augsburg (KORA). About confirm the diagnosis of aldosterone-producing adenomas 408 patients with PA and 408 hypertensive controls were finally analyzed. Bianca Ueberberg1, Ricarda Althoff1, Timo Deutschbein1, Nicole Unger1, Results Jakob Hinrichs2, Martin K Walz2, Kurt W Schmid3 & Stephan Petersenn1 The percentage of patients with a serum creatinine concentration above the 1Division of Endocrinology, Medical Center, University of Essen, Essen, normal range of 1.2 mg/dl was significantly higher in patients with PA than in Germany; 2Department of Surgery and Center of Minimally Invasive hypertensive controls (129 of 408 (31.6%) vs 48 of 408 (11.8%), P!0.001). Surgery, Kliniken Essen-Mitte, Essen, Germany; 3Institute of Pathology, Accordingly, mean glomerular filtration rate (GFR) was significantly lower University of Essen, Essen, Germany. (P!0.001). Subgroup analysis showed that this was independent of sex, age or diabetes, but hypokalemic patients with PA had lower GFR than normokalemic patients. In a second step we analysed the long-term effect of specific treatment on Background renal function. Adrenalectomy for aldosterone producing adenoma reduced The diagnosis of hyperaldosteronism is hindered by the absence of a well-defined systolic blood pressure from a mean of 160 to 143.7 mmHg. In parallel, we gold-standard. CYP11B2 (aldosterone synthase) belongs to the steroid- observed an increase in serum creatinine and a decrease of GFR from 71.4 to metabolizing enzymes catalyzing the last step of the aldosterone synthesis. 64 ml/min (P!0.001). A similar trend was seen with spironolactone treatment. To establish a molecular marker for aldosterone-producing adenomas, we Conclusions compared the expression in various adrenal tumors. Glomerular filtration rate is reduced in patients with PA. Normalizing systemic Methods blood pressure by removal of the adenoma reduces renal plasma flow. This Tissue from 20 aldosterone-producing adenomas (APA), 12 hyperplasias uncovers the real extend of renal impairment in PA. associated with hyperaldosteronism (H), 20 cortisol-producing adenomas
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P46 P48 Adrenal retinoid receptors: new findings and new questions Persistent increase of osteoprotegerin levels after cortisol normalization Behling Cheng, Fatema Al-Shammari, Isra’a Ghader, Fatima Sequeira, in patients with Cushing’s syndrome Jitendra Thakkar & Soania Kettaneh Francesca Sanguin, Valentina Camozzi, Nora Albiger, Carla Scaroni, Biochemistry Department, Kuwait University Faculty of Medicine, Kuwait Franco Mantero & Giovanni Luisetto City, Kuwait. Division of Endocrinology, Department of Medical and Surgical Sciences, Padova, Italy. Retinoid-X-receptor (RXR) and retinoic acid receptor (RAR) are transcription factors; each expresses in a, b and g isoforms. Whereas RAR plays roles in Osteoprotegerin (OPG) has been identified as a decoyreceptor that inhibits osteoclast growth and differentiation, RXR regulates lipids homeostasis. Specifically, RXRb differentiation and recently as a paracrine regulator of vascular calcification. OPG is mediates intracellular control of cholesterol levels. RXR is activated by 9-cis- suppressed by glucocorticoid administration. In this study, we evaluated OPG and retinoic acid (9-cis-RA), cervonic acid, docosapentaenoic acid, adrenic acid and bone metabolism in Cushing’s syndrome (CS) before and after surgical treatment. arachidonic acid. The present investigation was aimed to characterize adrenal Twenty-nine patients with CS (26 women and 3 men, mean age: 40.7–2.8 years) and retinoid receptors. Adrenals were collected from foetus (20th day of pregnancy), 27 age and sex-matched controls have been studied for bone mineral density, bone neonate and adult rats, and from the adult rats stimulated with ACTH metabolism, OPG and receptor activator of nuclear factor-kB ligand (RANKL). (30 mg/100 g) for four consecutive days. Retinoid receptors were studied by Sixteen patients were studied for atleast 18 months after surgery, with normalization western blotting. Cholesterol ester (CE) was determined by HPLC. Fatty acids or reduction of cortisol levels. BMD was significantly lower in CS than in controls and retinoic acids were analyzed by GC/MS and LC/MS, respectively. The results (lumbar spine:0.6G0.02 and 1.01G0.02, P!0.0001; femoral neck: 0.73G0.22 and showed that development of rats from foetus/neonate to adult was accompanied 0.81G0.2, PZ0.02). OPG levels were significantly increased in CS than in controls by increased accumulation of CE and expression of RXRa, RXRb and RARg in (4.5G0.4 and 3.2G0.3 pmol/l; PZ0.02). Ca, P, osteocalcin (OC) and PTH did not the gland. In contrast, adrenal expression of RARa diminished. Ligand analysis differ between CS and controls. A significant positive correlation was found between revealed all-trans-retinoic acid, cervonic acid, docosapentaenoic acid, adrenic serum cross laps and OC levels (r2Z0.43, P!0.01) and between total alkaline acid, and arachidonic acid; 9-cis-RA was not detectable. Based on these ligand- phosphatase and RANKL (r2Z0.42, P!0.005). After treatment we found no availabilities, RAR/RXR and RXR/RXR dimerizations could both exist in the difference of OPG levels and a significant increase of OC levels (from 16.4G4.1 to gland; their specific isoforms in partnerships remained unknown. ACTH- 33.5G8.7 ng/ml, PZ0.02). No other differences were observed between the two stimulation resulted in altered adrenal retinoid receptor levels, but without a groups. Increased levels of OC after recovery confirm the inhibitory effect of GC on common pattern. Adrenal RXRb was concentrated in the nuclear fraction, but was bone formation. also found in the pellet resulted from a high speed centrifugation of the post- In CS we found increased levels of OPG maintained after remission of the disease. nuclear fraction, which could not entirely be explained as ‘contaminated’. No High serum OPG is also demonstrated in microvascular damage and was associated ACTH-induced translocation of RXRb between nuclear and cytosolic fractions toan increased cardiovascularmortality. Therefore, highlevels of OPG could reflects was observed. Despite new questions raised, the present data suggest a possible the persistent damage of the glucocorticoid on bone and cardiovascular system. involvement of the retinoid receptors in regulation of rat adrenal development and steroidogenesis.
P49 Evaluation of aldosterone to renin concentration ratio as a reliable screening parameter for primary aldosteronism applying currently available assays Nicole Unger1, Timo Deutschbein1, Martina Bro¨cker-Preuss2, 1 3 3 4 P47 Bianca Ueberberg , Jakob Hinrichs , Martin K Walz , Kurt W Schmid , Klaus Mann1 & Stephan Petersenn1 Screening for aberrant peptide hormone responsiveness in primary 1Division of Endocrinology, University of Duisburg-Essen, Essen, aldosteronism Germany; 2Department of Clinical Chemistry and Laboratory Medicine, Oliver Zwermann, Yana Vakrilova, Martin Bidlingmaier, Felix Beuschlein University of Duisburg-Essen, Essen, Germany; 3Department of Surgery & Martin Reincke and Centre of Minimally Invasive Surgery, Kliniken Essen-Mitte, Essen, Medizinische Klinik Innenstadt, Ludwig-Maximilian-University, Munich, Germany; 4Institute of Pathology and Neuropathology, University of Germany. Duisburg-Essen, Essen, Germany.
Recent molecular studies suggest a role of ectopic G protein coupled receptors Plasma aldosterone concentration (PAC) to active renin concentration (ARC) in primary aldosteronism (PA). The clinical relevance of these findings is not ratio (ARR) is an established screening tool for primary aldosteronism. known. We therefore combined expression profiling and a clinical testing of Previously we provided reliable cut-offs measuring PAC by a radioimmunoassay hormone responsiveness in patients with primary aldosteronism. Sixteen (RIA; Byk&DiaSorin) und ARC by an established immunoluminometric assay tissues from aldosterone producing adenomas and 6 normal adrenal glands (Nichols Institute Diagnostics). Since the latter one is not longer available, we were subjected to a quantitative PCR for determination of mRNA expression aimed to establish cut-offs for currently available assays. levels of AT2R, GIPR, MC2R, GnRHR, LHR, TRHR, TSHR, Glucagon-R One hundred seven subjects were studied, including 20 patients with primary (GCGR), AVPR and 5HT4R. Twelve patients with confirmed primary aldosteronism (13 adrenal adenomas, 7 adrenal hyperplasia), 15 cortisol- aldosteronism due to adrenal adenoma (APA; nZ5) and bilateral adrenal producing adrenal adenomas, 14 pheochromocytomas, 16 nonfunctioning adrenal hyperplasia (BAH; nZ7) and 8 control subjects (C) could be enclosed in a test adenomas, 14 patients with essential hypertension and 34 normotensive protocol consisting of 8 stimulation tests on three consecutive days, including volunteers. Patients were on various medications except for aldosterone stimulation by posture, mixed meal, ACTH, GnRH, TRH, glucagon, antagonists. PAC was measured by RIA (Siemens AG), while ARC was vasopressin and metoclopramide (MCP), respectively. Most APA tissues determined by an automated chemiluminescent immunometric assay (Liaison, displayed ATIIR (16/16), MC2R (15/16), 5HT4R (15/16) and. AVPR (13/16) DiaSorin). Putative ratio thresholds were determined by ROC analysis. In 29 mRNA expression. In contrast, only in a minority of tissues GnRHR (4/16), subjects, PAC und ARC determined by the current assays were correlated to LHR (1/16), TSHR (1/16), GIPR (0/16), GCGR (0/16), or TRHR (0/16) values obtained by the Byk&DiaSorin/Nichols assay model. mRNA was detectable. Clinical testing revealed responsiveness of aldosterone ARR was significantly higher in patients with primary aldosteronism than in the secretion following ACTH (APA, 5/5; BAH 7/7), MCP (APA, 4/5; BAH 7/7), control groups (P!0.0001). ROC analysis suggested an ARR threshold of 14.3 posture test (APA, 1/5; BAH 3/7), mixed meal (APA, 0/5; BAH 0/7), TRH (sensitivity 90.0%, specificity 83.9%, AUCZ0.9144). Additional consideration (APA, 0/5; BAH 1/7), vasopressin (APA, 2/5; BAH 4/7), glucagon (APA, 1/5; of PAC O130 ng/l demonstrated a lower sensitivity (80.0%) with higher BAH 1/7) and GnRH (APA, 1/5; BAH 2/7). In three patients where both data specificity (95.7%). PAC measured by Siemens was lower (0.32!XC34 ng/l) were available, clinical and molecular studies were well correlated, especially compared to Byk&DiaSorin, and ARC measured by DiaSorin was higher (0.96! in the APA patient with GnRH responsiveness where GnRH expression was XC5 ng/l) compared to Nichols. Therefore, the current cut-off for ARR is much detectable. We conclude that peptide hormone responsiveness is a common lower than the previously ones established. finding in patients with primary aldosteronism based on clinical testing and An ARR of O14.3 is a reliable screening tool for primary aldosteronism peptide hormone receptors expression profiling. Whether hormone receptor under random conditions. Application of this assay-specific cut-off will clearly expression is sufficient to induce a clinically relevant autonomous aldosterone change the diagnosis in a relevant number of patients, compared to previously secretion remains to be determined. established ratios.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P50 P52 Metabolic and cardiovascular profile in adult patients with addison’s Relation between serum adiponectin level, subclinical Cushing’s disease under conventional glucocorticoid replacement therapy syndrome and non-functional adrenal incidentaloma Roberta Giordano1, Alberto Falorni2, Marcella Balbo3, Stefania Marzotti2, Asli Dogruk U¨ nal, Semra Aytu¨rk, Yasemin Kemal, Neslihan Bascil Tu¨tu¨ncu¨ Serena Romagnoli2, Elisa Marinazzo3, Ezio Ghigo3 & Emanuela Arvat1 & Nilgu¨nGu¨vener Demirag 1Department of Clinical and Biological Sciences, San Luigi Hospital, Baskent University Hospital, Ankara, Turkey. University of Turin, Orbassano, Italy; 2Department of Internal Medicine, University of Perugia, Perugia, Italy; 3Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Turin, Turin, In this study we compared plasma adiponectin levels between patients with non- Italy. functional adrenal incidentaloma and subclinical Cushing’s syndrome. Our aims were to determine whether there was any difference of plasma adiponectin levels, any relation between cardiovasculer risk factors and to investigate the importance Object of adiponectin levels in subclinical Cushing’s syndrome patients according to In Addison’s disease hydrocortisone or cortisone have so far been used at doses of non-functional adrenal incidentaloma patients. The patients referred from other 30–37.5 mg/day, respectively, though several studies showed that cortisol normal clinics to Baskent University Hospital Endocrinology Department due to adrenal production is about 5.7 mg/m2 (20–25 mg/day of hydrocortisone or cortisone, incidentaloma were taken to study. In the patients group that was defined as respectively). Differently from secondary hypoadrenalism, scanty data exist in subclinical Cushing’s syndrome, the fasting blood insulin and HOMA-IR levels patients with Addison’s disease on role of conventional glucocorticoid were high and adiponectin levels were distinctively low (P!0.05). Although in replacement and metabolic and cardiovascular outcome. A recent observational patients with subclinical Cushing’s syndrome relation between adiponectin levels study has reported increase mortality rate in Addison’s disease patients and cardiovasculer risk factors was not found, adiponectin levels were positively conventionally treated. related with body fat percentage and HDL-cholesterol, negatively related with Design waist/hip ratio, body free fat mass and trigliserid levels in group of nonfuntional In 37 Addison’s disease patients (11 M and 26 F; 20–71 years) under conventional adrenal incidentaloma. When investigated for HPA axis abnormalities, significant glucocorticoid replacement therapy (37.5 mg cortisone/day), BMI, fasting relation between adiponectin levels and cortisol levels after dexamethasone glucose and insulin, OGTT, cholesterol and triglycerides (TG), 24 h blood suppression were found. In subclinical Cushing’s syndrome patients with adrenal pressure and intima-media thickness (IMT) by eco-doppler ultrasonography were incidentaloma, the low adiponectin levels may be due to glucocorticoid excess measured and correlated with sex, age, disease’s duration, ACTH, PRA and independent of metabolic parameters. Plasma adiponectin levels in subclinical DHEAS. Cushing’s syndrome patients were no seem to be good marker for determination Results of cardiovasculer risks and treatment management. Mean BMI was in the upper normal range, though higher than 25.0 kg/m2 in 16 patients. Mean fasting glucose, insulin, HOMA and glucose after OGTT were in the normal range. HOMA was higher than normal in 4 overweight patients and in 2 of them OGTT was diagnostic for IGT. According to ATP III classification, mean total cholesterol was in the desiderable range, none of the patients had HDL P53 lower than 40 mg/dl, whereas LDL was higher than 160 mg/dl in 4 overweight patients; only the 2 IGT patients showed increased TG levels. In all patients 24 h Subclinical autonomous cortisol hypersecretion by adrenal incidenta- blood pressure showed a normal profile with a preserved circadian variation and lomas may be intermittent: results from a long term follow-up study IMT was below 0.9 mm. No correlation was found between the above mentioned Evangeline Vassilatou, Stamatia Michalopoulou, Andromachi Vryonidou, parameters. None of the patients showed a global CV risk above 5% at 10 years John Manolis, Constantine Panayiotopoulos & Ioanna Tzavara (according to ATP III). Amalia Fleming General Hospital, Melissia, Athens, Greece. Conclusion This study suggests that, in Addison’s disease, neither conventional glucocorti- Background coid replacement therapy nor the reduced DHEAS secretion are associated with Hormonal studies have detected subtle abnormalities of the hypothalamic– metabolic impairment and/or increased cardiovascular risk. pituitary–adrenal (HPA) axis due to autonomous cortisol secretion, in a percentage of patients with adrenal incidentalomas, a condition termed as subclinical Cushing’s syndrome. The diagnostic criteria and the clinical significance of this condition are still controversial and consequently there is uncertainty for its management. Data defining the natural course of these tumors, will help to determine clinical implications and appropriate management, but are still inadequate. P51 Objective Adrenocortical changes and arterial hypertension in lipoatrophic Prospective long-term follow-up study of patients with apparently benign adrenal A-ZIP/F-1 mice incidentalomas and without overt hyperfunction at initial diagnosis, in order to Valeria Lamounier-Zepter1, Stefan Bornstein1, Jaroslav Kunes2, assess their hormonal activity and their long-term growth pattern. Jozef Zicha2, Michal Krsek3, Monika Ehrhart-Bornstein1, Patients-methods Christian Ziegler1, Andrea Kiessling1, Richard Funk1 & Martin Haluzik3 From a group of 89 patients with adrenal incidentalomas, 34 patients with a mass 1 2 diameter 1.0–6.0 cm (2.2G0.8, median 2.0) were followed-up for 12–144 University Medical Center, Dresden, Germany; Institute of Physiology G AS CR and Center for Experimental Research of Cardiovascular Diseases, months, (62.1 33.5, median 57.0), with a hormonal (plasma cortisol rhythm, Prague, Czech Republic; 31st Faculty of Medicine, Prague, Czech Republic. morning plasma ACTH, serum DHEA-S, serum aldosterone and plasma renine activity, low dose dexamethasone suppression test, 24 h urinary VMA and metanephrines and 24 h urinary free cortisol) and morphological evaluation (CT The A-ZIP/F-1 transgenic mouse is a model of lipoatrophic diabetes with scan) every 12–24 months. The diagnosis of subclinical Cushing’s syndrome was severe insulin resistance, hyperglycemia and hyperlipidemia. Recently, a based on a post-LDDST plasma cortisol level O1.8 mg/dl combined with an regulatory role of adipose tissue on adrenal gland function and blood abnormal result of at least one other test of the HPA axis and the absence of pressure has been suggested. To further explore the importance of adipose clinical signs of cortisol excess. tissue in the regulation of adrenal function and blood pressure, we studied Results this mouse model of lipodystrophy. A-ZIP/F-1 mice exhibit significantly At diagnosis 23 patients had a normal adrenal function and 11 had subclinical elevated systolic and diastolic blood pressure values despite lack of white Cushing’s syndrome. During follow-up adrenal function remained normal in 22 adipose tissue and its hormones. Furthermore, A-ZIP/F-1 lipoatrophic mice patients, subclinical Cushing’s syndrome was reassessed in five patients, whilst have a significant reduction of adrenal zona glomerulosa, while plasma intermittent subclinical autonomous cortisol hypersecretion was found in seven aldosterone levels and aldosterone synthase mRNA expression remain patients. None of the patients developed Cushing’s syndrome. A change in mass unchanged. On the other hand, lipoatrophic mice present elevated size (R0.5 cm) was found in 12 patients (an increase in nine patients, with no corticosterone levels but no adrenocortical hyperplasia. Ultrastructural signs of malignancy and a reduction in 3). analysis of adrenal gland show significant alterations in adrenocortical Conclusion cells, with conformational changes of mitochondrial internal membranes and These data show that subclinical autonomous cortisol hypersecretion may be high amounts of liposomes. In conclusion, lipodystrophy in A-ZIP/F-1 mice intermittent in a significant percentage of patients. This finding supports a wide is associated with hypertension, possibly due to hypercorticosteronemia range of variability from non-functioning adrenal adenoma to autonomous and/or others metabolic-vascular changes. cortisol secreting adrenal adenoma. The spectrum of intensity of subclinical autonomous cortisol secretion may explain the contrasting results of studies
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 examining long-term adverse implications this disorder. These data also show that crisis, the frequency of AC was slightly higher in SAI than in PAI (15/100 patient a growth tendency is observed in some adrenal incidentalomas, without evidence years vs 13.4/100 patient years). Incidence of AC was not influenced by of malignant transformation. educational status, BMI, glucocorticoid dose, DHEA treatment, age at diagnosis, hypogonadism, hypothyroidism or growth hormone deficiency. In PAI, patients with concomitant non-endocrine disease tended to be at higher risk for AC (RRZ 1.24, PZ0.057). In SAI, female gender (RRZ1.26, PZ0.043) and diabetes insipidus (RRZ1.25, PZ0.033) were significantly associated with the incidence P54 of AC. AC occurs frequently in both PAI and SAI, mainly triggered by infectious disease. Preoperative paroxysmal attacks are not predictive of intraoperative However, so far only minor risk factors for AC could be identified in this large hemodynamic changes in patients undergoing laparoscopic adrena- cohort, indicating the need of repeated crisis prevention training in all patients lectomy for pheochromocytoma with AI. Sebastien Gaujoux1, Claude Lentschener2, Jean-Marc Thillois1, Yves Ozier2 & Bertrand Dousset1 1Surgery department-APHP, Paris, France; 2Anesthesia department-APHP, Paris, France.
Background Abrupt catecholamine release may cause paroxysmal attacks in patients with P56 pheochromocytoma, and is associated with major hemodynamic changes during adrenalectomy. We investigated whether preoperative paroxysmal attacks are The role of toll-like receptors in adrenal gland inflammatory response and tumorigenesis associated with further intraoperative adverse hemodynamic changes during 1 3 2 adrenalectomy for pheochromocytoma. Waldemar Kanczkowski , Henning Morawietz , Kai Zacharowski , Christian G Ziegler1, Monika Ehrhart-Bornstein1 & Stephan R Bornstein1 Material and methods 1 From 1994 to 2006, 88 patients underwent laparoscopic adrenalectomy for Department of Medicine, Medicine Clinik III, Carl Gustav Carus University Hospital, Dresden, Germany; 2Molecular Cardioprotection and pheochromocytoma. In our institution patients are scheduled when normotensiv, 3 and do not receive consistently preoperatively hypotensive drugs unless these Inflammation Group, Bristol Royal Infirmary, Bristol, UK; Department of drugs have been prescribed elsewhere. Surgery was conducted under standard Medicine, Medicine Clinic III, Carl Gustav Carus University Hospital, propofol, sufentanil, tracrium anaesthesia. An arterial line was inserted for arterial Dresden, Germany. pressure (AP) monitoring. Esmolol was administered when heart rate was above 120 mmHg, Nicardipine when systolic AP (SAP) was above 150 mmHg, and Sepsis and septic shock remain a major health concern worldwide, and an intact ! Norepinephrine when SAP was 90 mmHg after tumour removal. Paroxysmal adrenal cortex glucocorticoid (GC) stress response, is critical for organism to attacks were defined as paroxysmal palpitations or elevated heart rate, sweating, survive. Recently, we and others have shown that adrenal gland expresses flushing, headaches, nausea, or hypertensive access. Whether preoperative members of toll-like receptors (TLRs) family which are known to sense paroxysms were associated with esmolol, nicardipine, norepinephrine admini- pathogens and induce inflammatory response. Data performed on TLRs deficient c2 stration and postoperative morbidity was investigated. , Mann–Whitney and mice clearly demonstrate a critical involvement of these receptors in immune- t-tests were used. neuroendocrine bidirectional crosstalk during infection. TLR-2 and -4 deficient Results animals developed an impaired GCs response with cytokine dysregulation and Patients of both groups did not differ with respect to demographic data, ultrastructural impairments of adrenocortical cells. However, the exact preoperative hypotensive treatment, intraoperative increased SAP, intraoperative mechanism of TLR-mediated adrenal gland dysfunction during bacterial nicardipine, esmolol or norepinephrine use or postoperative morbidity. infections is not clear. Conclusion Therefore, the aim of this work was to elucidate adrenal gland inflammatory and Preoperative paroxysms were not predictive of intraoperative hemodynamic hormonal response to multiple bacterial-derived ligands, utilising adrenocortical cell changes, thus confirming that there is no evidence-based factors likely to predict line and human cells in primary culture. We found that both human primary intra and postoperative hemodynamic instability, or postoperative morbidity in adrenocortical cells and NCI-H295R – carcinoma cell line express several TLRs. patients undergoing adrenalectomy for pheochromocytoma. However, both cell types responded to bacterial-derived ligands differentially. In opposite to NCI-H295R carcinoma cells, adrenocortical cells in primary culture responded to lipopolysaccharide (LPS) and lipoteichonic acid (LTA) stimulation with an enhanced IL-6 and TNF-alpha cytokines and cortisol secretion. Interestingly, the stimulation of adrenocortical carcinoma cells with TLR-1/6 together with TLR-2 ligands (Pam3Cys4 or LTA) resulted in a dose and time dependent induction of IL-8, which in turn was not present in non-transformed cells. In conclusion, our data show P55 that TLRs may contribute to adrenal gland dysfunction during systemic or chronic infections by sustaining an excessive inflammatory response. Additionally, TLRs Adrenal crisis in primary and secondary adrenal insufficiency: may contribute to the adrenal gland tumorigenesis by inducing of CXC-chemokines frequency and causes secretion such as IL-8, which are found to be overexpressed in adrenocortical Stefanie Hahner1, Melanie Loeffler1, Benjamin Bleicken2, carcinomas (ACC) and to contribute to tumour growth. Christiane Drechsler3, Manfred Ventz2, Marcus Quinkler2 & Bruno Allolio1 1Endocrinology and Diabetes Unit, Department of Medicine I, University of Wuerzburg, Wuerzburg, Germany; 2Klinische Endokrinologie, Charite´ Campus Mitte, Charite Universita¨tsmedizin Berlin, Berlin, Germany; 3Department of Medicine I, University of Wuerzburg, Wuerzburg, Germany. P57 The sodium to urinary sodium to potassium to urinary potassium Adrenal crisis (AC) is a rare but life-threatening complication in chronic adrenal (SUSPUP) ratio in primary aldosteronism failure. Here we evaluated frequency, causes and potential risk factors of AC in a Holger S Willenberg, Chara Kolentini, Werner A Scherbaum & large sample of patients with primary AI (PAI) or secondary AI (SAI). Matthias Schott In a cross-sectional study 883 patients with AI were contacted by mail. 526 Department of Endocrinology, Diabetes and Rheumatology; University patients agreed to participate and received a disease specific questionnaire. Hospital Duesseldorf, Duesseldorf, Germany. Diagnoses and co-morbidities were verified by review of medical records. Four hundred and forty four data sets were available for further analysis (PAI nZ254, SAI nZ190). 42% (PAI 47%, SAI 35%) reported at least one AC. 384 Primary aldosteronism (PA) has a prevalence of about ten percent in a adrenal crises in 6092 patient years were documented corresponding to a hypertensive population and is an important risk factor for cardiovascular frequency of 6.3 crises/100 patient years (PAI 5.1, SAI 8.2). Precipitating causes disease. The aldosterone to renin concentration ratio (ARR) is an established were mainly gastrointestinal infection and fever (45% of cases) but also other diagnostic tool in the screening for PA. However, hormonal determinations stressful events (e.g. major pain, surgery, psychic distress, heat, pregnancy) and are time-consuming and expensive. Therefore, we studied the value of the sodium even sudden unexplained occurrence were reported. Patients with PAI reported to urinary sodium to potassium to urinary potassium (SUSPUP) ratio in 37 significantly more emergency glucocorticoid administrations (PZ0.003) and AC patients with PA, in 34 hypertensive patients to whom this diagnosis could be (PZ0.019). However, among those patients who had experienced at least one excluded (HTN).
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
The patients groups (PA and HTN) did not differ significantly with respect to sex, adrenocortical cells. We found also an increase in the cyclin D3 promoter age (57.7G1.6 vs 56.3G2.3, respectively), systolic and diastolic blood pressure activity and a significant stimulation of the CITED2 promoter activity which (means 156 over 93 vs 148 over 88 mmHg). As expected there was a significant peaked at 500 percent. THese effects were accompanied by an increase in difference in the ARR (135.6G98.8 vs 21.7G45.3, respectively) and in plasma CITED2 messenger RNA and CITED2 protein, as determined by real-time PCR aldosterone and renin concentrations. Analysis of the serum and urinary and western blotting, respectively. The stimulatory effect of ECCM could be elecrolyte concentrations showed that patients with PA had a significant higher reversed after silencing CITED2 through siRNAs and by blocking mitogen- SUSPUP ratios than did patients with HTN (36.9G26.4 vs 16.2G8.5, activated protein kinase activity using the MEK1-inhibitor PD98059. We respectively). Interestingly, treatment with hydrochlorothiazide (HCT) did not conclude that products secreted by endothelial cells are capable in promoting interfere significantly with the SUSPUP ratios in PA and HTN. proliferation of adrenocortical cells. This effect was associated with a significant After spironolactone treatment of patients with PA or operation of aldosterone- increase in CITED2 gene promoter activity and consequent CITED2 expression. producing adenomas the SUSPUP ratios became significantly lower (24.2G11.7) Thus, our data provide evidence that the endothelium regulates factors that are as renin concentrations and blood pressure became normal. necessary for adrenal organogenesis. We conclude that the SUSPUP ratio is a cheap tool helpful for the characterization of mineralocorticoid excess syndromes such as PA.
P60 Intraadrenal production of ACTH in macronodular bilateral adrenal P58 hyperplasia causing Cushing’s syndrome: its role in the physiopathology Characterization and differentiation of chromospheres isolated from of hypercortisolism bovine adrenal medulla Estelle Louiset1,Ce´line Duparc1, Lionel Groussin2,Je´roˆme Bertherat2, Kuei-Fang Chung1, Flavie Sicard2, Vladimir Vukicevic1, Linda Gebauer1, Xavier Bertagna2, Jean-Marc Kuhn3 & Herve´ Lefebvre1 Stefan R Bornstein1 & Monika Ehrhart-Bornstein1 1INSERM U413, University of Rouen, Mont-Saint-Aignan, France; 1Carl Gustav Carus University Medical School, Medical Clinic III, Dresden, 2INSERM U567, CNRS UMR8104, Department of Endocrinology- Germany; 2CEA, Grenoble, France. Metabolism-Cancer, Institut Cochin, Universite´ Paris V Rene´ Descartes, Paris, France; 3Department of Endocrinology, Institute for Biomedical Research, Rouen University Hospital, University of Rouen, Rouen, France. Chromaffin cells from adrenal medulla are the main source of epinephrine and norepinephrine hormones which are known to mediate so called fight-or-flight response to multiple environmental stress conditions. Chromaffin cells together Illicit expression of membrane receptors for circulating regulatory factors, such as with sympathetic neurons share the same sympathoadrenal cell lineage, but in GIP and LH receptors, has been well documented in ACTH-independent contrast to neurons they maintain their proliferation during whole life span. macronodular adrenal hyperplasias (AIMAHs) causing Cushing’s syndrome. In However, little is known about chromaffin cells regeneration in an adult adrenal addition, we have observed an abnormal expression of serotonin, arginine medulla. vasopressin and ACTH in a subpopulation of steroidogenic cells in two AIMAH In this study, we focused on isolation and characterization of progenitor cells from tissues. The aim of the present study was: (i) to investigate the presence of ACTH an adult bovine adrenal medulla. In the selective conditions, similar to the by immunohistochemistry in eleven additional AIMAHs; (ii) to detect ACTH neuronal progenitors, freshly isolated chromaffin cells in primary culture formed release by the tissue fragments, (iii) to determine whether ACTH secretion can be spheres which will be further referred as chromospheres. In addition, chromo- modulated by activation of illicit receptors, and (iv) to examine the role of local spheres expressed several progenitor markers including nestin and Sox1. In adult production of ACTH in the control of steroidogenesis. adrenal medulla, adrenocortical cells are in close contact with chromaffin cells. ACTH-like immunoreactivity was detected in AIMAH tissues, suggesting that Moreover, DHEA and DHEAS, hormones secreted by zona reticularis, are this regulatory signal may act through autocrine/paracrine mechanisms to suggested to influence the adrenal medulla function and regeneration. Therefore, stimulate cortisol secretion. Perifusion experiments demonstrated that adrenal we assessed whether these hormones may directly impact the differentiation slices spontaneously released detectable amounts of ACTH. In addition, ACTH potential of cells from chromospheres. Stimulation with DHEAS and BMP-4, secretion was significantly increased by GIP and hCG in tissues derived from factor known to drive neuronal differentiation, induced b-III-tubulin expression patients with food-dependent and LH-sensitive hypercortisolism. The ACTH suggesting that these factors may promote neuronal fate. In contrary, stimulation receptor antagonists corticostatin and ACTH (7–38) reduced basal and ACTH- with DHEA and dexamethasone induced PNMT mRNA expression which is induced cortisol production from the hyperplasia tissues. These data indicate that, known to promote chromaffin cells differentiation. Taken together, these data in AIMAH tissues, ACTH released by a subpopulation of adrenocortical cells show that cells from choromospheres have differential potential in their response exerts an intraadrenal stimulatory tone on cortisol secretion. to androgen stimulations which may influence their differentiation.
P61 P59 A case of renin-producing adrenocortical carcinoma with Cushing’s Evidence for the involvement of endothelial cell products in adrenal syndrome: in vitro effect of serotonin on renin and cortisol secretions CITED2 expression Estelle Louiset1, Karen Isvi2, Jean-Marie Gasc3,Ce´line Duparc1, Matthias Haase1, Ishrath Ansurudeen2, Sven Schinner1, Iryna Paramonova1, Bruno Cauliez4, Annie Laquerrie`re5, Jean-Marc Kuhn1 & Herve´ Lefebvre1 Matthias Schott1, Claudia Papewalis1, Alexander Krug2, Werner A 1INSERM U413, IFRMP 23, University of Rouen, Mont Saint Aignan, Scherbaum1 & Holger S Willenberg1 France; 2Department of Endocrinology, Institute for Biomedical Research, 1Department of Endocrinology, Diabetes and Rheumatology, University University Hospital of Rouen, University of Rouen, Rouen, France; Hospital Duesseldorf, Duesseldorf, Germany; 2University of Technology 3INSERM U833, Laboratory of Embryological ad Pathological Angio- Dresden, Medical Clinic III, Dresden, Germany. genesis, Colle`ge de France, Paris, France; 4Laboratory of Biochemistry, Institute for Biomedical Research, University Hospital of Rouen, University of Rouen, Rouen, France; 5Department of Pathology, Institute for The mechanisms that lead to tumor formation of and aldosterone secretion by Biomedical Research, University Hospital of Rouen, University of Rouen, zona glomerulosa cells in primary aldosteronism are not known. Recently, Rouen, France. endothelial cell-derived factors have been characterized that control the release of aldosterone by adrenocortical cells. In addition, we started to characterize the regulation of CITED2, a CBP/p300 interacting transactivator with ED-rich tail 2. A 48-year-old woman was referred for ACTH-independent Cushing’s syndrome Earlier, it was shown in mice that absence of CITED2 leads to adrenal agenesis. associated with a left adrenal tumor. Contrasting with hypercortisolism-related Since endothelial cells are in close proximity to adrenocortical cells, we asked hypertension and hypokalemia, renin and aldosterone levels were paradoxically whether endothelium-derived factors promote proliferation of adrenocortical cells increased. The tumor was surgically removed and pathological examination of the and – if so – whether CITED2 is involved in this process. We examined the effects tissue established the diagnosis of corticosurrenaloma. Fragments of the tumor of endothelial cell-conditioned medium on aldosterone release by and on the were obtained for in situ hybridization, immunohistochemical and cell incubation proliferation of adrenocortical cells and on the expression of CITED2, employing studies. The presence of prorenin mRNA and renin immunoreactivity was the NCI-H295R cell line and primary human adrenocortical cells. detected in the tumor tissue. Renin and cortisol were detectable in tumor cells We found a dose-dependent effect of endothelial cell-conditioned medium culture supernatants whereas aldosterone was not. ACTH and angiotensin II had (ECCM) on wst-1 salt metabolism by and 3H-thymidin incorporation in no action on renin and cortisol secretion. In contrast, 5-HT inhibited renin
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 production and stimulated cortisol release in a dose-dependent manner. Results Interestingly, 5-HT-induced cortisol secretion was inhibited by the 5-HT7 Ultrasonography detected putative enlarged parathyroid glands in 49 of 65 receptor antagonist SB269970 but not by GR113808, an antagonist at the eutopic patients (74.4%) with sensitivity of 83% and positive predictive value of 89%. 5-HT4 adrenocortical receptor. One month after surgery, UFC and plasma levels Sestamibi scintigraphy was positive in 55 patients (84.6%) with sensitivity of of renin normalized. Six months post-operatively, hypercortisolism and 88.7% and positive predictive value of 94.8%. there was no significant deference hyperreninism recurred concomitantly with hepatic and pulmonary metastatic between ultrasonography and scintigraphy in localization of adenomas. There diffusion of the disease leading rapidly to the death of the patient. Collectively, was a correlation between PTH level and scintigraphic localization of adenoma in vivo and in vitro data show that the adrenal carcinoma cosynthesized and (PZ0.001). If both ultrasonography and scintigraphy used for localization, they secreted renin and cortisol. Our results also demonstrate an ectopic expression of located 61 adenomas (93.8%) with sensitivity of 93.8% and positive predictive 5-HT7 receptors in the tumor tissue mediating a stimulatory effect of 5-HT on value of 95%. cortisol secretion. In contrast, 5-HT inhibited renin secretion by tumor cells Conclusion through an unknown receptor type. Ultrasonography is a sensitive and accurate method for preoperative localization of enlarged parathyroid glands in primary hyperparathyroidism, comparable in overall utility with sestamibi scintigraphy. These results suggest that a strategy of initial testing with one or the other method, followed by the alternate imaging test if the first test is negative, would provide correct parathyroid adenoma imaging.
Bone and calcium P62 Recognition of osteoporosis and analysis of influencing factors Jinho Park, Belong Cho & Hyuktae Kwon Seoul National University Hospital, Seoul, Republic of Korea. P64 Backgrounds Daidzein unlike other isolated isoflavones, preserves bone architecture As the average lifespan in human increases, osteoporosis and osteoporosis-related in ovariectomized female rats in vivo fractures have been major health care problems. Despite recent advances in Dalia Somjen1, Sara Katzburg1, Fortune Kohen2, Batya Gayer2 & medical treatment, few studies have assessed the recognition of osteoporosis by Erella Livne3 general adults. This study examined the recognition of osteoporsosis and analysed 1Institute of Endocrinology, Metabolism and Hypertension, Tel-Aviv the relating factors. Sourasky Medical Center and the Sackler Faculty of Medicine, Tel- Methods AvivUniversity, Tel-Aviv 64239, Israel; 2Department of Biological We made one to one questions in a rural area called chunjunlee in chunchon city. Regulation, The Weizmann Institute, Rehovot 76100, Israel; 3Department of The questionnaire contained general characteristics of people, sociocultural Anatomy and Cell Biology, Bruce Rappaport Faculty of Medicine, factors, questions constructed to know recognition of osteoporosis and factors that Technion-Israel Institute of Technology, Haifa 31096, Israel. were presumed to influence people’s recognition of osteoporosis. DEXA was done to people who visited medical office of free service. Results Ovariectomy of immature female rats, results in significant decrease of Total number of people who fulfilled the questionnaire was 204. They were trabecular bone volume and in cortical bone thickness. Previously we found composed of 81 men and 123 women. Women of 83% and of men 72.8% said that that estradiol-17b (E2) restored bone structure of ovariectomized female rats they had heard about osteoporosis. There was no significant recognition score (Ovx) to values obtained in intact sham-operated female rats. E2 also difference between men and women. In the items of recognition, wrong answer selectively stimulated creatine kinase specific activity (CK) a hormonal- rate about the association between osteoporosis and musculoskeletal disorders genomic activity marker. In the present study, we compared the effects of such as osteoarthritis, low back pain was above 90%. Significant factors that E2 and the phytoestrogens: daidzein (D), biochainin A (BA), genistein (G), influencing recognition were age, education level, menopause state and carboxy-derivative of BA (cBA) and the SERM raloxifene (Ral) in Ovx, on newspaper/magazine subscription. All men who were diagnosed osteoporosis both histological changes of bones and CK, when administered in multiple on DEXA sad that they didn’t have osteoporosis. daily injections for 2.5 months. Bone from Ovx rats, showed significant Conclusions disrupted architecture of the growth plate, with fewer proliferative cells and Many people had conceptual confusion between osteoporosis and other less chondroblasts. The metaphysis underneath the growth plate, contained muscular skeletal disorders such as osteoarthritis, low back pain. Physicians less trabeculae but a significant increased number of adipocytes in the bone played no significant role in improvement of people’s recognition of marrow. D like E2 and Ral but not G, BA or cBA, restored the morphology osteoporosis. Generally men thought that osteoporosis was problem of of the tibiae, similar to that of control sham-operated animals; the bony women. trabeculeae observed in the primary spongiosa was thicker, with almost no adipocytes in bone marrow. Ovariectomy resulted also in reduced CK, which in both epiphysis and diaphysis was stimulated by all estrogenic compounds tested. In summary, only D stimulated skeletal tissues growth and differentiation as effectively as E2 or Ral, suggesting that under our experimental conditions, D is more effective in reversing menopausal changes than any of the other isolated phytoestrogens which cannot be considered as one entity. P63 Comparison of ultrasonography and 99mtechnetium sestamibi in localization of parathyroid adenoma in primary hyperparathyroidism Shirzad Nasiri, Ahmad Reza Sourush, Amir Pejman Hashemi & Anushiravan Hedayat Tehran Univercity of Medical Science, Tehran, Islamic Republic of Iran. P65 Surgical management of renal hyperparathyroidism: a preliminary Aims series report Determine the utility of ultrasonography for the preoperative localization of Diaconescu Mihai Radu, Costea Ioan, Glod Mihai, Grigorovici Mirela & enlarged parathyroid glands in primary hyperparathyroidism and to compare this 99m Covic Adrian method with technetium sestamibi scintigraphy. University of Medicine and Pharmacy ‘Gr T Popa’, IVth Surgical Clinic, Methods Iasi, Romania. The results of ultrasonographic localization of enlarged parathyroid glands witch were performed by one experienced ultrasonographer were determined in 65 consecutive patients with primary hyperparathyroidism and compared with Background findings at surgery and results of 99mtechnetium sestamibi scintigraphy. All Renal hyperparathyroidism (RHPT) is a frequent complication of uremic patients patients had biochemically documented primary hyperparathyroidism based on on hemodialysis and despite various advances in medical therapy parathyroi- elevated serum calcium and parathyroid hormone. dectomy is necessary in a semnificative number of cases.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Patients and methods P67 We reviewed our experience (first in Romania) regarding thirtyfour patients Digital X-ray radiogrammetry in followed change of bone mineral with RHPT operated on in our clinic between 1994 and 2007 evaluating the density after the treatment in postmenopausal women diagnosis methods, surgical indications, techniques and results together with Corina Galesanu1, Ciprian Ciubotariu1 & Roxana Gabriela Galesanu2 the evolution of our own therapeutical concept. The study included 20 men 1University of Medicine and Pharmacy, IASI, Romania; 2Centre of and 14 women of median age of 48 (range 26–75) years, performing Radiology and Imaging Diagnosis, IASI, Romania. hemodialysis (nZ32) or peritoneal dialysis (nZ2) from 8.2 (range 3 to 16) years respectively. Two patients received an unsuccessful renal graft. The diagnosis was established by anamnesis, clinical complaints (mainly Objectives osteoarticular pains,osteoporosis, fractures and divulsions), muscle weakness, To evaluate the effect of alendronate, alfacalcidol, and combinat agent of severe itching and mental troubles), completed by anormal values of alendronate and alfacalcidol, in BMD change assess by Digital X-ray Radio- calcaemia, hyperphosphataemia and intact PTH. Ultrasonography and CT grammetry in postmenopausal women. scan were useful only in ‘adenomised’ parathyroids and co-existent thyroid Materials and methods pathology. Nine thousand and two hundred and sixty four healthy women with ages between Results 20 and 89 years referred to our densitometry service using DXR-BMD. Six All the patients were operated on. Twenty subtotal parathyroidectomies 12 total thousand and six hundred and twelve from these were in postmenopause. Using parathyroidectomies (4 with autoimplantation), and two limited resections WHO-criteria for osteoporosis diagnosis, 780 from them presented osteoporosis (adenomectomies) were performed (two video-assisted). There were no deaths and 1388 osteopenia. We selected 72 patients who received alendronate and the operative morbidity was 2,9% (vocal cord hemiparesis – one case). 70 mg/weekly; 67 patients who received alendronate 70 mg/weekly and 1 mcg Pathology revealed that RHTP was due to four gland diffuse hyperplasia alfacalcidol daily and 30 postmenopausal osteoporotic women who received (nZ18) or nodular hyperplasia (nZ14).Two neglected parathyroid adenomas 1 mcg aflacalcidol daily. Mean age of osteoporotic treated women was 60.9G7.4 with recurrent urolithiasis, finally considered as tertiary HPT, one parathyroid years. The treatment was administrated five years and going on. BMD by DXR was carcinoma (in the fourth parathyroid gland),one thymoma and one occult measured at each 12 months. Statistical analyses was, t-test (Student–Fischer). papillary thyroid carcinoma was identified. Clinical and biochemical cure Results was achieved at median term control of 38 (range 2–150) months in 85% In group treated with alendronate the BMD gain after one year was 0.013G (nZ29) of cases. 0.02 g/cm2 and 0.031G0.02 g/cm2 after five years In group treated with Conclusion combinated agent alendronate and alfacalcidol, BMD gain after one year was Parathyroidectomy is effective for long intervals as symptomatic therapy in 0.019G0.02 g/cm2 and after five years 0.045G0.02 g/cm2. In the last group treated cases of RHPT appearing in uremic patients on hemodialysis or after renal by alfacalcidol the gain BMD was 0.009G0.02 g/cm2 after the first year and transplant but the optimal technique must be individualised on each case and 0.020G0.02 g/cm2 after five years. still to be debated. Conclusions The increase of BMD in our group after administration of alfacalcidol was not statistical significantly. Alendronate induced significant increase BMD in postmenopausal women. The increase BMD after alendronate and alfacalcidol was significantly higher than after alendronate only, and demonstrated that the P66 combination is quite effective. Osteopenia/osteoporosis in adult thalassemic patients: contribution of growth hormone - insulin-like growth factor I deficiency Massimo Scacchi1, Leila Danesi 1, Agnese Cattaneo1, Elena Valassi1, Francesca Pecori Giraldi1, Crocetta Argento2, Emanuela D’Angelo3, Nadia Mirra3, Laura Zanaboni4, Benedetta Tampieri4, Maria Domenica 4 1 Cappellini & Francesco Cavagnini P68 1Chair of Endocrinology, University of Milan, IRCCS San Luca, Milan, Italy; 2Azienda Ospedaliera San Giovanni di Dio, Agrigento, Italy; 3Second BsmI, ApaI, TaqI, FokI polymorphisms of vitamin D receptor (VDR) Pediatric Clinic, University of Milan, Fondazione Policlinico Mangiagalli gene and bone mineral density in women with Graves’ disease Regina Elena, Milan, Italy; 4Department of Internal Medicine, University of Wanda Horst-Sikorska1, Magdalena Ignaszak-Szczepaniak1, Milan, Milan, Italy. Michalina Marcinkowska1, Anna Wawrzyniak1, Malgorzata Stajgis2 & Ryszard Slomski3 1Department of Family Medicine, Poznan University of Medical Sciences, GH and IGF-I exert an important role in the control of bone formation. Poznan, Poland; 2Endocrinology Outpatient Clinic, Poznan, Poland; Osteopenia and osteoporosis are a frequent recurrence in patients with 3Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland. thalassemia. Due to the high prevalence of GH deficiency (GHD) in adult thalassemic patients (Scacchi et al., Clin Endocrinol 2007), we investigated the possible role of GH - IGF-I abnormalities in the pathogenesis of the Graves’ (GD) hyperthyroidism induces accelerated bone turnover that leads to osteopenia/osteoporosis of this disease. diminished bone mineral density (BMD). Recent studies indicate the associations Study between VDR gene and autoimmune diseases. The role of VDR allelic variants in Sixty-four adult thalassemic patients (23 men and 41 women, age 31.4C6.8) predisposition to primary osteoporosis is also recognized. The authors analyzed if were studied. BMD was assessed by DEXA at lumbar spine in 62 patients and at VDR polymorphisms: BsmI, ApaI, TaqI and FokI may predispose women with proximal femur in 58. All patients underwent GHRH plus arginine testing. Graves’ hyperthyroidism to BMD reduction. The subjects were 75 premenopausal Severe GHD was defined by GH peaks lower than 9 mg/l, partial GHD by GH female Polish patients with GD aged 23-46 and 100 healthy women. BMD values peaks ranging from 9 to 16.5 mg/l. Blood samples for IGF-I measurement were were evaluated at lumbar spine (L1-L4 region) and femoral neck by dual energy collected. X-ray absorptiometry (DEXA method). The genotyping was performed using Results restriction fragment length polymorphism (RFLP). The association analysis of Lumbar osteoporosis and osteopenia were demonstrated in 74.1% and 22.5% of VDR polymorphisms and haplotypes with BMD as well as SNPs and haplotypes patients, respectively. Femoral osteoporosis and osteopenia were documented in association with Graves disease were performed. The strong linkage disequili- 37.9% and 55.1% of patients, respectively. Severe GHD was demonstrated in brium was found for: BsmI, ApaI, TaqI, that formed three the most frequent 25% of patients, while 17.1% displayed partial GHD. IGF-I SDS was low, i.e. haplotypes in Graves’ women: baT (47.9%), BAt (34.9%), bAT(16.4%). The below K1.88, in 54.6% of patients. Lumbar T-score values were not correlated lowest mean BMD values had homozygotic women with two copies of BAt. with either GH peaks or IGF-I SDS values. Femoral T-score values were However authors did not observe statistically significant association of analyzed positively correlated with GH peaks (rZ0.38, P!0.005) and IGF-I SDS haplotypes or polymorphisms with bone mineral density. The analysis of (rZ0.39, P!0.005). Furthermore, mean femoral T-score was significantly polymorphic variants distribution showed that only presence of F allele of lower in patients with severe GHD than in those with normal GH secretion VDR-FokI was more frequent in GD women as compared to controls (ORZ1.93; (K2.94C0.25 vs K2.15C0.12, P!0.01). 95% CI:0.97–3.84) with statistical tendency to significance (PZ0.058). Conclusions Conclusions GH-IGF-I deficiency appears to contribute to bone demineralization of adult 1. F allele of VDR-FokI polymorphism may predispose Polish women to GD. thalassemic patients at femural, but not lumbar level. This observation fits in 2. BsmI, ApaI, TaqI, FokI polymorphic variants of VDR gene do not predict well with experimental and clinical data demonstrating a greater action of the risk of decreased bone mineral density induced by excess of thyroid GH-IGF-I on cortical rather than trabecular bone. hormones in GD.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P69 were performed using a hologic-4500a densitometer. Data on birth weight, length Bone metabolism in hypothalamic obesity at birth, and gestational age was retrieved in a national database covering all birth Mirjana Doknic1, Sandra Pekic1, Dragana Miljic1, Marko Stojanovic1, clinics in Denmark in the current period. The relationship between Birth weight, Marina Djurovic1, Carlos Dieguez3, Felipe Casanueva2 & Vera Popovic1 BMC, Lean body mass and fat mass as tested using multiple regression analysis is 1Neuroendocrine Unit, Institute for Endocrinology, Belgrade, Serbia; shown in the table as partial correlation coefficients. 2Endocrine Section, Department of Physiology, Santiago de Compostela, Results Spain; 3Endocrine Section, Department of Medicine, Santiago de Data on birth weight and birth length were available on 754 participants. In Compostela, Spain. bivariate analyses, BMC at whole body, spine, and hip were significantly associated with current body weight (RZ0.50–0.30, P!0.001) and birth weight (RZ0.17–0.09, P!0.01). Birth weight was also significantly associated with Obesity protects from osteoporosis. Bone remodeling and energy metabolism current body weight (RZ0.09, P!0.01), current lean body mass (RZ0.15, could be regulated by the adipocyte-derived hormone, leptin acting on osteoblasts P!0.001) but not current fat mass (*P!0.05, **P!0.01, ***P!0.001). though hypothalamic pathways. Hypothalamic lesions cause obesity. Since most of these patients are also hypopituitary with low IGF1 which could affect bone metabolism the aim of our study was to investigate whether obesity would protect BMC them from osteoporosis. Three groups of patients were studied: (1) eight hypothalamic obese patients (HO R values WB Spine Hip K G G 2 4 female, mean age 25.5 2.1 years, BMI-38.4 2.8 kg/m ), (2) seven normal Birth weight 0.08* – – weight hypopituitary (HN K4 female, mean age 32.1G2.2 years, BMI-23.8G Current fat mass K0.35*** K0.38*** 0.67*** 1.3 kg/m2) and (3) four diet induced obese patients (DIO-3 female, mean age Current lean body mass 0.73*** 0.58*** K0.31*** 27.2G3.1 years, BMI K44.3G3.8 kg/m2). Patients were sex and age matched. Overall model 0.75*** 0.60*** 0.67*** The etiology of obesity in the HO and HN group was due to hypothalamo- pituitary tumor operation or hypothalamo-pituitary disconnection. All patients received standard hormone replacement therapy except for growth hormone Conclusion replacement after overnight fast serum leptin, IGF1, osteocalcin-OCL, CTx and Birth weight predicts peak bone mass, but this seems to be due to correlation 25-OH-vitamin D levels were measured. Body composition (Fat%) and bone between birth weight and body weight (and lean body mass) in young adult life. mineral density (BMD) were estimated by DEXA (Hologic). Relevant parameters are presented as meanGS.E.M. in Table.
BMI Leptin OCL CTx Vit. D IGF 1 DEXA BMD TBMC Groups (kg/m2) (ng/ml) (ng/ml) (ng/ml) (nmol/l) (ng/ml) Z score (g/m2) (kg) Fat% P71 (1) HO 38.4G 45.5G 16.2G 295G 24.0G 75.0G K0.7G 0.971G 2.3G 43.3G 2.8 4.8 2.9 12.6 4.0 6.0 0.1 0.1 0.2 2.4 (2) HN 23.8G – 33.1G 446G – 51.0G K1.8G 0.980G –– Every nanogram of 25(OH)D makes a difference: subgroup analysis of 1.3 4.2 15.1 5.7 0.7 0.1 institutionalized patients with vitamin D deficiency in Austria (3) DIO 44.5G 45.4G 23.8G 662G 65.8G 164G 0.4G 1.141G 2.9G 46.5G 3.8 5.0 2.4 15.3 9.2 8.7*,† 0.1† 0.1 0.2 3.1 Claudia Friedl, Harald Dobnig, Jutta Claudia Piswanger-So¨lkner, Barbara Maria Obermayer-Pietsch, Gunther Riedmueller & Astrid Fahrleitner-
*P!0.05 DIO vs HO; †P!0.05 DIO vs HN Pammer. Medicine University, Graz 8036, Austria. Conclusion 1. Obesity induced by hypothalamic lesion with concomitant hypopituitarism (low IGF1), protects from bone loss when compared with normal weight Elderly residents are at high risk for vitamin D deficiency due to hypopituitary patients with low IGF 1 levels. immobilization or little opportunity of uv exposure. Decreased cutaneous 2. When compared with diet-induced obesity despite significanlty lower IGF1 capacity to form cholecalciferol and diets low in calcium and vitamin D add levels bone mineral density and biochemical markers of bone turnover were to this problem. similar. In a prospective cohort study that we performed in 95 institutions in four different provinces of Austria we found that 93% of all patients had a 25(OH)D level %20 ng/ml. Aim of this study was to analyse whether differences exist in terms of parathyroid hormone and calcium metabolism as well as bone ultrasound measurements at different sites among groups of patients who already have very low levels of vitamin D (!15 ng/ml). Blood samples were collected in the months of May and June in a cohort of 961 female residents above 70 (mean age 84G6 years). Eighty percent of the patients had serum creatinine levels %1.2 and the remainder levels P70 %1.8 mg/dl. We formed following 25(OH)D groups: 0–4.9 (group A), 5– Birth weight and the relation to lean body mass and BMC in 9.9 (group B), and 10–15 ng/ml (group C). Residents of group A were on healthy men at peak bone mass: results from the Odense Androgen average 3 years older and had a slightly less BMI. Multivariate analysis Study adjusted for age, BMI, mobility status and creatinine clearance demonstrated Louise Frederiksen, Torben Leo Nielsen, Kristian Wraae, Claus Hagen, that group A had significantly lower corrected serum calcium levels (difference 0.07 mmol/l), a 28% increase in serum osteocalcin, a 95% Marianne Andersen & Kim Brixen ! Odense University Hospital, Odense, Denmark. increase in serum PTH levels compared to group C (all P 0.005). Quadriceps muscle strength was 12% lower in group A (P!0.01) as was the stiffness index at the calcaneus: Z-score K0.48 (vs K0.04 in group C, Background P!0.005). Radial and phalangeal SOS measurements were similarly low in Birth weight has been associated with low bone mass in later life. Previous all groups. studies, however, have relied on self-reported data on birth weight, included Our study demonstrates that even within a group of patients with already select populations, or been of a limited size. Moreover, it is unclear if the low 25(OH)D levels patients show significant differences in subgroups of association between birth weight and bone mass is be mediated by body weight, vitamin D deficiency in parameters relating to muscle strength, degree of lean body mass, or fat mass. hyperparathyroidism, bone turnover and bone mass. Aim We hypothesize that birth weight is associated with peak bone mass in men independent of current lean body mass and body weight. Participants and design The Odense Androgen Study is a population-based, prospective, observational study on the inter-relationship between endocrine status, body composition, P72 muscle function, and bone metabolism in young men. In brief, 3000 males aged Parathyroid hormone and glucocorticoid cooperatively induce RANKL 20–30 years were randomly selected from the civil registration database in Funen mRNA expression in osteoblasts through different mechanisms County, Denmark, and invited by mail to participate in the study. Seven hundred Fuminori Hirano, Atsushi Kobayashi, Naoki Maruyama, Keiji Komura, and eighty three gave written informed consent to participate in the study and the Kensaku Okamoto, Yuichi Makino & Masakazu Haneda data are presented here. Bone mass measurements (spine, hip, and whole body) Asahikawa Medical College, Asahikawa, Japan.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Glucocorticoid-induced osteoporosis is the most common form of secondary 1Endocrinology CHU, Clermont Ferrand, France; 2Medico surgical osteoporosis. Glucocorticoid is known to cause hyperparathyroidism due to intensive care CHU, Clermont ferrand, France; 3Surgery Clinique de la parathyroid hormone (PTH) secretion. In addition, glucocorticoid and PTH Plaine, Clermont Ferrand, France; 4Neurology CHU, Clermont Ferrand, have also been reported to induce RANKL mRNA expression in osteoblasts France. and promote osteoclastogenesis. However, little is known about cooperative effects of these hormones. The purpose of this study was to clarify the A 56 years old woman was admitted to an intensive Care Unit for generalized regulation of RANKL mRNA expression by glucocorticoid and PTH in seizure seven days following total thyroidectomy for toxic multinodular goiter. osteoblasts. We used normal osteoblasts and osteoblast-like cell line MG-63. Thyroidectomy included self transplantation of a right parathyroid gland. Quantitative real-time RT-PCR revealed that dexamethasone (DEX) and Pathologic analysis confirmed benign multinodular goiter, without parathyroid PTH significantly increased RANKL mRNA expression (15-fold, P!0.05) tissue. Post operatively, on LT therapy, follow up symptoms included facial for a time-dependent manner. In addition, PTH additively up-regulated 4 paresthesia associated to mild hypocalcaemia (1.56 mmol/l) at day 2, treated DEX-induced RANKL mRNA expression. Moreover, we found that DEX with oral calcium (1 g/day) and calcitriol 0.25 mg/day. Symptoms disappeared did not influence RANKL transcriptional activity by reporter gene assay and the patient was discharged. At day 7, she presented repeated generalized using human RANKL promoter. Furthermore, treatment with actinomycin D seizure requiring emergency in hospital admission. Blood total calcium and DEX markedly prolonged the half-life of RANKL mRNA, as compared concentration was dramatically low, 0.6 mmol/l, associated with low intact to treatment with actinomycin D alone (T1/2Zover 24 h vs 10 h), PTH concentration (10 ng/l – usual values 10–64). Immediately, calcium presumably indicating that DEX-induced RANKL mRNA expression is gluconate was infused, in conjunction with diazepam and phenitoine. Vitamin due to the stabilization of RANKL mRNA. In contrast, PTH clearly induced D intake was increased, up to 2 mg/day alfacalcidol, resulting in rapid RANKL transactivation and did not influence the stabilization of RANKL normocalcaemia. Yet, seizure recurred leading to a change in antiepileptic mRNA, suggesting that PTH regulates RANKL mRNA expression mainly drugs for levetiracetam. A CT scan demonstrated a 20 mm right frontal via RANKL gene transcriptional activation. In conclusion, we showed arachnoidal cyst. The patient remained well and was discharged on LT , that RANKL mRNA expression was cooperatively up-regulated by PTH via 4 alfacalcidol and levetiracetam. RANKL transcriptional activation and by glucocorticoid via the stabilization Conclusion of RANKL mRNA. Thus, glucocorticoid clinically regulates RANKL This report reminds the rare possibility of seizure in severely hypocalcaemic mRNA expression, at least in part, through two different mechanisms, adult patients, related to cerebral ionic and electric changes. The recurrence because glucocorticoid prolongs the half-life of RANKL mRNA directly and of seizure after correction of hypocalcaemia must suggest another activates RANKL gene transcription via glucocorticoid-induced PTH convulsive threshold lowering factor, in our report an arachnoidal cyst. secretion indirectly.
P73 Hyperparathyroidism-jaw tumor syndrome (HPT-JT): a new mutation in the HRPT2-gene Christine Haag1, Silke Pauli2, Egbert Schulze1, Karin Frank-Raue1 & Friedhelm Raue1 P75 1 2 Endocrine Practice, Heidelberg, Germany; Department of Human Subclinical hypothyroidism and bone mineral density Genetics, University of Go¨ttingen, Go¨ttingen, Germany. Zorica Rasic-Milutinovic, Dusan Milicevic, Zoran Gluvic, Marina Vujovic, Jelena Tica, Vesna Popovic-Radinovic, Gordana Perunicic-Pekovic & Inactivating germline mutations in the HRPT2 tumor suppressor gene are the Marija Popin-Taric cause of the hyperparathyroidism-jaw tumor syndrome (HPT-JT). The most University Hospital Zemun, Belgrade, Serbia. common feature of HPT-JT is primary hyperparathyroidism, followed by ossifying fibromas of the maxilla and mandible, renal cysts and solid tumors. Objective As recently recognized, mutations of this gene also play a central role in the Hyperthyroidism is accompanied by low bone mass. Because the reference range molecular pathogenesis of parathyroid carcinoma. of TSH levels is defined statistically, some individuals with high-normal TSH A 19-year-old woman presented with a giant cell granuloma of the right mandible levels (TSH !10 mU/l), may have mild hypothyroidism (subclinical hypo- which was surgically removed. One year later, she presented with a recurrence of thyroidism) and reduced bone mass. We therefore determined whether serum the giant cell granuloma. Serum calcium (3.65 mmol/l) and PTH (398 ng/l) were TSH levels correlate with bone mineral density (BMD) in persons with elevated and the patient was diagnosed for primary hyperparathyroidism. Surgical subclinical hypothyroidism. exploration revealed a parathyroid adenoma on the left side. Postoperatively Design serum calcium and PTH were within the normal range for the last 10 years. A cross-sectional study. Mutation analysis revealed the heterozygous mutation c.1423_1433delCT in exon Participants 16 of the HRPT2 gene. This mutation has not been described yet and leads to a Thirty-two postmenopausal women, 18 with hypothyroidism (Hypo) and 14 with shift in the reading frame with a premature stop-codon. subclinical hypothyroidism (Sub Hypo). The identification of the c.1423_1433delCT mutation is not only important for Measurements the patient herself, but it is also important for other family members who could We measured BMD at the lumbar spine and femoral neck using dual energy X-ray benefit from the identification as mutation carriers. The patients sister (33 absorptiometry, and serum TSH concentrations using immunoluminometry. Body years old) has an encapsulated tumor of the right hip since the age of 12, but mass index (BMI) was calculated from body weight and height. has not yet been diagnosed for the HPT-JT syndrome. Early diagnosis can be Results used for the detection and removal of malignant parathyroid and other BMD at the lumbar spine (0.816G0.136 vs 0.881G0.106 g/cm2, PZns), associated tumors. and total left hip (0.715G0.133 vs 0.673G0.094 g/cm2, PZns) didnot differ between the groups. Patients with Hypo had higher level of TSH (7.95G 1.51 vs 7.57G2.44, PZ0.03) and it correlated negatively with BMD at the lumbar spine and total hip. In regression analysis, even after adjustment for age, years since menopause and BMI, subjects with Hypo (TSHR10 mU/l) have shown significant association between TSH level and BMD at the lumbal spine (Adjusted R2Z0.82, PZ0.008) and femoral neck (Adjusted R2Z0.78, PZ0.004). In the group with Sub Hypo there were no significant P74 association between TSH level and BMD. Dramatic hypocalcaemia as a cause of generalized seizures following Conclusion thyroidectomy These results suggest that high normal TSH level, maybe is not the cause of Igor Tauveron1, Caroline Forichon1, Melanie Gardette2, Frederic Somda1, lower BMD in postmenopausal women, but low number of participants might be Francoise Desbiez1, Thierry Gillart2, Gerard Neouze3, Dominique Guelon2, the reason of questionable conclusion. Pierre Clavelou4 & Philippe Thieblot1
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P76 women with AN leading to decrease in bone mass. The precise mechanism for Seasonality, sun exposure, skin type and vitamin D levels influence enhanced bone resorbtion in AN is unclear but is tempting to speculate that leptin Parathyroid Hormone related Peptide (PTHrP) metabolism during might inhibit it. pregnancy and after delivery in mothers and their newborns Aris Siafarikas1, Max K Bulsara2 & Timothy W Jones3 1Princess Margaret Hospital, Department of Endocrinolgy and Diabetes, Perth, Australia; 2School of Population Health, University of Western Australia, Perth, Australia; 3Princess Margaret Hospital, Department of P78 Endocrinology and Diabetes, Telethon Institute for Child Health Research, Usual values and usefulness of crosslaps in pediatric practice University of Western Australia, Perth, Australia. Eric Mallet1, Agne`s Feray1, Marcelle Leroy2 & Jean-Paul Basuyau2 1Department of Paediatrics and Reference Center for Calcium and Phosphorus Metabolism Diseases, University Hospital, Rouen, France; PTHrP is an important factor for the regulation of calcium homeostasis around 2 delivery. The aim of this study was to longitudinally analyse PTHrP metabolism Biochemistry Laboratory - H. Becquerel Centre, Rouen, France. and influencing factors looking at mothers and their breastfed newborns from 32 weeks of pregnancy until 8 weeks after delivery. Nineteen families (8 Caucasian, Serum Crosslaps is a bone resorption specific marker already validated in adults 11 Arabic/Asian) participated in the study. We analysed PTHrP, 25 OH vitamin for osteoporosis helping in decision and therapeutic. Not yet clinically evaluated D, parathyroid hormone (PTH), alkaline phosphatase, albumin; serum and urine in children, we wanted to analyse the usefulness of this marker in paediatric calcium, phosphate and creatinine. Measures were obtained at 32 weeks of practice, easier to collect than the other bone resorption markers which need pregnancy (mothers), from cord blood and at 5 days and 8 weeks after delivery urinary collection often uncertain in children. (mothers and infants). UVB exposure was continuously quantified by spectral Patients and methods analysis using bio-weighted dosimeters. Surrounding factors and nutrition were Serum Crosslaps were measured using the One Step ELISA immunoassay assessed by questionnaires and analysis of meteorological data. (Osteometer) in a population basis of 175 healthy children. The data were Around delivery PTHrP-levels of mothers peaked to a level that was compared with results obtained in subgroups of children affected by bone G maintained subsequently (pmol/l S.E.M., 32 week/cordblood/day5/8weeks): metabolism diseases: osteogenesis imperfecta, mucoviscidosis, hypoparathyroid- G G G G ! 0.26 0.1/0.56 0.1/0.58 0.1/ 0.54 0.1, P 0.05. In newborns PTHrP on ism, hypercalcemia, corticotherapy, neuro-muscular pathology, precocious G day 5 decreased compared to cord blood levels and remained low (pmol/l puberty, anorexia nervosa. G G G ! S.E.M., cordblood/day5/8weeks): 0.54 0.1/0.27 0.1/0.35 0.1, P 0.005. Results Regression analysis revealed that PTHrP levels between mothers and their The paediatric reference data obtained in the population basis showed an children were not correlated. Subjects with mildly pigmented skin (WHO important dispersion and significant variations with age and growth: no significant ! types I and II) had higher PTHrP-levels (P 0.005). PTHrP was positively change occurred in either sex until ten years, then there was progressive increase ! correlated with sun exposure demonstrating seasonal variations (P 0.05). during puberty, peaking at 14–17 years in boys, earlier at 10–14 years in girls, ! PTHrP was inversely correlated with 25 OH vitamin D (P 0.05) and not before decreasing again until adults data. There was no significant difference dependent on PTH and calcium levels. between the results of population basis and subgroups of illness children. These results reflect that PTHrP is of importance for mothers around However, in cases of children with osteogenesis imperfecta, a decrease of serum delivery and during lactation and for newborns around delivery. It is the crosslaps was observed with bisphosphonate treatment. first study to demonstrate a longitudinal effect of sun exposure, seasonality, Conclusion skin type and vitamin D on PTHrP metabolism. Interindividual important changes and variations with age and growth make difficult the use of serum crosslaps in pediatric practice. It could be interesting in individual follow-up of pathology or treatment influencing on bone metabolism, as bisphosphonate treatment in osteogenesis imperfecta. It would be evaluated by carrying on the study on larger samples.
P77 The relationship between bone turnover and body weight and leptin in patients with Anorexia nervosa Marina Djurovic, Sandra Pekic, Dragana Miljic, Mirjana Doknic, P79 Milan Petakov, Marko Stojanovic & Vera Popovic Institute of Endorcinology, Belgrade, Serbia. Contribution of vitamin D supplementation to the vitamin D status of infants in the age of fortified milk Eric Mallet1, Jean-Paul Basuyau2 & Olivier Mouterde1 Anorexia nervosa (AN) is associated with bone loss due to weight loss, decreased 1Department of Paediatrics, Gastroenterology and Nutrition Unit, University caloric intake, amenorrhoea and behavioral changes. The most important Hospital, Rouen, France; 2Biochemistry Laboratory - H Becquerel Centre, predictor of the occurrence of bone loss is body weight (BMI !16.5 kg/m2). Rouen, France. Previous studies suggested that many factors including effects of chronic undernutrition in AN patients is associated with a reduction of bone formation (osteocalcin-OC) uncoupled with increased resorption markers (crosslaps-CTx). In line with European guidelines, infant formulas in France have been vitamin w The aim of the study was to investigate the relationship of bone turnover and body D-fortified with a vitamin D3 content of 400 IU/l. New guidelines for the weight and serum leptin levels in 13 AN patients (BMI 14.3G0.4 kg/m2; DSM- prevention of vitamin D deficiency and rickets have subsequently been published IV criteria). They were compared with 9 age matched lean controls (BMI 20.1G and the vitamin D supplement for formula-fed infants was reduced from 800 to 0.8 kg/m2; CO). After overnight fast serum leptin, osteocalcin-OCL, CTx and 400 IU per day. 25-OH-vitamin D levels were measured. Bone mineral density (BMD) were To contribute to the evaluation of the need for vitamin D supplementation, a study estimated by DEXA (Hologic). Relevant parameters are presented as meanG was conducted to assess vitamin D3 intake (cholecalciferol) provided by sunlight S.E.M. in Table. exposure and fortified milk, and intake provided by supplementation prescribed in Results form D2 ergocalciferol. This study was conducted in a population of Caucasian infants. The vitamin D2 intake, the type and quantity of milk received, time spent Age BMI Leptin OCL CTx Vit. D outdoors and clothing modalities were recorded. Gr (years) (kg/m2) (ng/ml) (ng/ml) (ng/ml) (nmol/l) DEXA Z score Vitamin D status was assessed on serum left over from a blood sample obtained during the infant’s hospitalization; 25(OH)D2 and 25(OH)D3 levels were AN 23.8G1.6 14.3G0.4* 2.3G0.6* 21.8G4.57* 0.7G0.2* 40.4G2.2 K3.2G1.5* CO 23.3G0.73 20.1G0.8* 9.7G2.1* 29.1G3.18* 0.5G0.1* 38.6G6.8 0.4G0.2* evaluated by HPLC followed by radioimmunoassay. Forty-five term infants between the ages of 2 and 14 months (26 boys and 19 girls) *P!0.05. were included, during Winter for 19 cases and during Summer for 26 cases. The contribution of 25(OH)D2 vitamin D supplementation (mean: 18 ng/ml; range: 2–47) was approximately equal to vitamin D intake from sun exposure and Conclusion 25(OH)D3-fortified milk (mean: 21 ng/ml; range: 5.5–32). Our results favour the role of body weight, fat mass and leptin in uncoupling of Three infants had a low 25(OH)D2 level and one had a level of 2 ng/ml. The bone turnover with decreased bone formation and increased bone resorption in 25(OH)D3 level was low (!10 ng/ml) for 5/36 infants, all included during
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Summer. subjects BMI, levels of calcium, PTH, 25 hydroxy-vitamin D, creatinine and The most original result of this study is the equivalent contribution to the infant’s creatinine clearance and bone mineral density (BMD) at lumbar spine, femur and vitamin D status of D3-intake by fortified milk and sun exposure and D2-intake by the distal radius by DXA were evaluated. prescribed vitamin D supplement. The vitamin D status appeared to be satisfactory Results under these conditions, with extreme values within the locally defined normal range. A positive association between BMI and DXA measurement at femoral levels was found (BMI-BMD: RZ0.52, P!0.004; BMI-T score: RZ0.53, P!0.002; BMI- Z score: RZ0.55, P!0.002). On the contrary, neither PTH, calcium, renal function nor 25-hydroxy-vitamin D showed significative correlation with BMD levels. P80 Conclusions BMI resulted a good predictor of BMD in male patients with PHPT as found in The influence of ESR1 gene genotype on bone mineral density in women with PHPT, confirming the important role of BMI as risk factor for bone premenopausal women with Grave’s disease damage in osteoporosis of both primary and secondary origin. On the contrary, Wanda Horst-Sikorska1, Michalina Marcinkowska1, Anna Wawrzyniak1, 1 2 biochemical indices of PHPT as well as renal function did not associate with DXA Magdalena Ignaszak-Szczepaniak , Malgorzata Stajgis & measures in male patients, differently from female. These findings could indicate Ryszard Slomski3,4 1 gender-dependent differences in the clinical expression of PHPT, particularly at Department of Family Medicine, Poznan University of Medical Sciences, bone level. A peculiar resistance of male bone to PTH excess in PHPT could be Poznan, Poland; 2Endocrinology Outpatient Clinic, Poznan, Poland; 3 also hypothesized. These findings suggest that the clinical management of the Department of Biochemistry and Biotechnology, Poznan University of modern form of PHPT should be differently by gender. Agriculture, Poznan, Poland; 4Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
Introduction P82 The etiology of this autoimmune disorder results from the presence of stimulating antibodies binding to TSH receptor. The disease has a strong genetic background Primary hyperparathyroidism during pregnancy: a case report associated with HLA and CTLA-4 genes. Hulya Dogru, Ercan Bicakci, Serpil Salman, Sema Yarman, Refik Tanakol, The aim of study Harika Boztepe & Faruk Alagol The aim of this study was to estimate the influence of polymorphic variants of Endocrinology and Metabolic Disease Department, Istanbul Faculty of ESR1 gene on the bone mineral density in young premenopausal women with Medicine, Istanbul University, Istanbul, Turkey. Grave’s disease (GD). Material and methods Primary hyperparathyroidism (PHP) during pregnancy is a very rare event that The study was conducted on 75 premenopausal women with GD. The average age increases maternal and fetal morbidity and mortality. Complications during of the women was 37 years (from 23 to 46), weight 64 kg (from 51 to 98 kg), pregnancy or neonatal period have included spontaneous abortion, stillbirth, height 1.64 m (from 1.50 m to 1.80 m). The analyzed group of women with GD in neonatal death, neonatal tetany. the state of hyperthyroidism. All of them still had regular menses at the time of Management of maternal PHP diagnosed during pregnancy should be based on this study. The control group consisted of 160 women without thyroid disease the patients’ symptoms and severity of the disease. Hyperparathyroidism In all of the cases measurements of BMD in the lumbar spine L1-L4 (LS) and characterized by progressive symptoms should be treated surgically, preferably femoral neck (FN). Laboratory evaluation included: serum TSH levels, free T4 during the second trimester as in the case reported here. A 27-year-old woman and T3 and TPO thyroperoxidase antibodies levels at the beginning of the study. was admitted to our clinic at four weeks of gestation with the complaints such as In all cases there were performed DNA isolation from the peripheral blood and nausea, vomiting and dyspeptic symptoms. One week before, routine biochemical PCR reaction. The PCR product was analyzed by restriction fragment length analysis revealed elevated serum calcium level of 13.3 mg/dl and was referred to polymorphism (RFLP) using PvuII and XbaI restrictases. our clinic. On admission biochemical tests were as follow: Serum calcium Results 13.7 mg/dl, phosphorus 2.2 mg/dl, albumin 3.6 gr/dl, PTH 109 pg/ml. Ultra- Homozygotic women with px haplotype had the lowest LS BMD value ! 2 sonography of the neck showed a parathyroid adenoma of 1.2 0.5 cm size, in the (1.113 g/cm ). For this haplotype the tendency dose effect was observed, but neighborhood of the inferior pole of the left thyroid lobe. Ultrasonography guided not statistically significant. washout was carried out from the suspected adenoma and PTH was measured The dominant effect was evaluated for PX haplotype, homozygotic PX haplotype O 5000 pg/ml within the nodule. After treatment with isotonic sodium chloride, had the highest LS BMD (1.246 g/cm2). A dose effect for PX haplotype was serum calcium dropped to 12 mg/dl and the adenoma was excised in second observed. trimester of the gestation. The postoperative course was uncomplicated. At the In these cases results were statistically significant. discharge from the hospital the patients’ serum calcium level was 9 mg/dl. Still Conclusion she has a healthy ongoing pregnancy. (1) px haplotype of ESR1 gene may determine lower BMD value in the lumbar Hyperthyroidism should be considered and the serum calcium level measured in a spine L1-L4. pregnant woman who has resistant nausea and vomiting. This condition can be (2) PX haplotype of ESR1 gene can determine higher BMD value in lumbar spine. misdiagnosed as hyperemesis gravidarum and underlying disease may be missed. When PHP is discovered during pregnancy, management depends on the degree of the hypercalcemia, gestational age, and presence of complications. Available evidence suggests that the typical mildly hypercalcemic and asymptomatic pregnant woman with PHP can be safely managed conservatively provided P81 neonatal hypocalcemia is sought for and treated. Otherwise, treatment should be surgery preferably in the second trimester of the pregnancy. Predictors of bone mineral density in men with primary hyperparathyroidism Francesco Tassone, Laura Gianotti, Micaela Pellegrino, Chiara Croce, Claudia Baffoni, Gianpaolo Magro, Flora Cesario & Giorgio Borretta Division of Endocrinology and Metabolism, S. Croce and Carle Hospital, Cuneo, Italy. P83 Lack of relationship between the BsmI polymorphism in the vitamin D receptor gene and the risk of glucocorticoid-induced osteoporosis in Introduction premenopausal asthmatic women on a long-term glucocorticoid therapy In primary hyperparathyroidism (PHPT) bone involvement is frequent. In women Urszula Tworowska-Bardzinska1, Bozena Bidzinska-Speichert1, with PHPT it has been previously reported that menopausal status together with Andrzej Obojski2 & Agnieszka Lenarcik1 PTH, calcium levels and renal function are independent predictors of bone 1Departament of Endocrinology, Diabetology and Isotope Treatment, density. In male subjects, the impact of PHPT on bone status is less defined. Medical University of Wroclaw, Wroclaw, Poland; 2Departament of Aim of the study Internal Medicine and Allergology, Medical University of Wroclaw, To investigate this study was possible predictors of bone mineral density (BMD) Wroclaw, Poland. in a series of male subjects affected by PHPT. Subjects and methods Sixty male patients with PHPT were consecutively studied (age, meanGS.D.: Results of many studies indicate that the BsmI polymorphism in the vitamin D 57.9G14.1 years; Symptomatic/Asymptomatic 32/28; PTH, median and receptor (VDR) gene may influence bone tissue metabolism and may be useful in interquartile levels: 119 and 95.0–228 pg/ml, calcium 11.1G1.0 mg/dl). In all identifying patients at greater risk of osteoporosis. As far as long-term
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 glucocorticoid treatment is a major risk factor for osteoporosis development, we The BMD was performed using dual-energy X-ray absorptometry (DXA) in looked for the BsmI VDR gene polymorphism and its relation to phenotypic lumbar spine (LS) and femoral neck (FN). WHO criteria were used for features characterizing bone status (BMD and metabolic bone turnover) in 74 defining osteoporosis: T-score %K2.5 S.D. Statistics analysis: the data were premenopausal women: 51 asthmatic patients treated for a long-term with GCs evaluated using SPSS 12.0. P value set at 0.05 as a minimal level of and 23 healthy controls. BMD was measured using DXA method. Serum levels of significance. osteocalcin and ICTP (as markers of bone turnover) were measured using IRMA Results 2 and RIA methods respectively. VDR gene genotypes were determined using Clinical characteristics: mean age (GS.D.): 22.2G3.5 years, BMI 17.7G2.4 kg/m , PCR-RFLP method. Results: Genotype bb was found in 32.4%, BB in 10.8%, and disease duration 33.3G9.2 months and amenorrhea duration 17.8Gmonths. bB in 56.8%. There were no significant differences regarding BMD, biochemical Sixteen woman (34%) were diagnosed of osteoporosis in LS and 3 (6.5%) in FN. and hormonal parameters between any of genotypes. Conclusions Genotype distribution was similar to those observed in other Caucasian BMD Lumbar T-Score Lumbar Amenorrhea duration populations. The data suggest that the VDR BsmI polymorphism does not seem Duration RP r P r P to be useful for identifying patients at greater risk of glucocorticoid-induced osteoporosis, however it needs to be confirmed by a population-based study. Weight (kg) 0.41 0.04 0.43 0.03 K0.40 0.08 BMI (kg/m2) 0.58 0.002 0.58 0.002 K0.31 0.04 Amenorrea K0.44 0.03 K0.45 0.02 – – duration (months) Estradiol 0.99 0.001 0.99 0.001 0.72 0.001 (pg/ml) P84 Body fat (%) 0.57 0.03 0.60 0.01 K0.46 0.01 Intra-operative and routine intact parathyroid hormone assay on the Beckman Coulter Unicelw DxI 800 1 1 1 Catherine Fille´e , Jean-Michel Allaeys , Anne-Marie Delait , Conclusion 2 1 Ve´ronique Jarrige & Jean-Marie Ketelslegers The women with AN have a decreased BMD in LS and FN, but the lumbar 1 2 Cliniques Universitaires St-Luc, Brussels, Belgium; Beckman Coulter spine is mostly affected by a major risk of fractures. The fat mass loss and Eurocenter, Nyon, Switzerland. the estrogen deficiency are, both, a very important risk factors to the BMD loss, fundamentally to level of LS. The amenorrhea depends fundamentally Background on nutritional factors. Parathyroid hormone (PTH) assay is critical for diagnosis of calcium disorders and intraoperative (IO) monitoring of parathyroid surgery. We evaluated the new Accessw Intact PTH (iPTH) on the UniCelw DxI 800 (Beckman Coulter). Methods Imprecision was evaluated for routine and intraoperative (15 min) procedures, at 3 control levels, run 20 times in duplicate over 10 days (NCCLS EP5-A protocol). Normal values were obtained from healthy blood donors (16–66 years; 123 in winter; 163 in summer). Pathological and IO conditions were tested. Results For routine assay (iPTH: 30, 291 and 892 pg/ml), intra-assay CVs were 1.9, 1.9, 2.4% and total imprecision was 2.4, 2.6 and 2.4% respectively; for IO procedure P86 (iPTH: 21, 206, 637 pg/ml), intra-assay CVs were 2.0, 2.5, 2.4% and total Vitamin D deficiency and supplementation in pregnancy, a randomised imprecision 4.4, 4.9, 6.2%, respectively,. iPTH mean normal value was 36 pg/ml study of 180 women in four ethnic groups (geometrical mean, 95% confidence limits:16–81). iPTH correlated negatively to CYH Yu, L Newton, M Sethi, TG Teoh & S Robinson calcemia (rZK0.25; P!0.001) and 25-OH vitamin D3 (rZK0.29; P!0.001). St Mary’s Hospital at Imperial Health Sciences Trust, London, UK. In winter, iPTH level was 10% higher than in summer (PZ0.03), reflecting differences in vitamin D3. Among 35 surgically proven cases of primary hyperparathyroidism (calciumO10 mg/dl), iPTH ranged from 39 to 252 pg/ml Objective (median: 81). iPTH was lower than 3 pg/ml in 2 children with idiopathic To determine the vitamin D status in pregnancy and to evaluate the effects of daily hypocalcemia and in 3 patients with malignancy-associated hypercalcemia. In 18 and of single-dose vitamin D supplementation. successful surgical procedures for primary hyperparathyroidism, iPTH concen- Design trations fell by 79% (55%–91%) 10 min after ablation, with no further decrease A prospective randomised study, in an inner city ante-natal clinic. after 20 min. In 1 case of partial removal of an invading parathyroid tumor, PTH Participants decreased by only 22% after 20 min. Forty-five women in each of the four ethnic groups, Indian Asians, Middle Conclusion Eastern, Black and Caucasian, were studied (incomplete delivery data at time of The Accessw Intact PTH assay is reliable for diagnostic purposes as well as for submission). intraoperative use, in the setting of a routine core laboratory. Intervention Women were randomised into three treatment groups: a single oral dose of 200,000 IU vitamin D, a daily supplement of 800 IU vitamin D from 27 weeks until delivery and a no treatment group. Results At 27 weeks gestation, there was a significantly lower concentration of P85 vitamin D levels in Asian (25C10 nmol/l), Middle Eastern (21C9nmol/l) C C Clinical and hormonal variables to predict bone mineral density loss in and Black (23 13 nmol/l) compared to the Caucasian group (42 17 nmol/l); P!0.001. Secondary hyperparathyroidism (PTH levels O anorexia nervosa patients Z Amalia Gonzalez, Mariela Varsavsky, Ines Luque Fernandez, 6.8 pmol/l; n 46) was significantly higher in Asian (26.7%), Middle Eastern (48.9%) and Black women (24.4%) compared to Caucasian women Socorro Leyva, Mercedes Palma Moya & Marisa Fernandez Soto ! Eating Disorders Unit, Endocrinology and Nutrition Department, University (2.2%); P 0.05. All ethnic groups had normal calcium levels at 27 weeks Hospital San Cecilio, Granada, Spain. and at delivery. Significant predictors of Vitamin D levels at 27 weeks are ethnic group, age, parity and daily sunlight exposure greater than 2 hours. There was a significant increase in the maternal vitamin D concentration in Objective the supplemented group (daily 42C12, stat dose 34C13 vs 27C14 nmol/l Anorexia nervosa (AN) is often associated with severe mineral bone loss and in the no treatment; P!0.01) and cord vitamin D concentration (daily 27C increased risk of fractures. The objective of this study was to assess the bone 14, stat dose 26C13 vs 17C14 nmol/l in the no treatment; P!0.0001). mineral density (BMD) in patients with AN and its relationship with different There was no significant difference in the method of supplementation. anthropometrics, clinical and hormonal parameters. Conclusion Patients and methods Vitamin D levels were significantlylower in Asian, Middle Eastern and Black women We evaluated 47 women with AN according to criteria of DSM-IV. The compared to Caucasian. Women may potentially benefit from vitamin D anthropometrics variables measured were: weight (kg) height (m), BMI (kg/m2) supplementation in pregnancy, which can be achieved with a single dose at 27 and corporal composition. The body fat were measured using a bioelectrical weeks gestation. impedance analysis system (TANITA). Hormonal profile: estradiol and IGF-1.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P87 P89 Clinical experience with Cinacalcet for treatment of persistent primary Relationship between parity and osteoporotic fractures in postmeno- hyperparathyroidism pausal osteoporotic women (PMOW) Sandra Martinez-Fuster, Victor Gonza´lez, Alicia Lo´pez, Oscar Moreno- F Papadopoulou, G Polizogoulis, A Sideridis, G Stafilidis, P Simeonidis, Pe´rez, Nieves Arias, Paula Revert, Ruth Sa´nchez, Evangelina Boix & P Panteliadis, X Terzelidis, G Petalotidis & A Georgiadis Antonio Miguel Pico´ Osteoporosis Center Lito Gynecological Hospital, Athens, Greece. Department of Endocrinology and Nutrition, Alicante General University Hospital, Alicante, Spain. Several studies have shown a positive correlation between parity and reduced hip fracture rate later in menopause while others have shown no Introduction correlation or a negative one. Thus, it is possible that some of the In primary hyperparathyroidism (PHPT) medical treatment is indicated if the conflicting results reported in literature may be attributable to differences in patient donot carry out the surgical criterion, donot accept surgery or there is the ages of the populations studied or of the concomitant presence or not of another serious comorbidity that makes impossible the intervention. Cinacalcet is osteoporosis. a calcimimetic that increase the sensitivity of the calcium-sensing receptor In order to elucidate these conflicting results, a population based (CaSR) to ionized serum calcium, decreasing secretion of PTH and serum observational retrospective study has been performed at 160 centers all calcium concentration. This drug is prescribed for secondary hyperparathy- over Greece. The fracture rate of 4616 postmenopausal osteoporotic women roidism in patients with dialysis and in parathyroid carcinoma. Recent trials (PMOW) (mean ageZ64.1G9.3 years) has been compared with the number suggests it use in the treatment of PHPT. of their children. Patients have been divided into two main groups. Group A Objective consisted of women with two or less children and Group B of women with To show our experience about the use of Cinacalcet for the treatment of 3 and more children. Descriptive statistics like the meanGS.D.and persistent PHPT. frequencies were used to present the data. In order to assess for Patients and methods relationships between categorical variables the c2 test was performed. Three patients (women), age range between 50 and 61 years, diagnosed of Statistical analysis was conducted using the software SAS, version 9.1 and persistent PHPT after surgery. The mean time of monitoring was 3 years (range statistical significance was established as 5%. The results are as follow: 2–6). Reasons to start Cinacalcet (initial dose 30 mg/12 h): failure of the second 1. 16.2% of these PMOW had a history of fracture and for 80.3% of them surgery, patient 1; gastric cancer and patient’s rejection to another surgery, patient was a hip fracture. 2; serious local fibrosis secondary to previous surgery (thyroid and parathyroid) 2. There was no correlation of the parity in general and the rate of fracture and patient’s rejection to another intervention, patient 3. In two patients previous (PZ0.6887). treatment with biphosphonates failed. 3. Group B women had higher fracture rate than Group A women which Results was a statistically significant result (P!0.05). Cinacalcet caused a mean decrease of 2.1 mg/dl (range 1.7–2.8) in serum calcium It can be concluded that more fracture-susceptible PMOW are those having concentration, without effect in PTH level. three children or more. It seems that the beneficial effect of multiparity on Conclusion BMD, as it has been described by others, may be lost after menopause Cinacalcet is an effective alternative in non-surgical treatment of PHPT. We need especially in an osteoporotic population. more studies to know it effects about mineral bone density and quality of life.
P88 R-568 improves transmembrane signal transduction of inactivating P90 mutations of the calcium-sensing receptor Ramona Rus, C Haag, E Schulze, K Frank-Raue, F Raue & Christof Scho¨fl Relationship between osteoporosis and living/working environment 1Division of Neuroendocrinology, Department of Neurosurgery, Friedrich- A Georgiadis, K Tapsis, K Tseronis, I Fillipitzis, P Fitili, K Zervas, Alexander University, Erlangen-Nuremberg, Germany; 2Endocrine A Ziogas, A Karapiperis & E Ntavas Practice, Heidelberg, Germany. Osteoporosis Center, LITO Gynecological Center, Athens, Greece.
Inactivating mutations of the calcium-sensing receptor (CaSR) gene, present in Osteoporosis can be caused by many miscellaneous factors. These factors include homozygous or heterozygous forms, cause neonatal severe hyperparathyroidism medical, lifestyle and socioeconomic variables, the latest being not well studied or familial hypocalciuric hypercalcemia. The R-568 binds to the transmembrane and defined in international bibliography. From these there are the factors region of the CaSR thereby enhancing its sensitivity to extracellular calcium regarding the working environment (house or office) and the living environment 2C ([Ca ]o) and inhibiting parathyroid hormone (PTH) secretion. The therapeutic (urban or countryside). Our hypothesis is based on the fact that women living in potential of calcimimetics like R-568 has been demonstrated in patients with an urban environment or working in an office environment should have lower primary hyperparathyroidism as well as in patients exhibiting secondary Bone Mineral Density (BMD) and thus, greater fracture possibility because of hyperparathyroidism. In the present study we tested, whether R-568 could their lower level of physical activity, greater alcohol/coffee consumption and improve transmembrane signaling of naturally occurring inactivating mutants of increased smoking frequency compared to women living in the countryside or the CaSR. women housekeeping. Mutant cDNAs of seven CaSR mutations (W530G, C568Y, W718X, M734R, In order to find whether this hypothesis is true, a population based L849P, Q926R and Q1005N) were generated and transfected into HEK293 cells. observational retrospective study has been performed. The fracture rate of Functional characterization was performed by measuring intracellular calcium in 4616 postmenopausal osteoporotic women (PMOW; mean ageZ64.1G9.3 2C response to varying [Ca ]o. The transfected HEK293 cells were stimulated with years) from 160 centers all over Greece has been compared with the two 2C G 3or10mM[Ca ]o with or without R-568 (1 mM). R-568 significantly enhanced aforementioned possible risk factors. Descriptive statistics like the mean S.D. 2C 2C the intracellular Ca response to 3 mM [Ca ]o in cells expressing the wild-type and frequencies were used to present the data. In order to assess for (WT) CaSR, and the W530G, Q926R and Q1005N mutants (P!0.01). relationships between categorical variables the c2 test was performed. 2C The C568Y mutant did not respond to [Ca ]o up to 30 mM. In the presence Statistical analysis was conducted using the software SAS, version 9.1 and 2C 2C R-568 (1 mM), however, 10 mM [Ca ]o caused an increase in intracellular Ca statistical significance was established as 5%. by 30 nM (nZ10). By contrast, in cells expressing the W718X, M734R, and The results are as follow: (1) 16.2% of these PMOW had a history of fracture 2C 2C L849P mutant no [Ca ]o-induced cytosolic Ca response could be observed and for 80.3% of them was a hip fracture (2) 84.1% of PMOW lived in urban even in the presence of R-568 (1 mM). environment and had lower fracture rate than women living in the countryside In conclusion, the allosteric calcimimetic R-568 could enhance transmembrane (P!0.05) and 3) 47.2% of the PMOW worked at home and had lower fracture signaling in certain inactivating mutants of the CaSR. This might offer medical rate than women working for more than 20 years in an office environment treatment to severely affected individuals (homozygotes) harbouring a (P!0.0001). calcimimetic-sensitive CaSR mutant. The sensitizing action of R-568 appears It can be concluded that more fracture-susceptible PMOW are those working in to be restricted to mutants, that have mutations in the extra- or intracellular part of an office environment and also living in the countryside. It can be assumed that the CaSR, since all non-responsive mutants were either truncated (W718X) or the first is related with lower BMD and the second with the more ‘fall-prone’ mutated in the transmembrane domain (M734R, L849P). nature of the country environment.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P91 correlation was observed only between OPG and osteocalcin in controls and in a group of CD patients after treatment. The slight negative correlation was found Determinants of spinal deformities in adult patients with untreated ! growth hormone deficiency (GHD) between OPG and spine BMD in whole examined group (P 0.05). Gherardo Mazziotti1, Antonio Bianchi2, Stefania Bonadonna1, Conclusions Vincenzo Cimino2, Alessandra Fusco2, Ilaria Patelli1, Laura De Marinis2 & The OPG is involved in the process of bone turnover in celiac disease, but the Andrea Giustina1 mechanism is not clear. The elevation of OPG might be a compensatory 1University of Brescia, Brescia, Italy; 2Catholic University of Rome, mechanism against other factors that promote bone damage, but perhaps it is a Rome, Italy. part of inflammatory process in CD.
Adult GHD patients may have reduced BMD with high risk of vertebral and non- vertebral fractures which is thought to be reverted by long-term rhGH replacement therapy. In this study we aimed at identifying the determinant P93 factors of vertebral fractures, as assessed by a radiological morphometric Insulin sensitivity and lipid status before and after radical treatment of approach, in a cohort of adult patients with untreated GHD. Forty-two patients primary hyperparathyroidism (27 males, 15 females; median age: 48 years, range: 30–67) with untreated severe Aleksandra Kendereski, Dragan Micic, Goran Cvijovic, Svetlana Zoric, (as defined by a peak GH response to a stimulation test of !3 mg/l) GHD were Mirjana Sumarac-Dumanovic, Danica Pejkovic & Maja Simic evaluated for vertebral deformities (T4-L5 quantitative morphometric analysis Institute of Endocrinology, Diabetes and Diseases of Metabolism, Belgrade, according to Genant score) and bone mineral density (dual-energy X-ray Serbia. absorptiometry). Radiological vertebral fractures were found in 33 patients (78.6%). Twenty-two patients had two or more fractures, whereas in 11 patients the fractures were single. Moreover, the fractures were mild in 54.8%, moderate It was previously shown that patients with primary hyperparathyroidism (PHPT) in 19.0% and severe in 7.1% of patients. Fractured patients had a duration of GHD are insulin resistant. The aim of our study was to evaluate the effect of surgical significantly longer as compared with the patients who were found without treatment on insulin sensitivity and lipid levels in patients with PHPT. In 21 G G 2 vertebral fractures (10.4G1.9 vs 3.4G0.9 years; PZ0.002). The duration of patients with PHPT (age: 56.24 8.69 years, BMI 25.2 3.81 kg/m ) lipid levels GHD was also correlated with the number of fractures. Fractured and non- (TC, HDL, LDL, TG, Lp(a)) and insulin sensitivity were determinated before and fractured patients showed not significant differences in age, sex, bone mineral 4 months after surgical treatment. Insulin sensitivity was evaluated using density, prevalence of untreated hypogonadism. Moreover, fractured and non- euglycemic hyperinsulinemic clamp. fractured patients showed comparable serum IGF-I values (79.3G6.9 ng/ml vs Results G 89.7G12.3 ng/ml). However, serum IGF-I values were correlated with the There was significant difference in insulin sensitivity (M index: 4.07 2.05 vs G ! number of vertebral fractures, independently of the duration of GHD. In fact, in 7.14 4.91, P 0.01) before and after surgical treatment, while there was no G G O the patients with lower serum IGF-I values (1st tertile) the prevalence of multiple change in BMI before and after testing (25.20 3.81 vs 25.39 3.56, P 0.05). G G O spinal fractures was significantly greater as compared to patients with higher IGF- There was no difference in TC (6.07 1.45 vs 5.97 1.35, P 0.05), G G O G G I values (3rd tertile; 76.9% vs 33.3%; PZ0.01), although the two groups of HDL (1.23 0.35 vs. 1.25 0.36, P 0.05), LDL (3.85 1.18 vs 3.93 1.26, O G G O G patients did not show significant differences in the overall prevalence of vertebral P 0.05), Lp(a) (0.21 0.27 vs 0.18 0.22, P 0.05) and TG (1.87 0.81 vs G O deformities (86.7% vs 73.3%). Furthermore, the patients with severe spinal 2.16 1.03, P 0.05) levels before and after surgical treatment. In conclusion, fractures showed significantly lower IGF-I values as compared to patients radical treatment improves insulin sensitivity in patients with PHPT. with mild spinal deformities (39.7G15 ng/ml vs 90G7.6 ng/ml; PZ0.009). In conclusion, in adult patients with untreated GHD the duration of disease seems to be the main predictor of vertebral fracture risk. However, patients with lower serum IGF-I levels are those at risk of a more severe bone impairment. P94 Scintigraphic, biochemical and clinical response to zoledronic acid treatment in patients with Paget’s disease of bone Avraam Avramidis1, Stergios Polyzos1, Efstratios Moralidis2, P92 2 1 2 Georgios Arsos , Zoe Efstathiadou , Konstantinos Karakatsanis , Osteoprotegerin and bone mineral density in adult patients with celiac Georgios Grollios3 & Marina Kita1 disease 1Department of Endocrinology, Hippokratio General Hospital, Thessalo- Jadwiga Szymczak1, Anna Bohdanowicz-Pawlak1, Ewa Waszczuk2 & niki, Greece; 2Department of Nuclear Medicine, Aristotle University, Urszula Tworowska1 Thessaloniki, Greece; 3Department of Radiology, Hippokratio General 1Department of Endocrinology. Diabetology and Isotope Treatment, Hospital, Thessaloniki, Greece. Wroclaw Medical University, Wroclaw, Poland; 2Department of Gastro- enterology and Hepatology, Wroclaw Medical University, Wroclaw, Poland. Introduction Bisphosponates have long been used with success in the treatment of Paget’s disease of bone (PDB). The aim of this study was to evaluate the early (up to three Background months) and late (at twelve months) scintigraphic, biochemical and clinical Calcium and vitamin D malabsorption in celiac disease (CD) predispose to high response to a single intravenous infusion of zoledronic acid (ZOL) in patients bone turnover and skeletal demineralization. Osteoprotegerin (OPG), a member with PDB serially assessed for one year. of the tumor necrosis factor receptor family, and ligand of receptor activator of Materials and methods NFkB (RANKL) inhibits osteoclast formation and activity. Nine patients with 30 bone lesions due to PDB were prospectively evaluated. The aim of this study was to evaluate the relationship between bone mineral Total serum alkaline phosphatase (SAP) was serially measured. Scintigraphy was density (BMD), bone-turnover markers and osteprotegerin in adult patients with performed before, three and twelve months after ZOL administration and bone CD and assess whether a gluten-free diet (GFD), calcium and vitamin D lesions were assessed quantitatively. supplementation are sufficiently effective for BMD restoration. Results Methods After treatment, pain was alleviated in five out of six patients starting from the BMD, calcemia, calciuria, and serum osteoprotegerin, Vitamin D, parathormone first month. At three months, a significant decrease of SAP levels compared to (PTH) and bone-turnover markers (ALP, osteocalcin, ICTP (C-terminal baseline values was found (322G211 IU/l before versus 101G36 IU/l three telopeptide of type I collagen)) concentrations were measured in 27adult CD months after, P!0.05), with normal values attained in all but one patient. The patients and in 26 controls. Then the CD patients were treated with a GFD and scintigraphic index of involvement (SII), a marker for the per-patient activity of calcium plus alfacalcidol for one year. the disease, was reduced from 14.4G7.6 to 7.2G1.8 (PZ0.01). The scintigraphic Results ratio (SR), a marker for the per-lesion activity of the disease, was reduced from Reduced BMD was diagnosed in 57–77% of the patients. Mean calcemia, 12.8G7.7 to 7.0G2.9 (P!0.001). The values of markers of disease activity calciuria, and 25(OH) Vitamin D were lower, but serum PTH and bone-turnover remained unchanged up to twelve months. markers were significantly higher in CD patients than in controls. After one year Conclusion of treatment, the biochemical abnormalities were considerably reduced, and BMD A single intravenous administration of ZOL leads to a favorable clinical, significantly increased (P!0.05), mostly in the lumbar spine. biochemical and scintigraphic response in patients with PDB starting Serum osteoprotegerin concentration was higher in CD patients than in controls as early as three months after treatment and lasting no !12 months before (PZ0.001) and after (PZ0.009) treatment. There was no correlation (i.e considerably longer than the existing other therapies). between OPG, PTH and bone turnover markers in CD patients. The negative
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P95 alkaline phosphatase (PZ0.004) and deoxypyridinoline (PZ0.029) at the end of the study. Those variations were significantly more pronounced in group A Significance of bone mineral density measurement at multiple skeleton Z Z Z Z sites (P 0.000, P 0.002, P 0.003 and P 0.02, respectively). There was no Panagiotis Athanassiou1, Ifigenia Kostoglou-Athanassiou2, significant difference in BMD parameters between groups. Charalampos Gerodimos1, Nikolaos Dadiras1, Eirini Batsila1, Conclusions Philippos Kaldrymidis2 & Miltiadis Arvanitakis3 Our data suggest that levothyroxine suppressive therapy raises bone turnover. 1Department of Rheumatology, St Paul’s Hospital, Thessaloniki, Greece; However, medium-term therapy does not seem to induce an increase in bone 2Department of Endocrinology, Metaxa Hospital, Pireaus, Greece; demineralization. It would be necessary to amplify the evaluation period to fully 3Department of Radiology, St Paul’s Hospital, Thessaloniki, Greece. exclude a deleterious effect of levothyroxine therapy on BMD.
Site-discordance in bone mineral density (BMD) assessment is common and affects patient categorization. Greater number of osteoporotic sites correlates with lower T score at each index site. The effect of BMD measurement at the contralateral femur on osteoporosis diagnosis has been previously evaluated. The aim of the study was to investigate the effect of BMD measurement at the P97 contralateral femur on osteoporosis diagnosis. A new form of hereditary low-turnover osteoporosis in a 3-generation Methods Finnish family BMD of the lumbar spine and both femurs was measured by dual energy X-ray Christine Laine1, Anne Saarinen1, Tero Laine2 & Outi Ma¨kitie2 absorptiometry in 93 consecutive Caucasian women agedR50 years (62.4G8.7 1Folkha¨lsan Institute of Genetics, University of Helsinki, Helsinki, Finland; (meanGS.D.) years) with a body mass index of 29.2G4.5 (range 20.8–45.2). 2Hospital for Children and Adolescents, University Hospital of Helsinki, Using the T score from each site, measurements were classified according to the Helsinki, Finland. WHO criteria for the diagnosis of osteoporosis as normal, if T score OK1, osteopenia, if T score!K1 and osteoporosis, if T score !K2.5. The results from the three skeleton sites were compared to each other using the statistical package Juvenile primary osteoporosis, unless diagnosed as osteogenesis imperfecta, SPSS and the effect of the inclusion of the contralateral femur on the diagnosis of has previously been considered a sporadic and self-limiting disease. osteoporosis was determined. New genetic findings, including osteoporosis-causing mutations in the Results LDL-receptor related protein (LRP) 5 and LRP6 genes, challenge this view. BMD did not differ between the two femurs (PO0.05, paired Student’s t-test). The pathogenesis of juvenile osteoporosis still remains largely unknown. We In 77 (82.8%) of the women the classification would be the same if either two or describe findings in a three-generation pedigree with a new form of autosomal three sites were measured. In 16 (17.2%) of the women the classification would be dominant osteoporosis. affected by the measurement of the contralateral femur. In 8 (8.6%) of them The proband, at age 35, presented with multiple painful thoracic vertebral T score of the lumbar spine was equal or lower than that of both femurs, thus compression fractures causing a loss of 7 cm of her adult height. Secondary lumbar spine measurement determined the diagnosis. In the remaining 8 (8.6%) causes of osteoporosis were excluded. She has no features of OI and no classification depended on the choice of the femur measured and would be peripheral fractures. The lumbar bone mineral density (BMD) Z-score is different if only the right or left femur was measured. K2.9. Assessment of the pedigree revealed osteoporosis in eight additional Conclusions family members, many with asymptomatic compression fractures. The BMD measurement was not different between the femurs. Although the number youngest is a boy of 12 years with asymptomatic compression fractures in of cases included is small, it appears that determining BMD at the lumbar spine his thoracic spine and a lumbar BMD Z-score of K1.7. Transilial bone and one femur is enough for a correct evaluation and diagnosis in the majority of biopsies from two treatment-naı¨ve adult family members revealed severe low- the patients (90%). Nevertheless, in a small number of patients the choice of the turnover osteoporosis with low trabecular bone volume, decreased osteoid and femur measured may affect patient diagnosis and classification. low numbers of osteoblasts. Mineralization and resorption rates were normal. A genome-wide micro-satellite analysis yielded a maximum lod score of 2.8 and further analyses are under way to identify the disease-causing genetic defect. No linkage was found in areas encoding type 1 collagen. Genetic testing for mutations in LRP5 and LRP6 was negative. The described three-generation family represents a new form of autosomal dominant early onset primary osteoporosis. The discovery of the underlying genetic defect may provide important new information about the biological P96 and pathogenetic mechanisms of osteoporosis. Effects on bone turnover and bone mineral density of levothyroxine suppressive therapy in patients with benign nodular goiter Leone Duarte, Jose Silva-Nunes, Ana-Filipa Lopes & Fernando Malheiro Endocrinology Department, Curry Cabral Hospital, Lisbon, Portugal. P98 Introduction In utero and postnatal exposure to phytoestrogens modulates the bone Thyroid hormones play an important role in bone metabolism. The potential mineral density of juvenile and adult female wistar rats action of prolonged levothyroxine therapy on bone mass reduction is still a matter Patrick Diel1, Gisela Degen3, Thorsten Hertrampf1, Claudia Ledwig1, of debate. Stefan Moors3, Frank Mo¨ller2, Almut Molzberger1, Olliver Zierau2 & Objective Gu¨nter Vollmer2 The aim of the present study was to assess the effects of levothyroxine treatment 1Abt. Molekulare Und Zellula¨re Sportmedizin, Deutsche Sporthochschule on bone mineral density (BMD) and biochemical bone turnover markers. Ko¨ln, Ko¨ln, Germany; 2Abt. Molekulare Zellphysiologie Und Endokrino- Methods logie, Technische Universita¨t Dresden, Dresden, Germany; 3Institut Fu¨r We determined thyroid function – TSH and free T4 (FT4), regional BMD Arbeitsphysiologie An Der Universita¨t Dortmund, Dortmund, Germany. parameters (lumbar spine, femoral neck, trochanter and Ward’s triangle) and biochemical bone turnover markers (serum calcium, parathyroid hormone, alkaline phosphatase and osteocalcin and urinary deoxypyridinoline) in 58 Effects of phytoestrogens on female estrogen sensitive tissues are discussed women with benign nodular goiter. Forty one were submitted to suppressive controversially. There is growing evidence that exposure early in life may have a levothyroxine therapy (group A) and seventeen remained without therapy for an larger (and lasting) impact than an exposure later in life. identical period (group B). We performed initial and final biochemical and To further investigate this issue we performed a study in female Wistar rats. densitometric evaluations and compared variations between groups, for Animals were divided into three groups: Group K received a phytoestrogen free all parameters. diet, group P phytoestrogen rich diet and G a phytoestrogen free diet Results supplemented with genistein (Gen, daily intake 100 mg Gen/kg per BW) prior The population studied was characterized by a mean age of 51G13 years and to mating, throughout pregnancy and up to weaning. Their offspring were kept on TSH 1.77G1.3 mUI/ml. None of the patients had initial osteopenia/osteoporosis the diets during growth and then sacrificed at the age of 25, 50 or 80 days. or alterations in biochemical evaluation. The mean daily dose of levothyroxine In groups G and P significant increases of the Gen plasma levels were detected. At was 97.5G32.8 mg and the mean duration of treatment was 10.3G6.8 months day 25, the uterine wet weight, the height of the uterine epithelium and the (mean cumulative dose of 30.8G24.3 mg). Considering all patients, there was a expression of complement C3 were significantly stimulated in group G animals significant reduction in TSH (PZ0.000) and an increase in FT4 (PZ0.001), compared to the K and P group. At day 80 no significant differences were
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 observed between the treatment groups and the control group. Interestingly, at day pathological jugular mass with enlargement of supraclavicular, submandibular 50 the uterine wet weight was significantly increased in groups G and P. The and paracarotid lymph nodes. Tumoral mass was only partially removed. PTCa trabecular bone mineral (BMD) density of the groups G, but also P was with infiltration of the thymic tissue was confirmed histologically. PET showed significantly elevated compared to group K, both in juvenile rats (at day 25) and in residual hypermetabolic mass (with latero-lateral distance 3.1 cm) and multiple adult rats (at day 80). bilateral lung metastases (14 in right lungs, 12 in left lungs). Due to the metabolic In summary, our results demonstrate that exposure to phytoestrogens during instability and size of the tumor residuum, patient was not appropriate candidate gestation, lactation and growth increases the BMD of juvenile but also adult for immunization with parathormone fragments – novel and perspective modality female rats. Interestingly, a phytoestrogen rich diet results in an increase of BMD in medical therapy of PTCa. Worsening clinical course of the patient and but in contrast to the administration of GEN, does not stimulate estrogen sensitive progression of lung metastases unabled repeated sugery. Rapid increase of uterine parameters. These findings support the hypothesis that lifelong exposure calcemia to 5.60 mmol/l required acute hemodialysis and consequent hemodia- to phytoestrogen by diet may be responsible for the different epidemiology of lyses in every other day intervals. Despite multinodal medical therapy – increased fracture risks in eastern and western countries and may protect against fluid intake, loop diuretics, parenteral bisphonates (pamidronate and zolendro- osteoporosis. nate) and calcimimetics (cinacalcet) and finally hemodialysis, patient died after 12-month duration of the disease. We are awaiting the results of molecular analysis of HRPT2 gene. The identification of a mutation would be valuable as question remains whether genetic testing of HRPT2 gene should be offered to and performed in all patients with PTCa and in all at-risk relatives of a patient who has PTCa with an HRPT2 P99 germ-line mutation. Monitoring serum calcium levels in all persons at risk Secondary osteoporosis in man with aromatase deficiency: positives and provides an alternative to definitive DNA diagnosis. negatives of estrogen therapy Mikulas Pura1, Marie-Laure Kottler2, Peter Vanuga1, Serge Carreau2, Karel Vitesnik1 & Herve Mittre2 1Department of Endocrinology, National Institute of Endocrinology and Diabetology, Lubochna, Slovakia; 2Molecular Biology Unit, Department of Genetics and Reproduction, Caen University Central Hospital of GCle´menceau, University of Caen, Caen, France. P101 FGF-23 and parameters of calcium and bone metabolism are positively To date only seven cases of naturally occuring inactivating mutations of the influenced by GH replacement in adult growth hormone deficiency aromatase gene in men have been documented. Osteoporosis is one of the typical patients from the KIMS survey signs of the aromatase deficiency in male patients. We report results of estrogen Walter Fassbender1, Sandra Schmitz1, Ulla Stumpf2 & Peter Kann3 therapy in patient with formerly described frameshift mutation of the CYP19 1Internal Medicine and Endocrinology, Kempen Hospital, Kempen, gene, ins 1058 T. Bone mineral density (BMD) was assessed during three phases Germany; 2University Hospital, Dusseldorf, Germany; 3University Hospital, of estrogen therapy. Patient was substituted by calcium and vitamin D throughout Giessen and Marburg, Germany. the study. Therapy started with t.d. estradiol (E2) at dose 50 mg daily two days in week (phase 1). BMD increased in all measured localisations (vertebral C16%, neck C5.5%, ultradist C11%). Due to mild increase of body weight (C3.6 kg) as Growth hormone deficiency leads to reduced bone turnover, mainly due to well as worsening of insulin resistance (fasting insulinemia 167.0 mIU/l opposed alterations in PTH circadian rhythmicity as well as to a lack of sensitivity of the kidney and bone to the effects of PTH. These mechanisms may be responsible for to 27.5 mIU/l in phase 1) we reduced dose of t.d. E2 to 25 mg daily one day in week (phase 2). After this change, fasting insulinemia moderated to 58.9 mIU/l, bone turnover changes and development of osteoporosis. Patients with GHD show however we registered fall of BMD in lumbar spine (vertebral K9%, neck abnormalities of renal phosphate metabolism, which may also contribute to the pathogenesis of bone loss in these patients. GH treatment leads to restoration of C14%, ultradist C11%). Therefore dose of E2 was increased and considering the renal tubular reabsorption and sensitivity of target organs to PTH, bone turnover patient’s preference we started equivalent i.n. formulation of E2 – 2 injections of and improvement of BMD under GH replacement therapy. E2 hemihydrate (1 injection z 0.07 ml contains 150 mgofE2 hemihydrate) The role of the phosphatonine FGF-23 in this complex process was investigated. weekly, i.e. 300 mg weekly equivalent to t.d. E2 in dose 50 mg daily one day in week. At this dose we noted divergent changes of BMD (assessment after phase 3, We measured the relationship between parameters of calcium metabolism such as vertebral C8%, neck K7%, ultradist K13%). Although showing positive effect Calcium, Phosphate, Creatinine and PTH and their correlation to the phosphatonine FGF-23 and 25-OH Vitamin D levels in GDH patients before, to BMD, general effect of E2 therapy (depending on dose, length, formulation) demonstrating as worsening of a priori presented metabolic syndrome, remains after 6 and 12 months therapy with growth hormone. questionable. EDTA-Plasma (due to better stability than serum samples) of 15 patients was investigated. Arithmetic means for intact FGF-23 before therapy were 17.3 pg/ml, after 6 months therapy 15.3 pg/ml and 23 pg/ml at 12 months (all P!0.001). C-terminal FGF-23 initial was 58 U/ml, at 6 months 47 U/ml and at month 12 108.6 U/ml (all P!0.001). Calcium values were 2.38, 2.44 and 2.43 mmol/l. Corresponding phosphate levels were 3.04, 3.39 and 3.08 mg/dl (all P!0.001). P100 As expected, FGF-23 was inversely correlated to serum phosphate. GH supplementation in GHD patients leads to normalization of tubular Agressive course of primary hyperparathyroidism caused by reabsorption of phosphate due to regulation by FGF-23 and reverses the GHD- parathyroid carcinoma: case report induced relative phosphate-deficient state. Restoration of the physiological Peter Vanuga1, Peter Kentos1, Alojz Gresˇ2, Andrej Kalis3, Peter Povinec4 & 1 regulation of phosphate metabolism emphazises the beneficial effect of GH Mikulas Pura supplementation on bone remodeling in GHD patients. 1Department of Endocrinology, National Institute of Endocrinology and Diabetology, Lubochna, Slovakia; 2Clinics of Surgery, Central Military Hospital, Ruzomberok, Slovakia; 3Department of Pathological Anatomy, Central Military Hospital, Ruzomberok, Slovakia; 4PET Centrum BIONT, Bratislava, Slovakia.
Parathyroid carcinoma (PTCa) is an uncommon cause of primary hyperparathy- P102 ! roidism (PHP), statistically representing 1–2% of all cases of PHP. Early Endogeneous calciotropic and sex hormones and their relationship to resection of the primary tumor is the only curative treatment, however this is bone mineral density in elderly females frequently incomplete. As a consequence, recurrence of PTCa presenting as Wolfgang Kemmler1, Simon Von Stengel1, Klaus Engelke1, Peter Diziol2 & locally invasive tumor and/or metastatic process is not rare. Morbidity and Willi A. Kalender2 mortality are generally caused by the effects of unremitting hypercalcemia rather 1Institute of Medical Physics, University Erlangen-Nurnberg, Erlangen- than tumor growth. Nurnberg, Germany; 2Roche Diagnostics, Mannheim, Germany. We present our own experience with management of the patient with PTCa. After the diagnosis of PHP was established, during two months patient underwent two unsuccessful surgeries (without histological confirmation of parathyroid tissue. Purpose Severe hypercalcemia 4.47 mmol/l with PTH-I level 600 pg/ml (reference value To determine the effect of endogenous calciotropic and sex hormone ! 68.3) was reason for urgent admission one month later. MRI showed concentration on bone parameters in postmenopausal women.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Methods brachydactyly with none having low calcium. Further investigations showed a We analyzed baseline data of the Senior Fitness and Prevention Study (SEFIP), an normal serum magnesium and a high parathyroid hormone of 7.6 pmol/l (normal: 18-month randomized controlled exercise trail with 246 females, 65 years and 1.1–6.9) with an ionised calcium of 1.07 mmol/l (normal: 1.05–1.30) and a older. Baseline assessments of Bone Mineral Density at the lumbar spine (LS) and phosphate of 0.64 mmol/l. Despite having the morphological features of proximal femur were performed using DXA technique. Blood samples were taken Albright’s osteodystrophy a low phosphate was inconsistent with the diagnosis from each participant after an overnight fast between 0700 and 0900 h. Serum- of pseudohypoparathyroidism type 1a. There was no provision for Ellsworth estradiol, testosterone, SHBG, DHEA-S, vitamin-D (25OHD) and PTH (Roche Howard test. A vitamin D level requested revealed severe vitamin D3 deficiency Diagnostics, Mannheim, Germany) were determined. For each of these (5.6 ng/ml; normal in summer: 10–60). She was thus diagnosed with independent parameter our cohort was grouped into terziles with the same pseudopseudohypoparathyroidism with vitamin D deficiency. numbers of subjects according to the hormonal concentration. Here, we focus on Pseudopseudohypoparathyroidism is considered to be an incomplete form of the comparison of spinal and femoral BMD between the highest (1) vs the lowest pseudohypoparathyroidism type 1a with normal blood biochemistry but abnormal terzile (3). morphological features of short height, excess weight, round face and Results brachydactyly. Her low calcium and phosphate and high parathyroid hormone Significant (P!0.01) between group-differences in respect to the BMD at LS and levels were from vitamin D deficiency. There are reports of vitamin D deficiency hip were observed for Estradiol (1O3), SHBG (1!3) and the Estradiol/SHBG mimicking pseudohypoparathyroidism type 2. Vitamin D deficiency also occurs fraction (1O3). Although there was a tendency for higher BMD-values in the in hyperparathyroidism but it is fairly uncommon in pseudopseudohypoparathy- highest terzile (1) significance could not be reached for Testosterone, DHEA-S roidism. Thus vitamin D should always be measured in patients with abnormal and 25OHD. No difference at all was determined for PTH. calcium or phosphate level. Conclusion Estradiol, SHBG and ‘bioavailable’ Estradiol clearly predict BMD at the lumbar spine and femoral neck in postmenopausal females 65 years and older.
P105 P103 A case of hyperaldosteronism due to bilateral macronodular adenomas with a renal mass in the left kidney Exercise effect on bone anabolic hormones in elderly females: Ioannis Legakis, Maria Alamani, Maria Manousaki & Ioannis Papadimitriou preliminary results of the senior fitness and prevention study (SEFIP) Henry Dynant Hospital, Athens, Greece. Wolfgang Kemmler1, Simon Von Stengel1, Klaus Engelke1, Peter Diziol2 & Willi A. Kalender2 1Institute of Medical Physics, University Erlangen-Nurnberg, Germany; Background 2Roche Diagnostics, Mannheim, Germany. Cases of combined primary aldosteronism and preclinical Cushing’s syndrome are reported extremely rare. Highlight of a report Purpose An unusual case of hyperaldosteronism due to bilateral macronodular adenomas To determine the effect of a combined ambulatory exercise program on sex with a left renal mass in a 55-year-old male is presented. MRI scan of the steroid concentration in postmenopausal females. abdomen revealed a 4.5 cm mass of the right adrenal and two nodules in the left Methods adrenal sized 2 and 3 cm, respectively in diameter. Additionally, a large mass on The Senior Fitness and Prevention Study (SEFIP) is an 18-month randomized the left kidney sized 10!12 cm was also detected. Increased plasma aldosterone, controlled exercise trail with 246 females, 65 years and older. The exercise group decreased serum potassium and low plasma renin activity were consistent with (EG) performed a vigorous endurance, strength and balance training two times aldosterone-producing adenoma. Although cortisol urine levels were marginally per week, the ‘wellness control group’ (WG) performed a low intensity and low ! elevated, serum cortisol diurnal variation was normal, with suppression of cortisol volume session once per week for 4 10 weeks during the 18 months. Both after 1 mg of dexamethasone. Adrenal scintigraphy with 131I-6-b-iodomethyl- groups were adequately supplemented with calcium and vitamin D. Serum- norcholesterol, after 2 days administration of cortisol, showed an uptake of the Estradiol, testosterone, SHBG, DHEA-S, vitamin D (25OHD) and PTH (Roche right adrenal mass with inhibition of the contralateral adrenal gland. Kidney Diagnostics, Mannheim, Germany) were determined twice, before and after the scintigraphy with 99MTC-DTPA showed a normal radioactive distribution with intervention always between 0700 and 0900 h after an overnight fast. the left renal mass appearing photopenic. Results Histopathology of the nodules showed clear cells admixed with paradoxical After 18 months samples were available for 110 women of the EG, and 114 hyperplasia of zona glomerulosa and fasciculata. The left renal mass primarily subjects of the WG. Although a tendency for more favorable changes in the composed of collagenized hyalinized fibrous tissue with many inflammatory cells exercise group were determined for 25OHD, PTH, DHEAS and Testosterone, surrounding necrotizing tissue with hemorrhage and cholesterol crystals. After significant between-group differences could only be observed for Estradiol (C G K G adrenalectomy the patient’s blood pressure was normalized. 6.1 15.7 vs 1.7 13.6%, ES) and ‘bioavailable’ Estradiol (E2/SHBG). Conclusion Conclusion This is the first case in the literature of bilateral involvement of the adrenals Our results indicate that besides mechanical pathways high intensity exercise causing hyperaldosteronism with a concurrent renal mass. programs may impact bone via changes of bone anabolic hormones.
P106 Clinical cases Coexistance of parathyroid tumors with metachronous metastasis to the P104 thyroid from renal clear cell carcinoma 20 years after nephrectomy Ioannis Legakis, Kaliopi Koutsoupa, George Doundoulakis, Maria Alamani A case of pseudopseudohypoparathyroidism with vitamin D deficiency & Efi Kyrodimou Indrajit Talapatra & David James Tymms Henry Dynan Hospital, Athens, Greece. Royal Albert Edward Infirmary, Wigan, UK. We report a rare case of a solitary metachronus metastasis of renal clear cell We describe below a 72-year-old woman who presented clinically with short carcinoma (RCC) in the thyroid coexisting with parathyroid tumors. The patient metacarpals and metatarsals and the following blood biochemistry: corrected had undergone 20 years ago radical left nephrectomy for RCC. Upon calcium of 2.16 mmol/l (normal: 2.05–2.60), phosphate 0.61 mmol/l (normal: presentation, the initial diagnosis based on clinical and echo findings was 0.8–1.45) and alkaline phosphatase of 108 U/l (normal: 35–104). She was 153 cm multinodular goiter. Fine needle aspiration (FNA) cytology of a growing non- tall and weighed 109 kg with a round face. She had a history of Monoclonal functioning nodule of the right thyroid lobe revealed clear cells with oxyphilic Gammopathy of unknown significance, vitamin B12 deficiency and was admitted granules suggesting RCC. Immunohistochemical studies showed the tumor cells 10 years ago with a corrected calcium of 1.72 mmol/l and has been on alfacalcidol to be negative for thyroglobulin staining. In addition immunostaining with keratin (1a-hydroxycholecalciferol) since then. Her current medications included ae1–ae3, epithelial membrane antigen, and vimentin gave positive results, alfacalcidol 1 mg on alternate days and vitamin B12 injection 1 mg every confirming further the diagnosis of metastatic RCC in our case. The coexisting 3 months. On enquiry she informed that all her three siblings and one son have parathyroid tumors were assessed preoperatively by Tc-99m substraction
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 scintigraphy, intraoperatively by monitoring parathyroid hormone and post- This study reveals an additional feature of male hypogonadism which should be operatively by histology. corrected by testosterone replacement therapy.
P107 P109 Adrenal incidentalomas: which do we send for operation? Ole Schmiedel & Aled Rees Recurrent silent and post-partum thyroiditis in a single patient: Centre for Endocrine and Diabetes Sciences, Cardiff, UK. evidence for a common aetiology Ian Scott, I Talapatra & DJ Tymms Royal Albert Edward Infirmary, Wigan, UK. Due to the increased availability and use of radiology, endocrinologists are referred patients with incidentally discovered, clinically silent adrenal masses with increased frequency. Controversies persist regarding their investigation and Silent and post-partum thyroiditis are autoimmune conditions, which result in a management. We present two cases focusing in particular on the role of radiology triphasic thyroid hormone disturbance. They are distinguished by the later in the management algorithm. condition’s relation to pregnancy. Their association in the same patient resulting A 43-year-old male underwent a CT urogram, which revealed an incidental 3! in recurrent episodes of silent thyroiditis suggests a common aetiology. 3!2 cm right adrenal mass. The patient did not have symptoms suggestive of We report a 32-year-old female with post-partum and recurrent silent thyroiditis mineralo- or glucocorticoid excess, but had been noted to have borderline continuing over a decade. She presented post-partum with thyroid overactivity, hypertension. MRI scan confirmed a mass with high signal intensity on T2. Initial followed by hypo- and euthyroidism. Over the next 10 years, she had seven and repeated biochemistry over 18 months showed normal urinary metanephrines, episodes of hyperthyroidism; thyroid function tests in the interim periods showed negative investigations for Cushing’s syndrome and normal PRA/Aldosterone euthyroidism or compensated hypothyroidism. During one toxic episode, a raised ratio. In May 2007, 2 years after his initial presentation, routine urine tests thyroglobulin level (189.1 mg/l) was found and a thyroid pertechnetate scan revealed elevated noradrenaline and normetadrenaline, in keeping with a showed no uptake. She never exhibited clinical evidence of Grave’s disease (no diagnosis of phaeochromocytoma. MIBG confirmed increased activity within goitre, infiltrative orbitopathy or dermopathy) nor of subacute thyroiditis (no viral the right adrenal mass. This case illustrates the importance of continued prodrome and no neck tenderness). The occurrence of recurrent hyperthyroid biochemical testing for phaeochromocytoma when the radiology is suggestive. episodes alongside raised thyroglobulin levels, the absence of neck tenderness A 71-year-old female was found to have a 4.5 cm right adrenal mass on abdominal and scintigraphic findings indicate she had a combination of post-partum and CT. She had normal adrenal biochemistry on several occasions. Physical recurring episodes of silent thyroiditis. examination was unremarkable and her blood pressure was 140/80 mmHg. Based Painless silent and post-partum thyroiditis are normally self-limiting and non- on the size of the tumour she underwent laparoscopic adrenalectomy. Histology recurring conditions. They show a triphasic thyroid hormone response of thyroid showed a haemangioma of the adrenal medulla. There was no evidence of overactivity, followed by hypothyroidism and recovery to a euthyroid state. A malignancy or an adrenal medullary or cortical endocrine cell tumour. minority of patients remain permanently hypothyroid. Our patient showed this Careful review of abdominal radiology is important when investigating adrenal classic hormone profile alongside raised thyroglobulin levels (excluding thyrotoxi- masses and may obviate the need for surgery in some patients, while prompting cosis factitia) and low uptake on thyroid scintiography (excluding Graves disease). continued biochemical evaluation for endocrine disease in others. We propose that a Silent thyroiditis is uncommon but may be underdiagnosed and there is limited greater emphasis should be placed on radiological review in current algorithms, but information on recurrence rates, variably described in between 5 and 65% of patients. recognise that discharge or ongoing follow-up of hormonally silent radiologically The association of both recurrent silent and post-partum thyroiditis in our patient stable lesions is still a dilemma. suggests these are likely to be a single disorder with a common aetiology. Radioiodine ablation of the thyroid is planned to prevent relapse.
P108 Prolonged QT interval on the electrocardiogram in hypogonadal men P110 Barbara Filippini1, Francesca Pecori Giraldi1, Paola Maria Toja1, Jorgo Michalidis2, Marco Stramba Badiale2 & Francesco Cavagnini1 Successful pregnancy outcome in a woman with acromegaly treated 1Department of Endocrinology, Ospedale San Luca, Istituto Auxologico with lanreotide before and briefly during the first trimester of gestation Italiano, University of Milan, Milan, Italy; 2Department of Rehabilitation Irina Vaychulis1,2 & Tatiana Vaychulis1,2 Medicine, Ospedale San Luca, Istituto Auxologico Italiano, Milan, Italy. 1Chelyabinsk State Medical Academy, Chelyabinsk, Russian Federation; 2Chelyabinsk Municipal Hospital No. 1, Chelyabinsk, Russian Federation. Background QT interval reflects cardiac ventricular repolarization and, if prolonged, increases A 39-year-old woman presented with a progressive enlargement of her feet, the risk of malignant arrhythmias such as torsade de pointes. QT interval duration hands, tongue, nose and ears, headaches, excessive sweating, weakness and is similar in boys and girls during childhood but shortens in males after puberty. In infertility. She was diagnosed with acromegaly at the age of 36, but had initially fact, reference limits for QTc in adults reflect this difference, i.e. lower than refused any kind of treatment. For a period of 3 years, the size of pituitary 460 ms in women and lower than 440 ms in men. Experimental studies suggest adenoma had enlarged from 10!12!20 to 13!19!22 mm, and the level of GH that testosterone is the major contributor to shortening of QT interval in men. had increased from 62.4 to 104 mU/I. Preoperative administration of somatostatin Purpose of this study is to evaluate the length of ventricular repolarization in male analogues was recommended. hypogonadal patients. At the course of treatment with lanreotide she conceived and decided to preserve Methods pregnancy. Lanreotide was discontinued after pregnancy was confirmed. In the The study was performed in 32 patients with secondary (25 patients) and primary first trimester, her GH and IGF-1 were in the normal range, followed by gradual hypogonadism (7 patients with Klinefelter’s syndrome) and 32 age-matched increase since the second trimester. No complications or visual impairment during eugonadal men. Patients were tested in basal conditions and after adequate gestation were observed, and a healthy female infant (weight 3560 g, length testosterone replacement therapy. Twelve-lead ECG recordings were obtained 52 cm) was delivered at term. and QT intervals corrected for heart rate according to Bazzett’s formula, i.e. After delivery high levels of GH and IGF-1 without significant enlargement of QTcZQT/ORR interval. adenoma were registered. When breast feeding was stopped, lanreotide treatment Results was resumed with marked effect: GH and IGF-1 levels have gradually dropped from Prevalence of abnormal QTc was significantly higher in hypogonadal patients 189 to 11.9 (reference range 0.2–13.0 mU/l) and from 1388 to 388 (reference range (16% vs 0% in controls, P!0.05). QTc interval normalized on hormone 101–267 ng/ml) respectively. The patient continues to receive injections of replacement therapy in patients presenting prolonged measurements in the lanreotide. The baby remains developmentally normal for 8 months of the follow-up. hypogonadal state. Heart rate and left ventricular mass did not differ among the There are few reported uncomplicated pregnancies in acromegalic women, having two groups and no known QT-prolonging factor was evidenced in patients with received depot somatostatin analogues at different stages of gestation period. We abnormal QTc values. present a case of conception and successful pregnancy outcome in a 39-year-old Conclusions woman with somatotropinoma, treated with lanreotide before and briefly during the Testosterone deprivation leads to an increased prevalence of prolonged QTc first trimester of gestation. interval and hypogonadal men appear at higher risk for cardiac arrhythmias.
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P111 Conclusion Androgenic alopecia and hirsutism in a 73-year-old woman: careful RCC should be considered in growth retardation and/or hypopituitarism in re-evaluation of ‘normal’ imaging findings may lead to a rare diagnosis children. Pituitary MRI can reveal the lesion. Early detection and treatment is Annette Christen1, Verena Tischler2, Pierre-Andre´ Diener2 & mandatory to prevent or to inverse growth retardation and other pituitary Michael Bra¨ndle1 hormones failure. 1Division of Endocrinology and Diabetes, Department of Internal Medicine, Kantonsspital St Gallen, St Gallen, Switzerland; 2Department of Pathology, Kantonsspital St Gallen, St Gallen, Switzerland.
A 73-year-old woman developed androgenic alopecia and progressive hair growth on the chest, back and abdomen over the course of 3–4 years. Menarche P113 was at age 16. She had irregular menstrual periods subsequently but gave birth to Unresectable huge sternal and mediastinal metastasis of follicular three children. She reached menopause at age 40. No history of weight loss or thyroid carcinoma; radiotherapy as first-line and palliative therapy sweating was reported. At presentation, we saw a 73-year-old lady with Asli Nar Demirer1, Semra Ayturk1, Neslihan Bascil Tutuncu1, pronounced hirsutism (Ferriman–Gallway-score 24/36). No virilizing signs of the Alptekin Gursoy1, Yucel Pak2 & Nilgun Guvener Demirag1 external genitalia were present but there was impressive androgenic alopecia. 1 2 Department of Endocrinology, Baskent University Faculty of Medicine, BMI was 31.5 kg/m , blood pressure was 160/85 mmHg, pulse was 68 bpm and Ankara, Turkey; 2Department of Radiation Oncology, Gazi University regular. The abdomen was soft; there were no masses palpable except for an Faculty of Medicine, Ankara, Turkey. incisional hernia. Hormonal evaluation of hyperandrogenism revealed elevation of total testosterone level to the neoplastic range. DHEA-S, androstendione, 17-OH-progesterone and a 24 h urine collection for cortisol were normal. Distant metastases as initial manifestation of follicular thyroid carcinoma is rare. Transvaginal ultrasound of the ovaries was ‘normal’ and abdomino-pelvic We report a case of an unusual initial presentation of follicular thyroid carcinoma CT-scan showed no tumorous lesions of the adrenal glands and ovaries. Careful on follow-up. A 52-year-old woman presented with a 12-month history of re-evaluation of the CT-scan indicated that the ovaries appeared to be too large in progressively enlarging mass in the anterior chest wall. The mass was fixed to the relation to age. We postulated excess ovarian production of testosterone and chest wall, measuring 12!10 cm in diameter. Computed tomography demon- performed bilateral ovarectomy. The histopathological examination of the ovaries strated a lobulated soft-tissue mass (17!11!6 cm) destructing sternum and showed stromal hyperthecosis. The postoperative testosterone-level normalized, extending into the anterior mediastinum. There was no lung metastasis. Invasion hirsutism and androgenic alopecia improved on follow-up. of tumor to the ascending aorta, superior vena cava, and right atrium could not be Ovarian hyperthecosis with hyperandrogenism is a rare cause of hirsutism and excluded. Multiple lymph nodes were observed in the supraclavicular regions. virilization in postmenopausal women and is difficult to diagnose as it may elude Ultrasonography of the thyroid gland showed 46!37 mm nodule in the left lobe imaging studies. It should be included in the differential diagnosis in with milimetric gross calcifications and cystic-necrotic areas. Hyperthyroidism postmenopausal women with recent-onset of androgen excess. Careful was detected. Biopsy from this nodule and the sternal mass revealed typical intraoperative examination of even normal-appearing ovaries is imperative, histology of follicular carcinoma. She was considered inoperable. Since there was particularly if no other cause of marked androgen excess is found. huge tumor burden and iodinated contrast exposure for several times during evaluation, we decided to treat the patient with external beam radiotherapy (EBRT) rather than radioiodine as first-line therapy. After a course of conventional radiation with 50 Gy in 25 fractions over 4 weeks, encompassing the thyroid bed and the gross disease, tumor regressed remarkably in 6 months. In conclusion, when surgical resection is not possible, EBRT may be used for palliative purpose to obtain local control for extensive disease as first-line therapy. The indications of EBRT for differentiated thyroid cancer still remain P112 poorly defined. Children with growth retardation due to Rathke cleft cyst Vassilios Petrou, Petros Papachilleos, Nikolaos Valvis, Dimitrios Ioannidis, Athanasia Tertipi, Thomas Georgoulas, Charalambos Chadjiathanasiou & Asteroula Papathanasiou Department of Endocrinology, Children’s Hospital ‘P. and A. Kyriakou’, Athens, Greece. P114 Severe secondary osteoporosis in a patient with systemic mastocytosis Rathke cleft cysts (RCCs) are non-neoplastic sellar lesions derived from remnants stabilized by therapy with low-dose pegylated interferon alpha of Rathke’s pouch, and mostly asymptomatic. Symptomatic RCCs occur usually O Dorothee Maria Baur, Alexander von Werder, Knut Brockow, Roland in middle-age, are 1 cm, and cause pituitary hypofunction, diabetes insipidus, M Schmid & Hans Weidenbach hyperprolactinemia or visual impairment. In children, RCCs are rare and usually Medical Department, Technical University of Munich, Klinikum rechts der asymptomatic. However, symptomatic cases may present with growth retardation Isar, Munich, Germany. and diabetes insipidus. We report two children with symptomatic RCC manifesting as growth retardation. First case Objectives A 14-year-old boy was admitted because of growth retardation (S.D.S. height We report on a case of a 32-year-old patient with urticaria pigmentosa, the K2.5) and delayed puberty. Serum levels of SmC (21 ng/ml), cortisol cutaneous form of mastocytosis, since the age of 13. A bone marrow biopsy (4.23 mg/dl), fT4 (0.61 ng/dl) and T3 (0.8 ng/ml) were low, TSH (1.84 mIU/ml) revealed systemic mastocytosis disease. In 2005, after a minor trauma, the patient was normal and PRL (2556 mIU/ml) elevated. Stimulation tests of growth had an X-ray of the spine which showed a new fracture of the thoracic vertebrae hormone (GH) secretion showed low GH (GHmax 1.6 ng/ml). Pituitary MRI 3–4. Further DXA examination of the bone mineral density showed osteoporosis revealed an intra- and suprasellar mass 1.2!3.8!2.3 cm with solid and cystic (T-Score K2.8 lumbar vertebrae; right/left femur K1.0/K0.9). As interferon elements. Visual fields were normal. After the start of cortisone and thyroxine the alpha is effective in mastocytosis and the pegylated form of the drug is better child presented polydipsia, and polyuria. Diabetes insipidus was diagnosed with tolerable, the clinical response of the pegylated interferon alpha was analyzed. water deprivation test and treatment with desmopressine was started. Trans- Methods sphenoidal dissection was performed. Histological examination showed a RCC. A treatment with pegylated interferon alpha 2a 90 mg s.c. once a week for Postoperatively, treatment with recombinant human growth hormone (rhGH) was 6 months was initiated. started improving child’s height. Results Second case No further fractures occurred and the bone mineral density increased (after A 12-year-old girl was admitted because of growth retardation (S.D.S. height 6 months T-Score 2.2 lumbar vertebrae; right/left femur K0.9/K0.7). Side effects K2.5). Hormonal tests were normal except for low level of SmC (220 ng/ml) and of the treatment were minor compared to the benefit. stimulation tests of GH secretion (GHmax 4.2 ng/ml). Pituitary MRI revealed an Conclusion intrasellar cyst 1.5!1.2!1.2 cm. Visual fields were normal. Trans-sphenoidal Low-dose pegylated interferon alpha therapy for 6 months in a young man with dissection was performed. Histological examination showed a RCC. Post- severe secondary osteoporosis due to systemic mastocytosis improved the bone operatively, the child presented polydipsia, polyuria and a water deprivation test mass density as well as clinical parameters. The drug appears effective in treating revealed diabetes insipidus and she started treatment with desmopressine. Height mastocytosis with osteoporosis and should be examined in more patients. was improved with rhGH.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P115 autonomous cortisol overproduction in all patients with PCOS in order to detect a The influence of application site on testosterone serum concentrations potentially curable underlying disease. after transdermal testosterone gel Sebastian Neggers, Richard Feelders, Maarten van Aken, Wouter de Herder, Aart-Jan van der Lely & Frank de Jong Erasmus University Medical Centre Rotterdam, Rotterdam, The Netherlands. P117 Simultaneous detection of a heterozygous deletion in the STX16 gene Background and loss of methylation at GNAS1A by methylation-specific MLPA in Testosterone (T) in a hydroalcoholic gel is commonly prescribed as androgen two patients with pseudohypoparathyroidism type 1b (PHP 1b) replacement therapy and may not be accompanied by peaks and troughs of serum Susanne Clausmeyer1, Gerd Perschon2, Anders Nygren3, Egbert Schulze1 & T levels as seen in T-injectables. We assessed in 17 subjects the differences in Friedhelm Raue1 serum testosterone (sT) and free T (fT) levels during four different application 1Endocrine Practice, Heidelberg, Germany; 2Practice for Internal Medicine periods. and Nephrology, Bremerhaven, Germany; 3MRC-Holland, Amsterdam, The Methods Netherlands. Patients where on daily 50 mg Androgelw, for 7 consecutive days in each cycle, on day 8 serum was sampled from both antecubital veins at 9.00 pm. Period 1 started with application at both shoulders and right upper arm up to 10 cm from The GNAS locus (chromosome 20q13) yields multiple transcripts, including the the elbow pit. Period 2 was equivalent to period 1 except that T-gel was applied to stimulatory G protein subunit a (Gsa), NESP55, GsaXL and two noncoding the left arm. Period 3 was similar to the second except T-gel was applied up to the RNAs, the GNAS1A-transcript (A/B) and the antisense transcript (AS). The left elbow pit. Period 4, T-gel was solely applied on the abdomen. corresponding promoters show a complex methylation pattern resulting in an Results allele-specific imprinting, with maternal expression of NESP55 and paternal No significant differences in (free) T levels were observed between regimens expression of GNAS1A, GsaXL and AS. Gsa in most tissues is derived from both 1 and 2. However, in period 3 sT and fT levels (medianGS.D.) sampled from the alleles, except for the renal proximal tubules where it is exclusively maternally left arm were higher compared to the right arm (sT left 15.60G22.17 nmol/l, right expressed. Expression of Gsa from the maternal allele in the kidney apparently 12.20G4.70 nmol/l, PZ0.011; fT left 0.39G0.74 nmol/l, right 0.29G requires silencing of GNAS1A by methylation, loss of methylation at GNAS1A 0.15 nmol/l PZ0.012). Significant lower sT (7.35G3.45 nmol/l, P!0.05) and leads to suppression of Gsa. Different endocrine disorders are associated with fT (0.16G0.08 nmol/l, P!0.05) were observed when T-gel was applied to the inactivating or activating mutations as well as impaired imprinting at the GNAS abdomen compared to all other applications. locus. Impaired imprinting of GNAS1A on the maternal allele has been identified Conclusion as the underlying cause of PHP1b, a disease characterized by hypocalcemia, Peaks of sT concentrations are observed during T-gel therapy with different hyperphosphatemia and elevated serum levels of parathyroid hormone (PTH), due application regimens. Serum sampling within the T application area may reveal to renal resistance to PTH. We here describe two patients, sisters aged 30 and 33 high T levels, possibly due to local T-accumulation. This should be taken into years, respectively, who presented with hypocalcemia (1.69 and 1.7 mmol/l; account with interpretation of sT levels and dose titration during transdermal normal range 2.2–2.65 mmol/l), hyperphosphatemia (1.54 and 1.68 mmol/l; androgen substitution. Efficacy of T application at the shoulders may be higher normal range 0.87–1.45 mmol/l), and elevated PTH (378 pg/ml; normal range compared to application at the abdomen. 10–65 pg/ml) but no other endocrine abnormalities. Sequencing of the Gsa gene did not reveal any mutations. By methylation-specific MLPA we detected a heterozygous deletion of exon 5 and 6 of the syntaxin-16 (STX16) gene and a loss of methylation at GNAS1A. A deletion within STX16, located about 220 kb upstream of GNAS1A, resulting in loss of methylation at GNAS1A, has been reported in multiple kindreds with PHP1b. Methylation-specific MLPA offers the possibility of detecting deletions as well as impaired methylation at the GNAS locus in a single assay. P116 Increased frequency of Cushing’s disease in patients with polycystic ovary syndrome WA Mann, C Hoffmann, M Shahin, K Jungheim, I Dornauf & KH Usadel Endokrinologikum Frankfurt, 60 596 Frankfurt, Germany. P118 TSH-secreting pituitary adenoma with GH-secretion Background Felix Flohr1, Martin Petrick2 & Jochen Seufert1 Cushing’s disease is defined as ACTH dependent pituitary Cushing’s syndrome 1Division of Endocrinology and Diabetology, Department of Internal and is rare with an estimated incidence of 5–25 per million/year. Polycystic ovary Medicine II, University Hospital of Freiburg, Freiburg, Germany; 2Division syndrome (PCOS) is a heterogenous disorder affecting up to 10% of women in the of Neurosurgery, University Hospital of Freiburg, Freiburg, Germany. reproductive age and shows clinical overlap with Cushing’s syndrome (obesity, hirsutism, cycle abnormalities, etc). An increased frequency of Cushing’s syndrome in selected patient groups has been postulated previously but is Hyperthyroidism due to TSH-secreting pituitary adenoma is a rare disease and unknown in patients with PCOS. accounts for 0.4% of all pituitary tumors. About 15% of these tumors show Patients co-secretion of prolactin or growth hormone. Three hundred and seventy-eight patients with PCOS according to the Rotterdam We report the case of a 44-year-old man, presenting with sudden onset of tremor criteria were included in the study. All patients received a clinical and laboratory and agitation and central thyrotoxicosis (TSH 1.01 mU/ml, fT3 8.44 pmol/l, fT4 evaluation including ACTH and basal cortisol levels. In case of abnormal 30.2 pmol/l). Ultrasound of the thyroid gland and TSH-receptor antibodies were parameters, further investigations were performed including Dexamethason normal. Imaging of the pituitary demonstrated a 12 mm pituitary macroadenoma. suppression test, 24 h urine secretion of cortisol, midnight salivary cortisol levels Evaluation of pituitary function revealed no signs of hypopituitarism, but an and imaging studies. elevated IGF-1 of 397 ng/ml and growth hormone (GH) of 2.8 ng/ml without any Methods clinical signs of acromegaly. GH was suppressed in an oral glucose tolerance test Clinical study, biochemical, functional and imaging studies. to a nadir of 0.6 ng/ml. The macroadenoma was completely removed by an Results endoscopic transsphenoidal approach. Histology showed a pituitary adenoma In 4 out of 378 patients, autonomous overproduction of cortisol was detected. (WHO grade I) with marked expression of GH (O30%), as well as TSH and Subsequent investigations revealed a pituitary tumor in all four of these patients. a-subunit. Three months after surgery, the patient was completely asymptomatic The affected patients underwent hypophyseal surgery with curative effect on the with normal thyroid function (TSH 0.73 mU/ml, fT3 5.17 pmol/l, fT4 18.7 pmol/l) hypercortisolemia and improvement of associated hormonal and metabolic and normal IGF-1 (132 ng/ml) and GH (0.1 ng/ml). There were no signs of disturbances. hypopituitarism and imaging of the brain showed no residual tumor. The lack of Conclusions acromegalic features is probably due to the sudden onset of hyperthyroidism and A frequency of 4/378 (1.05%) for Cushing’s disease in the PCOS patient group is only mildly elevated GH and IGF-1. much higher than the expected frequency in the general population. We propose This case highlights the potency of plurihormonal secretion of pituitary that Cushing’s syndrome is much more common in PCOS than previously adenomas. Transsphenoidal resection is the therapy of choice for TSH-secreting supposed. The current criteria for PCOS establish the diagnosis only if other tumors with reported cure rates of 50–80%. endocrine disorders have been excluded. This implies careful exclusion of
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P119 1Division of Endocrinology, Diabetes, Angiology, Nephrology, and Clinical Chemistry, Department of Internal Medicine, University Hospital of Atypical laminopathy revealed by non-insulin dependent diabetes and 2 conduction disturbances Tu¨bingen, Tu¨bingen, Germany; Department of Otorhinolaryngology and 1 1 Head and Neck Surgery, University Hospital of Tu¨bingen, Tu¨bingen, Marie-Christine Vantyghem , Fre´de´rique Defrance-Faivre , 3 2 1 3 4 Germany; Department of Diagnostic Radiology, University of Tu¨bingen, Christine Lemaire , Justine Burdese , BenoıˆtGal, David Launay , 4 5 6 Tu¨bingen, Germany; Department of Nuclear Medicine, University Hospital Corinne Vigouroux & Olivier Lascols 5 1Lille University Hospital – Endocrinology and Metabolism, Lille, France; of Tu¨bingen, Tu¨bingen, Germany; Department of General Pathology, 2Be´thune General Hospital – Diabetology, Be´thune, France; 3Lille University Hospital of Tu¨bingen, Tu¨bingen, Germany. University Hospital – Cardiology, Lille, France; 4Lille University Hospital – Internal Medicine, Lille, France; 5INSERM U 680 Universie´ Pierre et Marie 6 Background Curie UMR S6806, Paris, France; De´partement de Biologie Mole´culaire, Primary squamous cell carcinomas of the thyroid are uncommon entities with less AP-HP Hoˆpital St Antoine, Paris, France. than 100 cases described in the literature. Case report LMNA mutations cause a wide range of diseases involving either specific tissues We report on the imaging findings in a rare case of primary squamous cell in isolated fashion (cardiac and skeletal muscles, nerve, adipose tissue) or several carcinoma of the thyroid that was found to be the primary tumour of humerus and tissues in a generalized way (premature ageing syndromes.). The cardiac cervical lymph node metastases. Other sources of squamous cell cancer were disease is defined by conduction and rhythm disturbances, followed by dilated ruled out by a careful search, including whole body computed tomography (CT), cardiomyopathy, heart failure, and sudden cardiac death. We report an unusual positron emission tomography/CT after intravenous F-18 fluorodeoxyglucose, case of laminopathy revealed by diabetes associated with conduction disturbances complete otorhinolaryngological examination, and panendoscopy. related to a not-yet described LMNA mutation. A 36-year old woman was Conclusion admitted because of hyperglycemia (11 mmol/l) discovered after a 12-kg weight Primary squamous cell carcinomas of the thyroid, though very rare, should be loss. Clinical examination showed a BMI that was still 34 with android included in the differential diagnosis of metastatic disease of squamous cell repartition, waist acanthosis nigricans, hyperlordosis and short hands. Blood cancer. pressure was 130/67 mmHg and heart frequency 40 bpm related to an asymptomatic auriculo-ventricular conduction block requiring pace maker implantation. HbA1c level was 9.4% with mild increase of liver enzymes (ALAT: 64, ASAT 85 UI/l (N!30), cholesterol (2.31 g/l; N!2.0) and triglycerides (2.49 g/l; N!1.5). Blood magnesium level was 15 mg/l (N: 18– P122 22). A heterozygous deletion of C 2159 in exon 5 of the LMNA was identified in Cardiometabolic risk factors in type 2 diabetic patients according to the the propositus but not in eight family members. Nevertheless, family inquiry had definition for metabolic syndrome of International Diabetes Federation ! shown a history of dyslipidemia and premature sudden death ( 45 years old) in Petya Kamenova the mother who also had a pace-maker, grand-mother who had ‘muscular University Specialized Hospital for Active Treatment in Endocrinology weakness’, and two brothers of this grand-mother. The son of one of them also ‘Acad. Iv. Penchev’, Sofia, Bulgaria. had a pace-maker since the age of 35. To conclude, this case report shows that cardiac laminopathy may be revealed by diabetes and atypical lipodystrophy, linked to new LMNA mutation. However, suggestive phenotypes in the other Objective family members with absence of the described pathogenic genotype, rise the The study was to characterize metabolic syndrome (MS) in type 2 diabetic question of the association with another gene mutation or a role of patients (T2D pts) according to the definition of International Diabetes Federation hypomagnesemia. (IDF) and to test the hypothesis that this definition identifies insulin resistant subjects. Materials and methods Three hundred and eighty-three (194 females, 189 males) T2D pts of age 62.2G 2 10.4 years, HbA1c 7.5G1.4%, BMI 30.8G4.8 kg/m (meanGS.D.) took part in the study. Fifty persons with normal glucose tolerance (NGT) of mean age 60.7G P120 11.2 years served as a control group with regard to insulin sensitivity (IS). It was determined as a glucose metabolized (M; mg/kg per min) using a manual A Korean adult-onset type II citrullinemia with confirmed SLC25A13 hyperinsulinaemic euglycaemic clamp technique and homeostasis model mutation: a case report assessment of insulin resistance (HOMA-IR). The study was approved by Sang-Yong Kim, Hak-Yeon Bae & Jin-Hwa Kim Local Ethical Committee. Chosun University Hospital, Gwang-Ju, Republic of Korea. Results According to the definition of IDF, MS was diagnosed in 76.5% of the T2D pts (82% females, 70.9% males). The highest percent of the MS pts (75.1%) were Adult-onset type II citrul this rare metabolic disease for the adult patient who characterized by raised blood pressure, followed by those with reduced HDL exhibits mental changes and hyperammonemia without liver or brain diseases. cholesterol (63.5%), raised triglycerides (72.3%) and combined dyslipidaemia Recently, the SLC25A13 gene, which encodes the mitochondrial aspartate was established in 42.3% of the MS pts. IS of the MS pts M 3.238G1.673 was glutamate carrier protein named citrin, is demonstrated to be responsible for significantly lower compared to that of the pts with no MS (non-MS pts) M adult-onset type II citrullinemia. While there have been multiple cases reported in 6.893G3.846 and control group M 6.296G3.176 mg/kg per min, both P!0.001. the Japanese population, there is no report of adult-onset type II citrullinemia with HOMA-IR of the MS pts 6.02G1.69 was significantly higher compared to that of confirmed SLC25A13 linemia is an autosomal recessive disorder of the amino non-MS pts 3.07G1.27 and control group 3.54G1.92, both P!0.001. acid metabolism caused by a deficiency of liver-specific argininosuccinate Conclusions synthetase activity. This disease may occur at any stage in life with recurrent The diagnostic criteria for metabolic syndrome of IDF definition are easily episodes consisting of neurological signs and symptoms such as disorientation, applicable in routine clinical practice that makes it a very useful tool for early abnormal behavior (aggression, irritability, and hyperactivity), seizure, coma, and treatment of cardiometabolic risk factors. Nevertheless that insulin resistance is potential death from brain edema, which result from hyperammonemia. It should not included in IDF definition, according to our data, it identifies type 2 diabetic be considered that mutation in Korea. However, we experienced a 39-year-old patients with insulin resistance, as well. female who suffered from generalized weakness, dizziness, and lethargy and was diagnosed with adult-onset type II citrullinemia based on highly elevated plasma citrulline and ammonia and the SLC25A13 gene mutation. Thus, it is reported the first case of adult-onset type II citrullulinemia with confirmed SLC25A13 mutation in Korea with a brief review of the related literature. P123 Fungal thyroiditis Sowmya Narasimhan & Charles Gibbs King’s College Hospital, London, UK. P121 Primary squamous cell carcinoma of the thyroid Case Karsten Mu¨ssig1, Julia Dahm2, Assen Koitschev2, Marius Horger3, A 38-year-old HIV positive lady presented with a neck swelling and neutropenic Mark Mu¨ller4, Roland Bares4 & Manfred Wehrmann5 sepsis. Examination of the neck revealed a firm diffuse non-tender goitre with
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 cervical lymphadenopathy. She also had generalised lymphadenopathy, spleno- Cushing’s disease (CD) occur more frequently in females than in males, but in megaly and miliary opacities in the lungs on the chest radiograph. Disseminated men this disease seems appear at a younger age and with more severe symptoms cryptococcal infection was diagnosed following isolation of the organism in and clinical course. Aim of this study was to compare clinical features and blood and bone marrow. A radioisotope scan of the thyroid showed no uptake in biochemical indices of hypercortisolism in male and female patients with CD. the right lobe and reduced uptake in the left. Anti-thyroid microsomal antibodies Methods were negative. She had hypothyroidism with a free T4 of 5.3 pmol/l (NR 11.5– Forty-five patients (35 females and 10 males) with confirmed CD were analyzed. 23.2) and TSH 46 mU/l (NR 0.3–3.5), and was given thyroxine replacement. All patients underwent a complete biochemical and endocrine assessment; Histology from a core biopsy of the thyroid gland showed extensive replacement in selected case bilateral inferior petrosal sinus sampling (BIPPS) was also of thyroid tissue with organisms with a cell size considerably larger than an carried out. erythrocyte, surrounded by a halo effect. Cryptococcus was confirmed by Grocott Results silver stain. At diagnosis, males were younger than females (mean age was respectively Discussion 33.6G12.8 years vs 42.9G13.4 years). Males presented more severe Both goitre and thyroiditis due to opportunistic infection have been described in hypercortisolism with significantly higher ACTH levels, UFC, morning plasma patients with HIV infection. Cryptococcal infection presenting as hypothyroidism cortisol, midnight plasma cortisol, cortisol after 1 mg dexamethasone suppression associated with goitre in a patient with HIV could be misdiagnosed as test (DST) and cortisol after high-dose DST. No significant differences have been Hashimoto’s thyroiditis if infectious aetiologies are not considered. Thyroiditis observed between males and females regarding sensitivity and specificity of DST in HIV may be due to suppurative thyroiditis (streptococcal or staphylococcal), (low and high dose), ACTH and cortisol responses to CRH and DDAVP test and Tuberculous thyroiditis, Pneumocystis carinii or Cryptococcal infection. A basal and post-CRH ACTH gradient at BIPPS. MRI detected a pituitary adenoma lymphocytic auto-immune thyroiditis has also been reported as a specific AIDS- in 88% of patients with a significant prevalence of macroadenomas in males (40% related lesion. Thyroid function tests may be misleading in HIV because of rising vs 6%). In the other patients the MRI showed no evidence of tumor with a slight thyroxine binding globulin, effects on the pituitary–thyroid axis due to prevalence in man. Males patients presented high blood pressure values with hypermetabolism, and a sick euthyroid syndrome in the late stages of the higher prevalence of hypertension. The prevalence of osteoporosis and disease, although free T3 concentrations are relatively well maintained in the symptomatic fractures were higher in males patients compared with females. early stages. We conclude that thyroid FNA and in some cases, core biopsy will Conversely, no differences between sexes were found in BMI, fasting glucose, have to be carried out in HIV patients with goitre and hypothyroidism to obtain an cholesterol and triglycerides. accurate diagnosis. Conclusion Our study confirms that male patients present a CD at younger age with a more florid clinical presentation and a severe hypercortisolism; this finding might be at least due to a more prevalence of ACTH-secreting macroadenoma in these patients. P124 Increased levels of thyroid hormone and a non-suppressed TSH in two patients due to different mutations in T3 receptor beta (TRb) Robin Peeters1, Helena Sorensen1, Irene Keularts2, Christine Oldenburg2, Wilma Oranje3, Pieter Postema3, Wendy van der Deure1 & Theo Visser1 1Erasmus Medical Center, Rotterdam, The Netherlands; 2Meander Medisch P126 Centrum, Amersfoort, The Netherlands; 3Reinier de Graaf Groep, Delft, The Netherlands. Failure of restrictive bariatric surgery – sleeve gastrectomy – in severe hypothalamic obesity secondary to Langerhans cell histiocytosis: a case report Introduction Isabelle Runkle, Edurne Lecumberri, Pilar Matı´a, Miguel A Rubio, Resistance to thyroid hormone (TH) can be caused by a failure of TH to enter the Andre´sSa´nchez-Pernaute, Asuncio´n Nieto & Joaquı´n Mediavilla cell, or by a lack of action of intracellular TH. Hospital Clı´nico San Carlos, Madrid, Spain. Cases Patient A, a 60-year-old man, presented with an elevated TSH (15.8 mU/l (reference range: 0.4–4.3 mU/l)), an elevated FT4 (29.5 pmol/l (11–25 pmol/l)), Langerhans cell histiocytosis (LCH) is a rare disease often involving the and a normal T3. Reverse T3 (rT3), the inactive metabolite of T4, was clearly hypothalamo-pituitary axis. Extreme obesity is frequent, but effective treatment is elevated (0.82 nmol/l (0.14–0.34 nmol/l)). His medical history revealed a partial not. Malabsorptive bariatric surgery techniques are effective for weight loss in thyroidectomy because of hyperthyroidism. After disease recurrence, he was hypothalamic dysfunction. Laparoscopic sleeve gastrectomy (LSG) has recently treated with radioactive iodine in 2001. At presentation, he used 75 mgof emerged as a restrictive bariatric procedure to be used before biliopancreatic thyroxine daily. Additional evaluation showed no signs of TH dysfunction, and diversion or gastric bypass, thus reducing surgery-associated morbidity in other hormonal axes functioned normally. The differential diagnosis consisted of particularly obese patients. resistance to TH, a TSH producing tumor, or an altered TH transporter or Report metabolizing enzyme. We identified a novel mutation in TRb (Leu456Phe), We report a 20-year-old man, current smoker, puberty at thirteen, diagnosed as which was not found in his family members. The effect of the Leu456Phe having LCH involving lungs and maxilla treated with butazolidin. He related mutation is currently being tested. polyuria, polydipsia and hyperphagia. Normal libido, no erectile dysfunction. 2 Patient B, a 33-year-old man, presented with an elevated FT4 (42.1 pmol/l), an Weight 198 kg, height 190 cm, BMI 54.84 kg/m . Scarce body hair, goiter, elevated T3 (3.16 nmol/l (1.4–2.5 nmol/l)), and an elevated rT3 (0.72 nmol/l). bilateral gynecomastia. Testis 3–4 ml. Obstructive sleep apnea. Nevertheless, he had a non-suppressed TSH (3.31 mU/l) and no symptoms of Laboratory hyperthyroidism. Additional laboratory testing showed normal function of other pOsmolarity 289 mosm/kg (270–290), Uosmolarity 79 mosm/l per kg. TSH hormonal axes, and a normal TRH-test. His mother and aunt had elevated levels 13 mcU/ml (0.3–5), T4L 0.9 ng/dl (0.8–1.7), positive anti-TG and anti-TPO AB. of FT4 and a non-suppressed TSH as well, and one of them had an increased Undetectable GH, LH and FSH, f-testosterone 1.1 pg/ml (9–55), IGF-I 214 ng/ml, metabolic rate. Genetic testing revealed a mutation in TRb (Glu462Lys) in all PRL 329 mcUI/ml (79–208). Normal ACTH and ACTH-stimulated cortisol. three subjects. This mutation was previously described in three unrelated families, NMR resulting in a similar phenotype. Infiltration of hypothalamus and pituitary stalk. Conclusion Diagnosis We identified two different mutations in TRb, resulting in TH resistance in four Central diabetes insipidus, primary autoimmune hypothyroidism, secondary subjects. High levels of TH, a normal or slightly elevated TSH, and usually mild hypogonadism, morbid obesity. symptoms are suggestive for the diagnosis. Treatment Desmopressin, levothyroxine, testosterone gel. Hypocaloric diet, exercise, behaviour therapy, and sibutramine were of no benefit. Weight reached 220 kg (BMI 60.9 kg/m2). A LSG was used as first-step intervention. Maximum weight loss was 37 kg (EWL% – excess weight loss percentage – 26.4%) four months P125 following surgery. Due to voracious eating the patient reached 198.8 kg in the following 6 months. Effects of gender on clinical and biochemical features in Cushing’s Conclusion disease Restrictive bariatric surgery, such as LSG, does not seem to be effective as a first Marina Cardinaletti, Laura Trementino, Barbara Polenta, step prior to a malabsorptive procedure in especially obese subjects with Carolina Concettoni, Tatiana Mancini, Marco Boscaro & Giorgio Arnaldi hypothalamic dysfunction. Division of Endocrinology, Marche Region, Ancona, Italy.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P127 P129 Is metoclopramide test useful in differentiation of the clinical form of Ovarian hyperthecosis in a postmenopausal woman hyperprolactinemia? Sanjay Saraf, John Milles, Mike Moloney & Sud Ramachandran Katarzyna Jaskiewicz1, Jolanta Kunert-Radek1 & Marek Pawlikowski2 Good Hope Hospital, Sutton Coldfield, UK. 1Department of Clinical Endocrinology, Medical University of Lodz, Lodz, Poland; 2Department of Neuroendocrinology, Medical University of Lodz, Lodz, Poland. Ovarian hyperthecosis is a rare cause of androgenic alopecia in postmenopausal women. The physiological levels of androgens, secreted by ovarian stromal cells, are greatly increased with hyperplastic or neoplastic transformation leading to Metoclopramide (MCP) is a selective blocker of dopamine D2 receptor, possible clinical consequences. responsible for the dopamine inhibition of prolactin (PRL) secretion from the We report a case of 56-year-old woman with type 2 diabetes presenting with pituitary. In normal conditions, administration of the proper dose of MCP leads to hirsuitism and a history of male pattern hair loss over a two-year period. increase of PRL concentration in the blood serum. This response was applied in Biochemistry showed elevated levels of testosterone 9.7 nmol/l (range: 0.2– the diagnostic test (MCP test), useful to differentiate between hyperprolactinae- 2.9 nmol/l), extracted testosterone 8.5 nmol/l (range: 0.5–2.5 nmol/l) and mia linked with organic causes (prolactinoma and other lesions of hypothalamo- androstenedione 13.1 nmol/l (range: 1.7–12.9 nmol/l) whilst gonadotropins, pituitary region) and so-called functional hyperprolactinaemia. However, recently oestradiol, cortisol, prolactin and thyroid hormones were within the appropriate the value of this test is a subject of controversy. Because of that we evaluated the reference range. These hormone levels together with a non-suppression of usefulness of MCP test in our clinical material. We analyzed 228 patients with testosterone during low dose dexamethasone suppression test raised the hyperprolactinaemia, hospitalized in the Department of Clinical Endocrinology, possibility that the elevated testosterone was of ovarian origin. A transvaginal Medical University of Lodz, in 2006. In all patients, MCP test and magnetic ultrasound revealed bilateral solid adnexal masses, likely to be ovarian in nature, resonance imaging (MRI) were performed. In 48 (21%) patients, the pathological although no normal ovarian tissue was identified. changes in MRI (pituitary macro- and microdenomas, pituitary stalk suppression) Based on the above investigations a working diagnosis of ‘hyperandrogenism of were found and these patients were included to the organic hyperprolactinaemia ovarian origin’ was made at multidisciplinary team meeting and after discussing group. The remaining 180 (78.9%) patients without alterations in MRI were the treatment options with the patient a bilateral oophorectomy was carried out. included to the group of functional hyperprolactinaemia. The administration of The left ovary measured 50!30!25 mm and the right ovary 60!30!20 mm MCP in patients with pituitary tumors and with stalk suppression induced the and the resulting histology revealed significant bilateral ovarian hyperthecosis. slight increases of PRL concentration in 60 min of the test (30 and 40%, In our patient, surgical therapy had an excellent result. An alternative treatment respectively). In patients with functional hyperprolactinaemia, a sharp increase of option for ovarian hyperthecosis, as reported in various case reports, is GnRH PRL concentration (usually over 300%) was found. These results indicate that the agonist therapy. MCP test possesses the diagnostic value and may be usefull especially in cases A month following surgery the testosterone levels were normalized (between 0.2 with marked basal levels of PRL. and 0.4 nmol/l) and the patient reported a clear regression of both hirsuitism and hair loss. However, surprisingly her glycaemic control deteriorated significantly after surgery (pre-surgery HbA1c: 7.4%, post-surgery HbA1c: 9.5%) and this was contrary to expectations as studies suggested that the patient could have anticipated an improvement. At present, we can offer no satisfactory explanation of this last observation.
P128 Conversion from hypothyroidism due to Hashimoto’s thyroiditis into Graves’ hyperthyroidism in a case of thyroid hemiagenesis Marek Ruchala, Ewelina Szczepanek, Agnieszka Skiba, Rafal Czepczynski & Jerzy Sowinski Department of Endocrinology and Metabolism, Poznan, Poland. P130 A fetus affected with a complete androgen insensitivity syndrome due to a novel mutation of AR and persistent Mullerian structures Background Cristina Eller Vainicher1, Marina Muzza1, Luigi Gaetti2, Laura Fugazzola1, Thyroid hemiagenesis (TH) is a rare inborn anomaly, occurring if one of the Gaetano Bulfamante3 & Anna Maria Spada1 thyroid lobes fails to develop. Due to mostly asymptomatic course, it is usually 1Endocrinology and Diabetology Unit, Medical Science Department, detected incidentally, during investigation of concomitant abnormalities of the Fondazione Ospedale Maggiore, Mangiagalli e Regina Elena IRCCS, thyroid function or structure. University of Milan, Milan, Italy; 2Anatomopathology Department, Carlo Case report Poma Hospital, Mantova, Italy; 3Anatomopathology Department, San Paolo A case of Graves’ hyperthyroidism following primary hypothyroidism due to Hospital, University of Milan, Milan, Italy. Hashimoto’s thyroiditis (HT), accompanying a TH, is reported. The patient first presented symptoms of hypothyroidism at the age of 49, when HT and left thyroid lobe agenesis was diagnosed. L-Thyroxine replacement therapy Complete androgen insensitivity syndrome (CAIS) is a rare X-linked disorder caused restored euthyroidism. Two years later, first clinical symptoms of by androgen receptor gene (AR) mutations that result in complete impairment of hyperthyroidism appeared, persisting despite the cessation of L-thyroxine genital virilisation. Usually CAIS patients, who have normal production of AMH by and treatment with propranolol. Due to intensifying clinical and laboratory Sertoli Cells, do not show Mullerian derivatives, although the persistence of signs of thyrotoxicosis associated with an increase in thyrotropin receptor Mullerian duct derivatives up to now have been described in nine cases. antibody concentration (TRAb), Graves’ disease was diagnosed. The Here, we report the case of a fetus aborted at 20 weeks for genital ambiguity. antithyroid pharmacotherapy by thiamazole was used. However, because In particular, during autopsy, external and internal (upper third of vagina, uterus and of severe side effects it was discontinued, and the patient underwent fallopian tubes) properly developed female genitals were found. Moreover, radioiodine treatment. The administered therapy resulted in subsidence of undescended testes characterized by a large hyperplasia of Leydig cells were also thyrotoxicosis. Though, four months after 131I administration, the patient identified. Interestingly, a cousin and two aunt showed a similar phenotype. The developed symptoms of hypothyroidism with a marked increase in subsequent genetic analysis demonstrated a novel mutations affecting the ligand thyrotropin level, so substitution with L-thyroxine was reintroduced. binding domain of AR (D768V). The immunoistochemistry of the testes for AMH Hormonal balance was soon achieved, which was reflected in the was positive. In previous cases described in the literature no mutations of AMH and improvement of the patient’s clinical state. No relapse of hyperthyroidism AMHR have been described and all the hypothesis that have been suggested to was detected, and a slow, gradual decrease in the TRAb level was observed. explain this phenotype such as inappropriate synthesis or action of AMH, in utero The patient, whose observation period has now reached five years, continues exposure to diethylstilboestrol, impaired uptake of AR complex at nuclear level and to be followed-up in the outpatient clinic and under L-thyroxine replacement early testicular descent so that Mullerian structures are beyond the reach of AMH therapy, remains both clinically and biochemically euthyroid. action, have been eventually ruled out. So, considering that AR mutation justify only Conclusions half phenotype, that Sertoli cells during fetal life don’t express AR and that AMH act To our knowledge, this is the second case of conversion from primary within the first 8 weeks of gestation, before Leydig cells start to synthesize hypothyroidism due to HT into Graves’ hyperthyroidism coupled with TH, testosterone, we ruled out a possible connection between androgen resistance and the reported in the literature. Each of these three entities, may influence the thyroid lack of Mullerian derivatives regression. We hypothesized the presence of an function in a different way, hence, systematic follow-up and individual unknown gene involved in AMH processing or in downstream AMH transduction, therapeutic management is required. suggesting the necessity of performing linkage analysis.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P131 P133 A long standing lymph node metastasis from occult thyroid papillary Cross-sex hormonal therapy in transsexuals: a survey in Munich carcinoma: 10 years evolution until positive diagnosis Maria Angeles Bazarra-Castro, Caroline Sievers, Christina Dimopoulou, Cristina Preda1, Roxana Stanciu1, Alexandru Grigorovici1, Victor Costan1, Stephany Fulda, Thomas Wetter, Karin Mu¨ller, Harald Schneider, Carmen Vulpoi1, Doina Piciu2 & Eusebie Zbranca1 Johanna Pickel & Gu¨nter Karl Stalla 1University of Medicine and Pharmacy ‘Gr.T.Popa’, Iasi, Romania; Max Planck Institute of Psychiatry, Munich, Germany. 2Institute of Oncology ‘I.Chiricuta’, Cluj, Romania. Introduction Papillary thyroid carcinoma is a slow growing tumor and is reputed to have an Transsexualism associates biological normality with the conviction of belonging excellent prognosis. In 10–20% of cases, the presence of lymph node metastases to the opposite sex and the gender reassignment request. The therapy includes led to diagnosis. psychological, hormonal and surgical treatment. Only limited clinical studies Objective addressing cross-sex hormonal therapy and side effects exist. To present a patient with enlarged lateral cervical masses, present for 10 years, Methods that proved to be lymph nodes with metastatic thyroid papillary carcinoma. Here, we report the results of a drafted questionnaire evaluating etiological Case report aspects and treatment outcome. The questionnaire was distributed to transsexual We report a case of an 26-year-old female patient with 10 years evolution of patients participating in the German transsexual meeting in July 2007 in Munich. enlarged cervical masses in the absence of readily palpable thyroid nodularity. Thirty-eight data sets were analysed. All patients received hormonal therapy; 70% Thyroid ultrasonography disclosed tow solid nodules !0.5 ml in the left lobe. of the male-to-female transsexuals (MFT) and 55.5% of the female-to-male Thyroid function was normal and technetium Tc 99 m pertechnetate scan transsexuals (FMT) had undergone surgery at study time point. revealed no ‘cold’ nodules. A lymph node biopsy was required and the lesions Results were histologically metastasis of papillary carcinoma. The patient underwent total Out of 38, 20 were MFT (average age 43.3G11.5 years; average age of diagnosis thyroidectomy with lymph node neck dissection and superior mediastinal lymph 39.4G11.7 years) and 18 FMT (average age 36.2G8.4 years; average age of node dissection followed by radioactive iodine therapy. After 4 months, the diagnosis 31.6G8.4 years). All patients followed differing treatment regimes: wholebody scan was negative and the tyroglobuline decreased from 701 to 55% of the MFT received transdermal estrogenes, 65% oral estrogenes, 30% oral 21.97 ng/ml. progesterone and 2% intramuscular progesterone. In FMT, 23.5% received Conclusions transdermal testosterone and 94.1% intramuscular testosterone. 95% of all MFT In a young patient with lateral cervical masses, the diagnosis of lymph node and 100% of FMT patients reported to be satisfied with the HT. However, 25% of metastasis from occult papillary carcinoma should be considered. Even the MFT reported symptoms such as general weakness and tiredness while 44.4% of diagnosis was made after 10 years of slow evolution, the right treatment (surgery FMT reported side effects such as acne, sudoration and depressive mood. MFT as and radioiodine therapy) succeeded. well as FMT (55 and 61.1%, respectively) reported a significant weight increase following hormonal therapy (mean increase 6.9G3.6 kg). Conclusion Although patients report overall satisfaction with the hormonal treatment, the preliminary data points to a high prevalence of side effects. Further analysis in a larger sample of patients will be performed to elucidate if certain subgroups are more affected than others to optimize future cross-sexual therapy concepts.
P132 FSH secreting pituitary adenoma: a case report Mariana Cioloca1,Jo´zsef Bala´zs1, Imre Egyed3, Zolta´n Hanze´ly4, Alexandru Lupsa2,ImreKun1, Anisie Nasalean1 & Camelia Gliga1 1Clinic of Endocrinology, Targu-Mures, Romania; 2Clinic of Neurosurgery, P134 Targu-Mures, Romania; 3Pathology Department, Emergency Clinical Optimization of chronic disease patient management: a pilot project on Hospital County Mures, Targu-Mures, Romania; 4National Institute of Sandostatinw LARw treatment via homecare service Neurosurgery, Budapest, Hungary. J Roemmler1, J Schopohl1, S Seibling2, S Petersenn2, A Rinke3 & T M Gress3 1Department of Internal Medicine of the University of Munich, Innenstadt, Gonadotroph adenomas represent 40–50% of pituitary macroadenomas. Only a Munich, Germany; 2Department of Endocrinology of the University of small subset of these tumors secrete sufficient hormone to elevate serum Essen, Essen, Germany; 3Department of Gastroenterology of the University gonadotropin levels (functioning gonadotroph tumors). of Marburg, Marburg, Germany. We are presenting the case of a 30-year-old male patient (E.R) having a characteristic symptomatology for the pituitary macroadenoma: headaches, impaired visual acuity and reduced visual field (based on ophthalmological In chronic diseases patient (pat) often need continuous med treatment. examination). MRI (with gadolinium-based contrast agent) showed an intrasellar In acromegaly and neuroendocrine tumors (GEP-NET), long term monthly mass with sphenoidal, nasal and suprasellar extension, measuring 4!5cm. injections of somatostatin analogues as Sandostatinw LARw (SAw) are the Transfrontal pituitary adenomectomy was performed. Postoperative CT scan treatment of choice. Problems regarding pat management and drug application showed no remnant tumor. The patient had a favorable clinical evolution, might arise in not-specialized centers such as general practicioners (GP). To headaches and visual symptoms improving after surgery. Postoperatory, the optimize pat’ management and compliance a homecare project* was piloted with patient presented polyuro–polydipsic syndrome. Endocrine studies were specially trained nurses who applied SAw at pat’ home. Pat’ informed consent and performed only after surgery. The clinical examination indicated normal doctors’ (doc) written delegation were prerequisites. Prior consulting between secondary sexual characters, normal testes shape and consistency, with a testes nurses, doc and pat took place, and GPs were informed. 3 centers included 41 pat volume over the maximum Prader level. Postoperative hormonal assays (15 acromegaly, 25 GEP-NET, 1 thyroid-ca) from 02-10/2007.153 applications indicated: secondary hipoadrenalism, central hypothyroidism, normal PRL were conducted (Ø 3.7, doses: 15!30 mg, 21!20, 4!10). Fifty percent of pat serum level, low testosterone, LH and GH serum levels and very high FSH received SAw for the first time. The project was evaluated by an independent serum level. The substitutive hormonal therapy was initiated with: cortisol, survey interviewing 16 pat, 9 doc and 10 nurses. All pat were very satisfied. For antidiuretic hormone and thyroid hormones. One month postoperatory, the patient 69% the well organised service was the most important benefit, for 44% the time was asymptomatic, without additional visual impairment. The hormonal assays saving. Eighty percent of the doc were very satisfied as the program showed indicated persistent high FSH serum level, normal thyroid hormones, benefits regarding pat’ satisfaction, time savings and low drop out rates (7/41 pat). testosterone, LH and PRL levels, with low cortisol serum level. The therapy Reasons for pat not participating were good contact, long experience and was supplemented with Bromocriptine (10 mg daily) and with undecanoate proximity to GP/clinic. Nurses were characterized as professional, friendly and testosterone (80 mg daily p.o.). Three months postoperatory, the FSH serum level well-organized. Nurses mentioned no or little problems with project start or med was persistently high and PRL level was under the normal values. LH and thyroid applications. Cooperation with doc was good. Training was found to require hormones serum levels were normal and testosterone level was over the normal improvements especially regarding possible side effects and disease background. values. All participants recommended continuation of the homecare service. Homecare The persistent postoperatory high FSH serum levels are suggestive for an FSH service is an innovative concept optimizing med care in chronic disease. Benefits secreting pituitary adenoma. The treatment management has to be reevaluated are time saving for doc and pat, simplification of processes, professional injection depending on the clinical and paraclinical evolution. of med resulting in higher pat’ satisfaction and compliance.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P135 We present a novel heterozygous compound inactivating mutation of the Acute neurological onset in primary hyperaldosteronism CYP19A1 (P450arom) gene in a 26-year-old 46-XY Caucasian Italian male Mara Carsote1, Corina Chirita2, Dan Hortopan2, Razvan Petrescu3 & leading to aromatase deficiency. The patient phenotype resembled those observed Catalina Poiana1 in the other estrogen-deficient patients: tall stature with continuing linear growth, 1Department of Endocrinology, Carol Davila University of Medicine and bilateral genu valgum, unfused epiphyses and delayed bone age, osteopenia. Pharmacy, Bucharest, Romania; 2C.I.Parhon Institute of Endocrinology, A dysmetabolic syndrome characterized by overweight (BMI 29), hyperinsuli- Bucharest, Romania; 3Central Military Emergency Hospital, Bucharest, naemia, low serum HDL and increased LDL was present. Virilization, penis and Romania. testis (15 and 20 ml for right and left testes respectively) size were normal. Right cryptorchidism was surgically corrected when he was 3-year-old. Sperm count was normal with reduced viability. Gonadal axis presented normal serum LH and Among hypertensive population, almost 10% have primary hyperaldosteronism. testosterone, increased serum FSH and undetectable estradiol. DNA analysis: all In these cases, most abnormalities are related to hypokaliemia with progressive or coding exons with their flanking intron sequences of the CYP19A1 gene, along acute onset of the symptoms. with untranslated exon I.4 and its 5 flanking region, were amplified by PCR and We present the case of 34-year-old male patient, without significant pathological sequenced on a ABI Prism 3100 Genetic Analyzer. DNA sequencing of the history, with a sudden neurological episode, dominated by tetraplegia and mild CYP19A1 gene revealed a pattern of compound heterozygosity due to a 23 bp elevated blood pressure. Extremely low values of serum potassium are found. deletion in exon IV and a point mutation in the first nucleotide of intron IX, Diabetes mellitus is also discovered. High levels of aldosterone (3 times above respectively. The heterozygous deletion would be expected to cause a frameshift normal) are found. The computed tomography revealed a left adrenal tumor of 1.3 with a premature stop codon at nucleotide 361 in exon IV; instead the single base by 1 cm diameters. The neurological signs are remitted in 2 weeks after mutation in the first nucleotide of intron IX would lead to an aberrant splicing of administration of spironolactone and hydro-electrolytic solutions. Surgical the mRNA. This new case of aromatase deficiency confirms the well-known effect resection is performed and hystopathological diagnosis of Conn’s syndrome is of congenital estrogen deprivation on skeletal maturation and bone mineral confirmed. Normal postoperative serum potassium, aldosterone and glucose are density. Furthermore the concomitant presence of cryptorchidism described in found. other two men with aromatase deficiency support a possible role of estrogens in Particularities of the case are: acute onset of hypokalemia with neurological the male gonadal development. complications, completely reversible with potassium supplements and excellent evolution after surgery, no other medication being necessary. Even if some typical features of Conn’s syndrome are present, our case is a male, and the disorder is seen more frequently in women.
P138 P136 Galactocele and prolactinoma: a pathogenic association? Tumors of the clivus: various entities requiring different therapies 1 2 1 1 1 2 1 Corina Chirita , Mara Carsote , Dan Hortopan , Andrei Goldstein & Jo¨rg Flitsch , Jakob Matschke & Dieter K Lu¨decke 2 1 Catalina Poiana Department of Neurosurgery, University Medical Center Hamburg- 1 2 2 C.I.Parhon Institute of Endocrinology, Bucharest, Romania; Department Eppendorf, Hamburg, Germany; Institute of Neuropathology, University of Endocrinology, Carol Davila University of Medicine and Pharmacy, Medical Center Hamburg-Eppendorf, Hamburg, Germany. Bucharest, Romania.
Introduction Introduction Besides an incidental finding on MRI, headache, cranial nerve palsy, or pituitary Galactocele is a rare form of cystic, benign lesion of the breast, occurring when a insufficiency may lead to the diagnosis of a clivus tumor. Hormone secreting mammary duct becomes obstructed and over filled with milk. It usually appears in pituitary adenomas mimicking a clivus tumor can be easily identified by hormone postpartum women, either lactating or not, but it is extremely rarely seen in testing, however, have to be considered prior to surgical procedures. postmenopausal women or in men. Methods Subject Within the last 3 years, 9 patients were transferred to us with the diagnosis of a We present the case of a 37-year-old female patient, nullipara, diagnosed with a clivus tumor for surgical therapy. microprolactinoma 18 months ago, and treated with bromocriptine since then Results (7.5 mg daily). The ultrasound of the breast showed normal aspect. The patient Clinically, headaches led to initial MR imaging in 7 cases, 2 patients presented stopped the treatment for 2 months and resumed it when prolactin levels rose with VI nerve palsy. Two patients were diagnosed with prolactinomas prior to again up to 100 ng/ml. On admission in our hospital, the physical examination surgery, one patient had a mucocele of the sphenoid sinus with erosion of the revealed a large, painless left breast, with no localized masses at palpation. clivus, another patient was diagnosed with a chondrosarcoma. In one patient a Ultrasound scan indicated a large cyst (O10 cm), with drop shadows inside. The fibrous dysplasia of the clivus was found, 4 patients suffered from clivus mammography showed a large, homogenous cyst. Aspiration of the cyst revealed chordomas. The prolactinoma patients were managed with dopamine agonists, all a milky fluid, rich in lipid droplets, and with no bacterial growth, confirming the other patients were operated on via the transsphenoidal route, leading to complete diagnosis of galactocele. After the aspiration, the echographic image disappeared. resection of the mucocele and partial removal of the other entities. In cases of Particularities of the case chondrosarcoma and chordoma, a proton beam radiotherapy was recommened. 1. The rarity of a galactocele in women not connected with pregnancy or lactation. Conclusion 2. The possibility of hyperprolactinemia (even mild) due to the prolactinoma to In every patient, a careful exclusion of a prolactinoma is mandatory prior to a induce the growth of the cyst. 3. The difficulty of etiological diagnosis based only surgical intervention. The authors also recommend a preoperative CT study in on mammography and ultrasound. osteolytic skull base tumors to exclude a (although rare) fibrous dysplasia. Depending on histology, a proton beam radiotherapy has to be considered in cases of chordomas, chondromas, or chondrosarcomas.
P139 Biochemical markers of bone in coeliac disease P137 Tijana Radovanov1, Vera Uzurov2, Ivana Bajkin1, Milica Medic-Stojanoska1 & Branka Kovacev-Zavisic1 A novel compound heterozygous mutation of the aromatase gene in 1Clinic of Endocrinology, Diabetes and Metabolic Disorders, Clinical adult man: new insight into the role of estrogen on gonadal development 2 1 2 1 2 Center of Vojvodina, Novi Sad, Vojvodina, Serbia; Clinic of Hemathology, Fabio Lanfranco , Lucia Zirilli , Matteo Baldi , Alessandra Luberto , Clinical Center of Vojvodina, Novi Sad, Vojvodina, Serbia. Elisa Pignatti2, Francesca Magnani2, Gianluca Aimaretti1, Cesare Carani2 & Vincenzo Rochira2 1Division of Endocrinology and Metabolic Diseases, Department of Internal Introduction Medicine, University of Turin, Turin, Italy; 2Chair of Endocrinology, Prevalence of celiac disease (gluten enteropathy) in general population is around Integrated Department of Medicine, Endocrinology Metabolism and 1:100–300. Half of these patients are women. Most common age for diagnose is Geriatrics, University of Modena and Reggio Emilia, Modena, Italy. third year or third to fourth decade of life, due to mild clinical signs. In the
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 moment of diagnosis, 30% of patients already have lowered bone mineral density We report of two sisters with hyperandrogenism, menstrual abnormalities, and (BMD). Pathophysiologic mechanism for lowering BMD is secondary, severe insulin resistance. The elder sister was seen after puberty at age 21 and she regulative, intestinal hyperparathyroidism. was referred for the evaluation of hirsutism and polymenorrhoea; the younger was Aim seen earlier in life, at age 15, for the evaluation of secondary amenorrhoea. In both To trace changes in biochemical markers of bone, before and during the therapy, of them, we performed the diagnosis of polycystic ovary syndrome (PCOS) in in two female patients of various age with celiac disease. accordance to the Rotterdam criteria. They also presented a lipodystrophic Materials and methods phenotype, characterized by loss of fat from the extremities, trunk and gluteal Patient A: 21-year-old in generative period; patient B: 53-year-old, two years in regions and excess fat deposition in face, neck, axillae and back. The two sisters menopause. After diagnosing celiac disease, patients were on ‘gluten free’ diet. started an oral treatment with metformin (1700 mg/day), that was continued Biochemical markers of bone metabolism, osteocalcin and croslaps were elevated uninterruptedly for 2 years. Because of the lack of improvement in clinical and in both patients, together with high values of parathormone and low levels of metabolic pattern, pioglitazone (30 mg/day) was added to metformin, with calcium in sera. This was a classic representation of secondary, regulative, progressive amelioration of hyperandrogenism, insulin resistance and hyper- intestinal hyperparathyroidism. Along with proper diet, patients were given insulinemia. Menses also improved, with restoration of a eumenorrhoeic pattern, supplementation of alphacalcidiol and calcium. but weight and waist circumference remained unchanged. The characteristic Results phenotype and the marked insulin resistance induced us to screen them for During the therapy, there was significant decrease in values of crosslaps, candidate genes involved in insulin signalling pathway. We detected a osteocalcin and parathormone, with normalization of calcium levels in both heterozygous missense mutation in codon 482 (R482Q) of the lamin A/C gene patients. After 5 to 6 months, levels of osteocalcin in patient A and B was consistent with the diagnosis of Dunnigan-type familial partial lipodystrophy. decreased 35.4 and 90%, respectively. Decrease of crosslaps was 41.2 and 83.5%; Notwithstanding the autosomal dominant inheritance of the disease, LMNA decrease of parathormone was 30.8 and 77.6% for patients A and B, respectively. genotyping showed that none of the alive members of the family was carrier of the After a year patient was diagnosed an osteoporosis and antiresorptive therapy R482Q mutation (father and grandmother were not screened because deceased). with alendronat was induced. At the end of the analysis, we reformulated the diagnosis into PCOS secondary to Discussion and conclusion Dunnigan-type familial partial lipodystrophy. This form widens the knowledge of During celiac disease there is significant increase in bone metabolism. Although the monogenic forms of PCOS, gives new insights into the relationships between there is reversibility in bone metabolism disturbances during therapy of gluten insulin resistance and PCOS, with practical consequences on therapeutic choices. enteropathy (celiac disease), therapeutic approach differ depending on different risk factors non related to celiac disease.
P142 P140 Coexistence of primary hyperparathyroidism and hyperthyroidism due to Graves’ disease: case report Prospective study of latent pernicious anemia markers in patients with Mihaela Vlad1, Doru Bordos2, Marioara Cornianu3, Delia Panduru1, type 1 diabetes mellitus 1 1 a Delia Dragomir & Ioana Zosin Nu´ria Alonso, M Luisa Granada, Berta Soldevila, Isabel Salinas, 1Clinic of Endocrinology, University of Medicine and Pharmacy ‘Victor Eva Aguilera, Jordi Junca`, Rocı´o Puig, Raquel Pla, Eva Martı´nez-Ca´ceres & Babes’, Timisoara, Timis, Romania; 22nd Surgical Clinic, University of Anna Sanmartı´ Medicine and Pharmacy ‘Victor Babes’, Timisoara, Timis, Romania; Hospital Universitari Germans Trias i Pujol, Badalona, Spain. 3Department of Pathology, University of Medicine and Pharmacy ‘Victor Babes’, Timisoara, Timis, Romania. Introduction Patients with type 1 diabetes mellitus (DM1) present a high prevalence of The simultaneous occurrence of primary hyperparathyroidism and hyperthyroid- autoimmune associated diseases. Recently, we described a prevalence of latent ism due to Graves’ disease in the same patient is quite rare. Primary hyperpara- pernicious anemia (LPA) of 12.4% in DM1. thyroidism accounts for hypercalcemia in only 1% of the thyrotoxic patients. The Objectives occurrence of hypercalcemia in thyrotoxic patients may represent a challenging A 5-year follow-up study of a cohort of DM1 patients in order to evaluate the diagnostic approach. evolution of biochemical markers of LPA, defined as a serum pepsinogen I (PI) In this report, we describe the first case diagnosed in the Clinic of Endocrinology concentration below normal limits. Timisoara with hyperthyroidism due to Graves’ disease and hypercalcemia due to Material and methods G PTH-secreting adenoma. One hundred and eighty six DM1 patients (93 men, aged 30 9.4 years). In 2001 A 55-year-old woman was referred to our clinic for investigations. She had signs and 2006, in all of them we measured the serum concentration of PI and gastrin, and symptoms of thyrotoxicosis and Graves’ ophtalmopathy. In routine HbA1c, cobalamin and parietal cell antibodies (PCA). laboratory investigations, hyperthyroidism and mild hypercalcemia were Results detected. Thyroid ultrasonography revealed a small goiter with hypoechoic Twenty-three of 186 DM1 patients presented LPA at baseline in 2001. In 2006, 17 parenchyma. Under thyrostatic therapy the patient became euthyroid. Further, of these patients confirmed with low serum PI and in five the levels normalized. laboratory determinations revealed maintaining of hypercalcemia and decrease One patient was lost at follow-up. All those patients whose PI levels normalized of phosphoremia. Parathyroid hormone determination indicated high value. in 2006 had normal gastrin concentrations and negative PCA in 2001, while 13/18 In ultrasonography, a small hypoechoic nodule was revealed in the lower (72%) of patients with low serum PI in 2001 and 2006 had positive PCA at posterior part of the right thyroid lobe, corresponding to right lower parathyroid baseline. In 2006, PI was low in 6 new patients who presented normal PI in 2001. gland. No complications of hyperparathyroidism were detected. The patient was From these, two patients presented positive PCA and other two high gastrin operated, subtotal thyroidectomy and right inferior parathyroid adenoma removal concentrations. The cobalamin concentration in 2001 was similar in patients with being performed. Postoperatively, the total calcium and phosphorus returned to or without LPA, but in 2006 it was significantly lower in the group with LPA Z normal values and the clinical condition of this patient was very good. diagnosed in 2001 (P 0.007). Conclusion Conclusions The persistence of hypercalcemia in patients with Graves’ disease after achieving Most DM1 patients with low serum PI concentrations present positive PCA, while euthyroid status raises the suspicion of primary hyperparathyroidism. The high in those in which PI normalize during the follow-up the PCA are negative. The values of PTH confirm the coexistence of these two endocrine disorders, having prevalence of LPA in DM1 patients increases with the follow-up. The detection of probably no causal relationship. Thus, early diagnosis and surgical therapy of low PI concentrations allows the identification and treatment of patients with low hyperparathyroidism, before occurrence of complications, confer a good cobalamin concentrations before they develop clinical anemia and neurological evolution and prognosis for these cases. complications.
P141 Monogenic form of polycystic ovary syndrome due to mutation in lamin P143 A/C gene: case report of two sisters Partial pituitary failure presenting as adrenocortical failure in Giulia Forlani, Alessandra Gambineri, Laura Patton, Uberto Pagotto & pregnancy Renato Pasquali Omar Mustafa, Hassan Shehata & Ratnasingam Nithiyananthan Endocrinology Unit, Bologna, Italy. Epsom General Hospital, Epsom, Surrey, UK.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
A 39-year-old lady presented with chest infection and was found to be A 46-year-woman was admitted with decreased appetite, weight loss, nausea, hyponatraemic (114 mmol/l) during her third pregnancy. Short synacthen test constipation, poor concentration, cough and shortness of breath on exertion. She (SST) revealed inappropriately low ACTH (39 ng/l) with adrenocortical failure had long standing history of low backache and had been taking paracetamol and (cortical 163, 355, 503 at 0, 30 and 60 min respectively). She was started on codeine in combination, amitriptyline, tramadol, stemetil, diclofenac, and replacement hydrocortisone. Adrenal autoantibodies were negative. Other tests calcichew D3 one tablet/day On examination, blood pressure was elevated, showed IGF-1 14.8 (13–50 hmol/l), growth hormone !0.1 (!10 mU/l), erythematous nodules seen over right shin. Initial investigations showed prolactin 677 (!700 mU/l), oestradiol 106, LH 3.7, FSH 6.7. Thyroid function normocytic anemia, elevated urea, creatinine (283 umol/l) and calcium. test TSH 2.61 (0.35–5.5 mU/l), Free T3 3.0 (3.0–6.5 rmol/l), Free T4 9.7 (10.0– Paratharmone was still detectable even after stopping calcichew D3 and urea, 23.0 rmol/l) twelve weeks postpartum. CT of adrenals was normal. MRI pituitary creatinine(190 umol/l) and calcium continued to be elevated even after showed normal pituitary gland. She managed to breastfeed postpartum. The first rehydration and intravenous bisphosphonate. Imaging studies showed normal pregnancy (emergency caesarean section, 39 weeks) was complicated by pre- chest X ray and ultrasound of thyroid and CT abdomen and chest revealed eclampsia, pneumonia and vaginal bleeding requiring dilatation and curettage. In borderline spleenomegaly with multiple coalescent nodular lesions and patchy her second pregnancy, she had antenatal and postpartum bleeding but breastfed. lower lobe fibrosis in lungs. Bone marrow study showed normal cellularity. A postpartum SST showed partial recovery of the adrenocortical function 313, Diagnostic splenectomy was done, histopathology of which confirmed 525, 612 nmol/l at 0, 30, 60 min respectively. ACTH was 20 hg/l. Insulin sacroidosis. Renal function improved, (creatinine 145 umol/l) and calcium tolerance test revealed partial pituitary failure with maximum cortisol of returned to normal in the next 3 days. 449 hmol/l and maximum growth hormone of 9.1 mU/l at 90 min. TRH Granuloma is the site of calcitriol and sometimes paratharmone related protein stimulation test showed normal TSH response. The gonadotrophin stimulation production resulting in hypercalcemia. Steroids inhibit the calcitriol production in test was not done as she had regular periods. She is well at present, without granulomas. Hypercalcemia per se with its consequences on kidneys or direct hormone replacement and under regular follow-up. She has been advised to take involvement of interstitium by granuloma result in renal failure. hydrocortisone at times of stress. This case illustrates the dilemmas in interpreting In our patient, splenectomy resulted in removal of bulk granulomas and thus results, especially during pregnancy. While the initial SST indicated adrenocor- calcitriol and possibly paratharmone related protein. This helped in return of tical failure, the aetiology could not be determined due to pregnancy. Subsequent normal renal function and calcium. investigations suggest partial pituitary failure that became apparent at times of stress. Aetiology of pituitary failure remains elusive and is thought to be due to either lymphocytic hypophysitis or Sheehan’s syndrome.
P146 Testosterone treatment improves muscle strength, lean mass and quality of life in prefrail and frail elderly men: results from a P144 randomised double-blind placebo-controlled study The safety and efficacy of injectable testosterone undecanoate during Upendram Srinivas-Shankar1, Steve Roberts2, Judith Adams2, routine clinical management of hypogonadism: an analysis from a long- Martin Connolly3, Jackie Oldham2 & Frederick C W Wu1 term ‘real-life’ study 1Manchester Royal Infirmary, Manchester, UK; 2University of Manchester, Hermann M Behre1 & Joerg Elliesen2 Manchester, UK; 3University of Auckland, Auckland, New Zealand. 1Center of Reproductive Medicine and Andrology, University Hospital Halle, Halle, Germany; 2Bayer Schering Pharma AG, Berlin, Germany. Introduction Testosterone (T) improves muscle strength in hypogondal patients. It is unclear if Objective testosterone has similar effects in frail elderly men with low T. We conducted a This open-label, single-arm study assessed the long-term safety and efficacy of randomised double-blind placebo-controlled parallel group study to determine the injectable testosterone undecanoate (TU; Nebido) in men with hypogonadism. effects of T on muscle mass and strength, physical function and quality of life in Methods frail elderly men from the general population. Men aged 18–75 years with hypogonadism (baseline serum total testosterone Methods !10 nmol/l) were recruited. The study was performed under conditions designed Two hundred and sixty-two prefrail and frail elderly men (criteria of Fried et al. to resemble routine clinical management: patients with underlying conditions 2001), mean age (range) 74 (65–89) years received testosterone (25–75 mg/d) such as diabetes mellitus and hypertension were eligible for inclusion, and or placebo gel for 6 months. Outcome measures included muscle strength variable injection intervals were permitted. The study protocol was approved by {(primary end points – isometric peak torque, knee extension (EIMPT) and the appropriate independent ethics committees. Patients received intramuscular flexion (FIMPT)}, physical function tests, lean mass (DXA) and quality of life injections of 1000 mg TU at treatment visits separated by intervals of 6–10 weeks {aging males’ symptom (AMS) scale}. Ethical approval was obtained from the (after the first injection) or 10–14 weeks (after all subsequent injections). Here, Central Manchester research ethics committee. we report the findings of an analysis performed at the end of the interval following Results the tenth injection (1.8–2.6 years after patient entry into the study). The primary T at baseline was 10.9G3.1 and 11G3.2 mean (S.D.) nmol/l in active and placebo endpoint of the study was the serum level of prostate-specific antigen (PSA; groups. T increased to 22.9G10 nmol/l in the active with no change in placebo assessed at baseline and at alternate treatment visits). Secondary variables group (11.3G5.2 nmol/l). EIMPT improved by 6% (PZ0.042) in active and 3% included trough total testosterone levels (assessed at baseline and all treatment (PZ0.17) in placebo group. Men who reached target testosterone levels visits). during treatment achieved higher EIMPT (10% increment) versus those that Results did not (2%). Physical function tests improved but did not reach statistical A total of 77 patients (mean (standard deviation) age, 47.8 (11.6) years) were significance. Somatic subscale domain of AMS improved; adjusted difference included in this analysis. Mean PSA levels remained close to baseline throughout (95%CI) for active vs. placebo group was K1.2 (K2.4 to K0.04). Lean mass (baseline: 0.81 (0.78) ng/ml; before ninth injection: 1.14 (1.1) ng/ml). Mean increased (1.07 kg, P!0.0001) in the active versus placebo group. haematocrit remained with the normal range, and treatment was generally well Conclusions tolerated. Trough total testosterone levels were restored to the physiological range Treatment with transdermal testosterone for 6 months, leads to improvement in after the second injection and throughout the remainder of the study (baseline: 5.8 lean mass, muscle strength and physical symptom – related quality of life in (3.0) nmol/l; before tenth injection: 13.6 (3.7) nmol/l). prefrail and frail elderly men. Conclusions This ‘real-life’ study – performed under routine clinical conditions – confirmed the safety of long-term intramuscular TU treatment in men with hypogonadism. The efficacy of treatment in restoring and maintaining physiological levels of serum testosterone was also demonstrated. P147 Severe nonalcoholic fatty liver disease in a young woman with polycystic ovary syndrome and insulin resistance: case report Letitia Leustean1, Cristina Preda1, Carmen Vulpoi1, Maria-Christina Ungureanu1, Cristina Cristea1, Cristina Cijevschi2, Dragos Nemescu3 & P145 Eusebie Zbranca1 Hypercalcemic renal failure in splenic sarcoidosis 1Department of Endocrinology, University of Medicine and Pharmacy Ramalingam Srinivasan, Nigel Huston & Thaung Myint ‘Gr. T. Popa’, Iasi, Romania; 2Institute of Gastroenterology, Iasi, Romania; James Paget University Hospital, NHS Foundation Trust, Great Yarmouth, 3Department of Obstetrics and Gynecology, University of Medicine and UK. Pharmacy ‘Gr. T. Popa’, Iasi, Romania.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Women with polycystic ovary syndrome (PCOS) and insulin resistance have Myelolipomas are rare benign tumours resulting from myeloid and adipose an increased risk of developing many of the consequences of the metabolic mature cells proliferation, both elements have a clonal origin from a syndrome. Obesity, but in particular metabolic syndrome seems to be the common precursor. Myelolipomas predominantly involve the adrenal gland main cause of nonalcoholic fatty liver disease (NAFLD) so, it is not but may develop in extra-adrenal sites. They are hormonally inactive but surprising that NAFLD is very common in patients with PCOS. We present may coexist with active diseases such as adrenogenital syndrome. They are the case of a 23-year-old woman diagnosed with PCOS and insulin often asymptomatic but rarely they cause symptoms due to their size or resistance in our Endocrinology Clinic (irregular menses, hyperandrogen- spontaneous retroperitoneal haemorrhage. The myelolipomas, as a response emia, polycystic ovary morphology and increased ovarian volume on pelvic to chronic hypoxia, are frequent in more severe forms of thalassemias but ultrasound, high levels of fasting insulin and after glucose administration). not in traits. 17-a-hydroxilase deficiency is a rare cause of congenital The clinical approach revealed a body mass index (BMI) of 34 kg/m2 with adrenal hyperplasia due to defect in cytocrome P450C17 with elevated waist circumference of 108 cm, no evidence of hirsutism and a blood levels of ACTH leading to hypertension, hypokaliemia, and sexual pressure of 180/120 mmHg. The lab tests showed elevated serum development abnormalities. We report a case of a 48-year-old patient with aminotrasferase levels (ALTZ203 U/l, ASTZ145 U/l), normal alkaline primary amenorrhea who was diagnosed with a 17-a-hydroxylase deficiency. phosphatase and a high level of fibrinogen (525 mg/dl). She had no risk Since diagnosis, desametasone, hydrocortisone, antihypertensive and EEPP factors for viral hepatitis and denied having any history of alcohol use. therapy was prescribed but the patient assumed it discontinuously. Further work-up of the abnormal liver enzymes revealed negative serologic Mycrocytic hypochromic anemia was present due to a b-thalassemic trait. studies for hepatitis B and C, negative test results for antimicrosomal and The erythropoietin response to anemia was near to the lowest limit, although antinuclear antibodies, and a normal plasma ferritin level. The abdominal chronic renal failure was present. An abdomen MRI documented two ultrasound showed hepatic steatosis. We excluded other possible causes for bilateral voluminous masses at the adrenal site. Left adrenalectomy was secondary hypertension. We suggest that evaluation for liver disease should performed. The histological examination of the mass recognized a be considered at a much earlier age in women with PCOS and components myelolipoma. This is the only case in literature that describe the of the metabolic syndrome. concomitant presence of myelolipomas and b-thalassemic trait in a patient with 17-a-hydroxylase deficiency. Some hypothesis on the pathogenesis of adrenal myelolipoma can be made. Perhaps, the patient had periodical high ACTH levels due to the low adherence to suppressive therapy and the chronic adrenal gland stimulation resulted in myeloid metaplasia of adrenocortical cells. It is well known that ACTH has stimulatory effect on erythropoietin production. These two actions can be responsible of the myelolipoma growth in a patient with b-thalassemia trait.In this case the P148 chronic stimulating ACTH effect strengthened that of a mild anemia. A case of hungry bone syndrome during therapy with methimazole for hyperthyroidism Francesca Sanguin, Valentina Camozzi, Franco Mantero & Giovanni Luisetto Division of Endocrinology, Department of Medical and Surgical Sciences, Padua, Italy. P150 131 We describe a case of severe hypocalcemia after methimazole treatment for Subclinical Cushing’s syndrome (CS): role of I-iodomethylnorcho- lesterol scintigraphy in predicting the evolution of the disease Graves disease, which closely resembles classic hungry bone syndrome. 1 1 1 A 41-year-old woman with a history of Graves disease presented to our Internal Rosa Maria Paragliola , Pietro Locantore , Maria Pia Ricciato , Vittoria Rufini2, Germano Perotti2, Carlo Antonio Rota1, Medicine ward with tachyarrythmia. Laboratory data showed a severe 1 1 hyperthyroidism, an ecocardigraphy demonstrated a dilated cardiomyopathy. Alfredo Pontecorvi & Salvatore Maria Corsello 1Department of Endocrinology, Catholic University School of Medicine, The patient was given beta-blockers, low molecular weight heparin, and 2 methimazole (30 mg/day). One month after the start of treatment she was Rome, Italy; Department of Nuclear Medicine, Catholic University School readmitted to hospital with dyspnea, tachyarrhythmia, and hypotension. Few of Medicine, Rome, Italy. hours after admission the patient experienced a tetanic crisis. Total serum calcium was 1.83 mmol/l (normal, 2.10–2.55 mmol/l), and ionized calcium was Subclinical CS, mild hypercortisolism without overt clinical manifestations, is the 0.84 mmol/l (normal, 1.19–1.29 mmol/l). The patient had low thyroid hormone most frequent (5–8%) hormonal abnormality detected in patients with secreting levels. Methimazole was stopped and levothyroxine was started at a low dose. In adrenal incidentalomas. addition, the patient was given IV calcium gluconate (720 mg elemental calcium Unclear clinical features and mild hypercortisolism make the diagnosis per day), magnesium sulphate (2 g per day), and potassium chloride (30 mEq per problematic, although laboratory criteria have recently been reviewed. In these day), following a complete resolution of tetanic symptoms and normalization of cases, scintiscan is a central tool to define the adrenal functional activity. serum and ionized calcium. A 60-year-old man was referred to us because of hypercolesterolemia and It is assumed that hypocalcemia was a complication of medical therapy for hypertension treated by calcium-antagonists and alpha-lytics. thyrotoxicosis. Thus far, only a few cases of hypocalcemia after medical CT performed because of suspected kidney stones showed a 4 cm right adrenal treatment of hyperthyroidism have been reported. To the best of our knowledge, mass with radiological features indicative for adenoma. this patient is second case of hungry bone syndrome following drug treatment of The adrenal ‘incidentaloma’ was evaluated for possible hypersecretion: screening thyrotoxicosis in the literature. We suggest following serum calcium levels for the tests for primary hyperaldosteronism and pheochromocytoma were negative. first few weeks of methimazole therapy in hyperthyroid patients. Circadian rhythm in serum cortisol concentration and urinary free cortisol (UFC) were normal. Plasma ACTH concentration was low (7 pg/ml). Overnight dexamethasone 1 mg suppression test (DST) was uncertain: serum cortisol at 8 AM was 21 ng/ml. 131I-iodomethylnorcholesterol scintigraphy showed unilateral uptake on the side of the adrenal mass (concordant uptake). Because of the borderline biochemical findings and subclinical presentation, P149 careful observation associated with treatment of metabolic syndrome was preferred. A new evaluation was planned after 6 months. At that time a marked Giant myelolipoma in a patient affected by 17-a-hydroxylase deficiency increase of urinary free cortisol, elevated midnight cortisol and nonsuppressible and b-thalassemic trait cortisol (60 ng/ml) after 1 mg DST were observed. ACTH was less than 5 pg/ml. Eugenia Sacco1, Alessandra Fusco1, Antonio Bianchi1, Francesca Lugli1, Abdominal CT was unchanged. Furthermore, in spite of medical therapy, a Linda Tartaglione1, Bianca Maria Ricerca2, Francesco Danza3, worsening in metabolic and blood pressure control was detected. Therefore Giovanni Doglietto4, Alfredo Pontecorvi1 & Laura De Marinis1 the patient underwent surgery. Postsurgical hypoadrenalism is currently treated 1Endocrinology Unit, Catholic University of the Sacred Heart School of by HC. Medicine, Gemelli University Hospital, Rome, Italy; 2Catholic University of This case confirms the usefulness of radiocholesterol scintigraphy in detecting the Sacred Heart School of Medicine, Gemelli University Hospital, Institute adrenal hyperfunction in patients with subclinical CS. An incidental mass of Haematology, Rome, Italy; 3Catholic University of the Sacred Heart showing unilateral concordant radionuclide uptake in spite of the absence of clear School of Medicine, Gemelli University Hospital, Institute of Radiology, clinical and laboratory findings is predictive of a possible evolution in overt CS Rome, Italy; 4Department of Surgical Sciences, Catholic University of the and makes necessary a close follow up. Sacred Heart School of Medicine, Gemelli University Hospital, Rome, Italy.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P151 Case report A 60-year-old patient, with a long evolution history of morbid obesity (BMI Two unusual cases with pancytopenia associated with Sheehan’s 2 syndrome 52.2 kg/m ) and HBP since the age of 28, was submitted to gastric banding in Hulusi Atmaca1,2, Taner Bayraktaroglu1,2, Ayla Gokmen Akoz1,2 & December/2006. He lost about 30 kg in the 6 months following. Three months after Birsen Unsal Koyuncu1,2 surgery, clinical and laboratory hypoglycaemias were detected, sometimes with 1Medical Faculty, Endocrinology and Metabolism, Zonguldak Karaelmas sudden loss of consciousness. The fasting test was performed and blood test University, Zonguldak, Kozlu, Turkey; 2Medical Faculty, Hematology, results revealed: glucose 34 mg/dl; insulin 19.8 uUI/ml; Cpeptide 1.53 ng/ml. Zonguldak Karaelmas University, Zonguldak, Kozlu, Turkey. An abdominal helicoidally CT scan showed a 1.9 cm tumour in the head of the pancreas and a 1.1 cm tumour in the neck of the pancreas. Selective intraarterial injection of calcium gluconate was performed; there was a significant increase in Introduction serum insulin concentration after injection in gastroduodenal and splenic arteries, but Sheehan’s sydrome was known varying degrees of hypopituitarism due to not after injection in mesenteric or hepatic arteries. After medical therapy with postpartum ischemic necrosis by different etiologies. We report two case who are oral diazoxide, he was submitted to proximal pancreatectomy on 07/07/24. presented with pancytopenia which is unusual and rarely observed an important The postoperative course was complicated by pancreatic fistula, retroperitoneal clinical finding associated with Sheehan’s syndrome. abscess and transient hyperglycemias. Histopathology revealed an insulinoma with Case 1 well-defined contours. Three months after surgery the patient is asymptomatic and A 57-year-old woman has complaints of malaise, fatigue, and dyspnea without euglycemic. lymphadenopatia and hepatosplenomagaly. She had excessive bleeding after last Conclusion delivery at age 36 with subsequently lactation failure and amenorrhea. Hypoglycaemic state in morbidly obese patients following bariatric surgery may Endocrinologic evaluation revealed hypopituitarism, and her complete blood occuras a result of endogenous hyperinsulinism. In the presence of hypoglycaemia, it count showed anemia, leukopenia and thrombocytopenia due to decreased seems important to establish a differentialdiagnosis between insulinoma and NIPHS. hematopoiesis with hypocellularity in bone marrow. Sheehan’s sydrome is treated with hormone replacement therapy included prednisolone and L-thyroxine. After three monts of replacement, hematologic findings is fully recovered. Case 2 Seventy-two-year-old woman is presented with hypoglycemia and pancytopenia, P154 and her physical examination and history of a previous massive postpartum Serious hypocalcemia as the first display of coeliac disease of the Down hemorrhage suggested Sheehan’s syndrome. Hormone profiles revealed syndrome patient hypopituitarism, magnetic resonance imaging of pituitary gland showed empty Zuzana Semanova´1, Danica Telepkova´2,Ma´ria Tajta´kova´3 & 3 sella. After a week of prednisolone and L-thyroxine replacement therapy, Ma´ria Zakuciova´ hematologic findings recovered completely. 11st Private Hospital, Kosˇice-Sˇaca, Slovakia; 2Private Rheumatologic Conclusion Ambulance, Kosˇice, Slovakia; 31st Internal Clinic FNLP, Kosˇice, Slovakia. Pancytopenia is rare complication in association with Sheehan’s sydrome, and devoleped due to loss effect of pituitary hormones on metabolic reactions to hematopoiesis related to hypopituitarism. It was recovered with replacement therapy The coeliac disease is the autoimmunity disease of small intestine, which is the within a week to 3 months. The diagnosis of Sheehan’s syndrome can be delayed due immune response result to various proteins of cereals, especially wheat gliadin. in to slow progression. Obstetric history, menstruation and lactation status must be adulthood it often manifests with various symptomatology, which includes questinoted and included careful management to avoid postpartum complications. metabolic osteopathy arising on secondary hyperparathyreosis. There is casuistic model of 24-year-old patient with Down syndrome and documented autoimmunity thyroiditis, where the coeliac disease manifested by serious hypocalcemia with patologic fractures of both femur necks. In our endocrinology ambulance, she was consulted because of the legs swelling with P152 the suspicion for the insufficient thyroidal hormones substitution. She had bones Pituitary carcinoma presenting as Cushing’s disease pains for 1 year sharply worsening last month and finished to total immobility. During laboratory screening there was found serious hypocalcemia (Ca: Elisabeth Spilcke-Liss & Henri Wallaschofski 2C Ernst-Moritz-Arndt-University, Greifswald, Germany. 1.30 mmol/l, Ca : 0.94 mmol/l). Following examinations confirmed serious bones impact (T score – 3.54, max in area of L4 – 5.155) and fractures of both femur necks. At our department of Endocrinology a 44-year-old patient with typical clinical signs Considering to known association between M. Down and coeliac disease there was of Cushing’s disease presented. Diagnostic procedure showed an ACTH-producing added the antigliadin antibodies examination, antibodies against tissue transguta- adenoma of the pituitary gland, so the patient underwent transsphenoidal surgery. milation and endomysial antibodies, which were highly positive and confirmed Afterwards, hypercortisolism persisted and was treated with Ketoconazole. After a supposed malabsorption syndrome diagnosis. short period of time a pituitary hemorrhage occurred and resulted not only in a At present day, the pacient adheres antigluten diet, serum concentrates of calcium are complete remission of Cushing’s symptoms, but also in hypopituitarism. One year through permanent supplementation (Ca, vitamin D) near bottom limit of reference later, the symptoms reoccured and MRI showed a regrowth of the pituitary adenoma. range and there is planned femur necks fractures solution. Surgery was repeated and this time histology showed a pituitary carcinoma. In the There is frequent association between coeliac disease and other autoimmunity following years, therapy strategies included radiatio, adrenectomy and chemother- diseases particularly autoimmunity thyroiditis. The relationship between coeliac apy but these could not prevent the development of liver metastases and tumour disease and autoimmunity thyroiditis was already described 30 years ago and on the progress, so the patient died 6 years after the onset of the disease. base of present knowledges there is recomended according some authors to make screening for coeliac disease of the autoimmunity thyroiditis pacients and vice versa.
P153 P155 Hypoglycaemia following gastric banding 1,2 1,2 1,2 1,2 1,2 2,3 Brown tumor of the mandible and osteitis fibrosa cystica in A Oliveira , P Freitas , M Matos , E Vinha , D Braga , J Maia , hyperparathyroidism: a rare disease mimicking an osseous metasta- C Bartosch2,4, M Expo´sito2,4 & J Medina1,2 1 sized malignancy Department of Endocrinology of Hospital Sa˜o Joa˜o-EPE, Oporto, Portugal; Oliver Waidmann, Natalia Grigorian, Stefan Zeuzem & Jo¨rg Bojunga 2Faculty of Medicine, University of Oporto, Oporto, Portugal; 3Department 4 Department of Medicine I, Goethe-University, Frankfurt am Main, of Surgery of Hospital Sa˜o Joa˜o-EPE, Oporto, Portugal; Department of Germany. Pathology of Hospital Sa˜o Joa˜o-EPE, Oporto, Portugal. Background Osteolytic metastases of the bone occur in several malignant tumors. Beside osseous Introduction metastases, endocrine diseases like primary hyperparathyroidism can mimic Recently, noninsulinoma pancreatogenous hypoglycaemia syndrome (NIPHS) osteolytic metastases. has been described following Roux-en-Y Gastric Bypass Surgery in morbidly Case report obese patients. It has been proposed that hypoglycaemia might be a consequence A 53-year-old woman was sent to the hospital by an oral surgeon with a worsening of of a failure to adaptively decrease insulin secretion after surgery. The authors her general condition, fatigue, a painful tumor of the mandible, diffuse bone pain and present a case of a morbidly obese patient with severe hypoglycaemias beginning the diagnosis of a suspected metastasized malignancy. Laboratory testing showed 3 months after gastric banding surgery. a severe hypocalcaemia and a massive elevation of parathyroid hormone levels.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
A bone scintigraphy showed an enhancement in the mandible as well as several other reintervention. Histologically the tumour was densely granulated, with strong diffuse lesions in the costae, the sacrum and the right ankle. Histological examination of a immunostaining for prolactin, Ki-67 labelling index of 7% and p53 immuno- tumor biopsy indicated a giant cell tumor. CT scans of the abdomen and thorax reactivity of 42%. Bromocriptine was prescribed in a maximum daily dose of 45 mg, showed calcification of the stomach and diffuse calcifications of the kidneys, but no and a 92% reduction in prolactin levels was attained. Despite reduction in the cystic tumor. A cervical sonography showed a nodal lesion at the lower part of the right component, there were no significant changes in the solid component after treatment. thyreoidal lobe consistent with an enlarged polar body. In synopsis of all diagnostic Particular therapeutic questions arise. First, restoring eugonadism and normopro- findings, the diagnosis of a primary hyperparathyroidism with so called ‘brown lactinemia is not feasible and the involvement of critical neural structures represents tumor’ of the mandible and osteitis fibrosa cystica was made. The parathyroid gland the major concern, but surgical approach of the solid component is difficult. High was surgically resected and histological examination showed an adenoma of the doses of bromocriptine or cabergoline may be associated with long term side effects. parathyroid gland. Three months after surgery, a complete remission of the There is still the possibility of radiotherapy, with its known consequences. Second, hyperparathyroidism as well as a regression of the tumor of the mandible and this clinical course and the high Ki-67 labelling index associated with p53 staining the skeletal lesions were documented. alert to the possibility of a tumour withaggressive behaviour and malignantpotential. Discussion It has been demonstrated here that multiple osteolytic lesions and hypocalcaemia do occur not only in metastatic malignant tumors but are also found in endocrine diseases like primary hyperparathyroidism. Therefore, a careful diagnostic workup is essential in ensuring an optimal treatment. As in the present case, diagnosis is P158 sometimes complicated due to the clinical appearance and histological Does cyproterone acetate promote multiple meningiomas? differentiation between a giant cell tumor and the so called ‘brown tumor’ Sebastien Froelich1, Nassim Dali-Youcef2, Patrick Boyer1, Pierre Kehrli1, associated with primary hyperparathyroidism. Daniel Maitrot1, Johan Auwerx2 & Jean-Louis Schlienger1,3 1Neurosurgery Department, Centre Hospitalo-Universitaire, Strasbourg, France; 2IGBMC, Illkirch-Graffenstaden, France; 3Internal Medicine Department, Centre Hospitalo-Universitaire, Strasbourg, France. P156 Consequences of childhood onset growth hormone deficiency (COGHD) Multiple meningiomas are rare benign tumors (1.5% of all meningiomas). They in cases of familial hypopituitarism are either sporadic or associated with neurofibromatosis. Their long term Milica Medic Stojanoska1, Sandra Pekic2, Tijana Radovanov1, Branka morbidity is high due to the frequency of surgical procedures needed to overcome Kovacev Zavisic1, Jovanka Novakovic1 & Vera Popovic2 the absence of efficient adjuvant therapy. We present a cohort of patients in whom 1Clinic of Endocrinology, Diabetes and Metabolic Disorders, Clinical we strongly suspect cyproterone acetate to be responsible for the development and Center Vojvodina, Novi Sad, Serbia; 2Clinical Center of Serbia, Institute of progression of multiple meningiomas. Endocrinology, Belgrade, Serbia. Patients and methods We report 9 female patients (33–62 yo, mean: 46 yo) with multiple meningiomas (2 to 11) without any clinical evidence of neurofibromatosis. All patients were COGHD may be of genetic origin associated with deficiency of other pituitary treated with cyproterone acetate (50 mg/day) for various indications for a time hormones. Non treatment with GH in these cases can cause metabolic and other period ranging from 10 to 20 years. disturbances. The aim of this research was examining consequences of non treated Results COGDH in three sisters with familial hypopituitarism. Three sisters 60-, 59- and A rapid onset of clinical symptoms was observed in 6 patients with rapid 54-year-old with familial hypopituitarism (GH,TSH, gonadotropin and prolactin decreased visual acuity in 5 patients, suggesting rapidly progressive meningio- deficiency) which was diagnosed 46 years before were examined. Substitution mas. Lesions were preferentially located on the skull base. Cyprotenone acetate therapy performed only with thyroid hormones and gonadal steroids. We examined was stopped at the time of diagnosis in 2 patients. Six patients were followed anterior pituitary hormones, body mass index – BMI, body composition by BIA, radiologically for a period exceeding 5 months (8 to 81) before treatment lipids, OGTT with glycemia, insulin and C-peptide, bone metabolism and withdrawal. A significant increase in tumor size and/or the development of new densitometry by DXA. Levels of pituitary hormones confirmed above mentioned lesions was observed in all cases. In six patients, the follow-up period after deficiency and good substitution of thyroid deficiency. Therapy with gondal steroids treatment withdrawal was more than 5 months (5 to 32 months, mean: 17 months) was interrupted some years ago. Low level of IGF-I (!0.25 ng/ml) in all of them and no clinical nor radiological progression was observed. confirmed GHD. BMI and body composition were normal in all. High level of total Discussion cholesterol, LDL, triglycerides and low level of HDL were present in all of them. We strongly suspect cyproterone acetate as a promoting factor in the development of OGTT excluded disturbances of carbohydrate metabolism. Bone markers showed multiple meningiomas in concert with a particular endocrine status. We could face a accelerated bone metabolism only in the oldest sister (osteocalcin 51.5 ng/ml, particular histopathologic entity considering the preferential skull base location of b-crosslaps 932 pg/ml). Two sisters had osteoporosis (T score: K2.76 in the oldest lesions and the unusual absence of progression after treatment withdrawal. and the second oldest K4.2), and the youngest one had osteopenia with T score K2.4. Conclusion Conclusion Although undescribed in the literature, the possibility of a relationship between Non treated COGDH in familial hypopituitarism can cause disturbances in lipid and multiple meningiomas and cyproterone acetate, needs to be further investigated. lipoprotein metabolism, bone mineral density and bone metabolism without disturbances of carbohydrate metabolism, obesity and pathological body composition.
P159 How the workup of low renin hypertension lead to the diagnosis of SIADH P157 Chara Kolentini1, Nils Morgenthaler2, Gerhard Mertes3, Angela Cupisti4, Giant prolactinoma: what is the best therapy? Matthias Schott1, Werner A Scherbaum1 & Holger S Willenberg1 Ana Catarina Matos, Filipe Mota, Olinda Marques, Rui Almeida, 1Department of Endocrinology, Diabetes and Rheumatology, University Carlos Alegria & Fernando Pardal Hospital Duesseldorf, Duesseldorf, Germany; 2BRAHMS AG, Hennigsdorf, Hospital de S. Marcos, Braga, Portugal. Germany; 3Department of Internal Medicine, St Josef Hospital Linnich, Linnich, Germany; 4Hospital Dueren, Institute of Pathology, Dueren, Germany. Giant prolactinomas are uncommon, with some individual case reports described in the literature, but with few series documenting treatment outcomes. They represent a therapeutic challenge, since restoring normoprolactinemia, eugonadism and A patient was referred to us because he had hypokalemic hypertension and no reducing tumour size may not be realistic goals. Specific complications may also detectable blood concentrations of renin and aldosterone. In addition, this patient arise during treatment that change the initial management plans. The authors had an adrenal mass. Since he was hyponatremic, he was put on fludrocortisone. describe a case of a 28-year-old male with visual impairment and behavioural At presentation, we found that the patient was normonatremic and hypokalemic changes. The diagnosis of a macroprolactinoma was made, characterized by a lesion and had a high sodium to urinary sodium to potassium to urinary potassium with 76 mm of larger diameter, supraselar extension, large anterior-superior cystic (SUSPUP) ratio. But review of older laboratory results showed an inadequate component and posterior-inferior solid component in relation with vascular and high urinary concentration of sodium and a very low SUSPUP ratio. Hormonal neural structures of the skull base. The endocrine study revealed prolactin levels of studies revealed that the patient had undetectable low renin and aldosterone 158 700 uUi/ml (58–254), without associated hypopituitarism. A craniotomy was levels. However, pro-brain natriuretic peptide (proBNP) and copeptin as a performed, but relapse of the cystic component in the first year of follow-up led to measure of vasopressin were elevated to an astonishing degree. The diagnosis of a
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 syndrome of inadequate secretion of antidiuretic hormone (SIADH) was made. Intervention and diagnosis A computed tomography scan of the thorax showed a tumor in segment 7 and 8. The lesion was operated by a transsphenoidal approach with typical pituitary The histology gave the diagnosis of a mall cell lung cancer and staining of the adenoma tissue, although with a somehow inhomogeneous texture, found biopsy samples to copeptin were positive. intraoperatively. However, the diaphragma sellae did not descent, despite the We conclude that SIADH may present as a form of low renin hypertension and that dominant suprasellar tumor parts on preoperative MRI imaging. Moreover, the the use of modern markers such as proBNP and copeptin are useful in establishing the diaphragma sellae was completely intact. Intraoperative high-field MRI imaging diagnosis of SIADH. We also conlcude that the SUSPUP ratio may help to confirmed a large suprasellar tumor remnant with an already empty sellae distinguish between mineralocorticoid excess and other form of hypertension. beneath. Extending the transsphenoidal approach, a firm, partial calcified tumor originating from the diaphragma itself, was resected completely followed by an extensive reconstruction of the sellar floor. Histopathologically the intrasella¨r parts of the lesion were composed of a sparsely granulated GH-secreting pituitary adenoma and a distinctly separated non- P160 secreting adenoma with immunohistochemical expression of LH and FSH again Clinical efficacy of intramuscular versus oral testosterone undecanoate anatomically separated by the diaphragma sellae from the suprasellar part of the in adult men with hypogonadotropic hypogonadism lesion constituting a typical meningioma. Monica Livia Gheorghiu1, Corin Badiu1, Andra Caragheorgheopol2, Conclusion Mihaela Giurcaneanu2 & Mihai Coculescu1 We present the rare coincidence of three immunohistochemically different and 1Carol Davila University of Medicine and Pharmacy, Bucharest, Romania; clearly separated scull base tumors with acromegaly mimicing a single intra- and 2C.I.Parhon Institute of Endocrinology, Bucharest, Romania. suprasellar tumor on preoperative MRI imaging.
Aim To evaluate the clinical efficacy of androgen replacement therapy with oral or intramuscular (i.m.) testosterone undecanoate (T.U.) in male patients with central P162 hypogonadism. Etiology of patients attending an outpatient clinic of a tertiary care Patients and methods centre for primary amenorrhoea: a retrospective study We retrospectively evaluated 40 patients with hypogonadotropic hypogonadism: Geeta Chhibber, Bindu Kulshreshtha, AC Ammini, Kiran Kucheria & 29 with pituitary tumors or craniopharyn-giomas, 11 with non-tumoral Alka Kriplani hypogonadism (median age 47 years, range 20–62), before and after androgen India Institute of Medical Sciences, New Delhi, India. replacement therapy, with the approval of the local Ethical Committee. We evaluated the sexual dysfunction (as declared by the patient), serum testosterone, haemoglobin, hematocrit, cholesterol, triglycerides (measured with commercial Introduction kits in venous blood sampled at 8.00–9.00 am). Primary amenorrhoea is defined as the absence of spontaneous menses by 16 Results years of age.There have been few, if any detailed reports of primary amenorrhoea In 28 patients treated with oral T.U. (median dose 120 mg/day in 3 doses) from India. for 6–24 months, the morning serum testosterone raised from 0.21G Aim 0.4 ng/ml (medianGstandard deviation) to 1.01G1.37 ng/ml (P!0.01), but To assess the clinical profile and aetiology in patients presenting with primary was normal only in 2 patients (7%) (normal values 2.41-8.27 ng/ml). In 17 amenorrhoea attending a tertiary care hospital in India. patients treated with 1 g i.m. T.U. at 0, 6, then 12 weeks intervals, evaluated Materials and methods at 1.5–10 months (median 4.5 months) from the therapy initiation, serum A retrospective study was undertaken of patients presenting to a tertiary care testosterone raised from 0.62G0.77 ng/ml to 5.24G4.2 ng/ml (P!0.01). It institution over five years. Data was retrieved from medical records. Chief was normal in 12 patients (70.5%), low in 1 (5.8%) and high in 4 patients presenting complaint/s, associated symptoms, height, dysmorphic features, (23.5%). The sexual dysfunction improved in 7/15 patients (46%) on oral mental subnormality, pubertal features were noted. Hormonal and sex steroid T.U.andin8/10patients(80%)oni.m.T.U(PZNS). Hematocrit increased assay, pelvic ultrasound and karyotyping results noted. CT and MRI scans were to higher values in patients on oral T.U (from 37.5G3.3% to 41.9G4.02, done wherever indicated and final diagnosis noted. P!0.01) than in patients on i.m. T.U. (from 38.5G4.7% to 41.1G3.9%, Results P!0.01), P!0.01, in none over 50%. Serum cholesterol and triglycerides There were 207 patients in our study with average age of presentation being 18.3 did not change significantly after any of the T.U. treatments. years, ranging from 16 to 31 years. One hundred and thirty-four patients presented Conclusion with primary amenorrhoea as their chief complaint (64.7%), others with failure to Morning serum levels of testosterone were normal and the sexual function was gain height (6.7%), lack of/delayed appearance of secondary sexual characteristics improved in most patients with central hypogonadism treated with i.m.T.U., but (26.7%) and obesity (1.9%). Frank mental retardation was seen in 5 and poor only in few patients treated with oral T.U. scholastic performance in 13. Gonadal dysgenesis was the commonest diagnosis (39%) followed by hypogonadotrophic hypogonadism (22.3%), hypothyroidism (6.2%), Mullerian agenesis (4%), genital tuberculosis (2.8%), testicular feminization syndrome (2.4%) and other miscellaneous causes. Conclusion P161 As compared to previous series from western data, our data shows that the average age of presentation is considerably later, mental subnormality is less and possibly Coincidence of a diaphragma sellae meningioma and two different aetiology is different. Racial and environmental differences may play a role in these pituitary adenoma subtypes in a single intra- and suprasellar lesion as well as the fact that ours is a referral unit. Juergen Kreutzer1, Michael Buchfelder1, Christopher Nimsky1, Ingmar Blumcke2, Boris von keller1, Walter Saeger3 & Rolf Buslei2 1Department of Neurosurgery, University of Erlangen-Nuremberg, Erlangen, Germany; 2Institute of Neuropathology, University of Erlangen- Nuremberg, Erlangen, Germany; 3German Pituitary Tumor Registry, Institute of Pathology, Marienkrankenhaus, Hamburg, Germany. P163 Clinical presentation of a patient with pseudohypoparathyroidism type 1a (Albright syndrome) Objective Gabriela Madaras1, Erika Fulop2, Daniela Popoviciu2, Jozsef Balazs1 & Despite a wide variety of differential diagnosis, modern MRI imaging usually Zoltan Madaras3 enables a good preoperative evaluation of the aetiology in most cases with scull 1Endocrinology Clinic, Targu-Mures, Romania; 2Neurology Clinic No II, base and sellar lesions. However, in some cases MRI visualization alone may also Targu-Mures, Romania; 3Ophtalmology Clinic, Targu-Mures, Romania. be misleading with a consecutive need to adapt intraoperative strategies. Clinical presentation The case of a 67-year-old male patient with the history of a bacterial meningitis, Background visual deterioration and the onset of diabetes mellitus is presented. MRI imaging Pseudohypoparathyroidism (PHP) is a heterogeneous group of disorders charac- demonstrated an intra- and suprasellar lesion of about 22 mm in diameter terized by hypocalcemia, hyperphosphatemia, increased serum concentration of compressing the optic chiasm. The sella floor was enlarged. Visual acuity was 0.1 parathyroid hormone (PTH) and insensitivity to the biological activity of PTH. and 0.06 with concentrically narrowed visual fields. From a neuroendocrino- Case report logical standpoint IGF-1 was elevated consisted with the diagnosis of a large We present the case of a 38-year-old man admitted to the Neurology Clinic in GH-secreting macroadenoma and acromegaly. November 2007 for a witnessed grand mal seizure that resolved without
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 intervention. Patient had a history of mental retardation, but no history of seizures in subtypes including activated T-helper 1 lymphocytes, natural killer cells and the past. On admission vital signs were stable and the physical exam showed a monocytes. In patients with Hashimoto’s thyroiditis, type 1 diabetes mellitus and positive Chvostek sign, obesity and a characteristic set of skeletal abnormalities Graves’ disease high levels of CXCL10 ligand in serum have been found. including short stature, round face, short neck and short 4th and 5th metacarpals. Therefore, we investigated the role of CXCL10 gene polymorphisms in patients Relevant laboratory findings: calcium 1.56 mmol/l (N 2.1–2.55), phosphorus with Addison’s disease (AD) and in patients with Graves’ disease (GD). 1.51 mmol/l (N: 0.74–1.52), PTH: 134 pg/ml (N: 15–65), urinary calcium: Materials and methods 0.01 mmol/d (N: 2.5–8), urinary phosphorus: 43.1 mmol/d (N: 35–80). CT of the Patients from Germany with Addison’s disease (nZ174), Graves’ disease head showed calcifications of the basal ganglia and multiple calcifications of (nZ171) and healthy controls (HC: nZ285) were genotyped for the CXCL10_89 the soft tissues, electrocardiogram revealed prolonged QT interval and the and for the CXCL10_90 (AD: nZ183; GD: nZ82) polymorphism within the ophtalmological exam showed bilateral cataract. The patient had an impaired CXCL10 gene. Additionally patients with Graves’ disease and healthy controls mentation with an IQ of 55. from Poland (GD: nZ181; HC: nZ147) and Serbia (GD: nZ177; HC: nZ151) Discussion were genotyped for the CXCL10_89 polymorphism using real time PCR. Based on the examinations above, we interpreted the case as a typical presentation of Results pseudohypoparatyroidism type 1a (giving the striking phenotypic characteristics). In patient with Addison’s disease, the CXCL10_89 (G/A) heterozygosity was This autosomal dominant genetic disease has a prevalence of 3.5 cases per 1 million more frequent (58.6 vs 46.7%) while the (G/G) homozygosity rate (25.9 vs people. The mainstay of treatment is vitamin D metabolites, such as calcitriol, and 36.5%) was found less than in healthy controls (PZ0.031). No differences were calcium. The goals of therapy are to maintain serum calcium levels within the observed in the genotype-frequencies for CXCL10_90 and CXCL10_89 reference range to avoid hypercalciuria and to suppress PTH levels to normal. Our polymorphisms in Graves’ disease. patient also needed neurological medication for the epileptic seizures. 0.00019) than Conclusion weight of examined patients (PZ0.632958). CXCL10_89 gene polymorphism was significantly associated with Addison’s disease in the German population but not with Graves’ disease. Our results point out that CXCL10 could be a candidate gene in the pathogenesis of Addison’s disease. Nevertheless, functional studies are underway to put these findings into physiological contexts. Comparative endocrinology P164 c-AMP production in in vitro VIP- and PACAP-induced adrenal secretion of the lizard Podarcis sicula Salvatore Valiante1, Marina Prisco1, Rosaria Sciarrillo2, Piero Andreuccetti1, Vincenza Laforgia1 & Maria De falco1 P166 1 2 University of Naples Federico II, Naples, Italy; University of Sannio, The prevalence of transsexualism (TS) and other gender identity Benevento, Italy. disorders (GID) in Russia: an overview of existing data Yuliya Tishova1, Ludmila Rudenko1, Stepan Matevosyan2 & Svetlana Kalinchenko1 The action of the regulatory neuropeptides vasoactive intestinal polypeptide (VIP) 1 2 and pituitary adenylate cyclase-activating polypeptide (PACAP) carries out through Research Center for Endocrinology, Moscow, Russian Federation; Moscow City Center for Psychoendocrinology, Moscow, Russian Federation. the shared receptors VPAC1 and VPAC2 and the exclusive PACAP receptor PAC1, all of which are G protein-coupled receptors. Formerly, we showed that the administration of both peptides enhance catecholamine, corticosterone and Background aldosterone release from adrenal cell co-culture. Further, the distribution of VIP The prevalence of TS and other GID, as well as men/women ratio (MWR) of the and PACAP receptors in the adrenal glands of the Italian wall lizard, Podarcis sicula, pathology is the topic of a high interest for professionals in this field. The earlier was previously demonstrated: VPAC1 was found within steroidogenic tissue, data from Russia reported the MWR as 1:3 and were different from reported by VPAC2 and PAC1 within chromaffin tissue. In the present study we investigated the other countries. c-AMP signaling pathway involved in the VIP and PACAP-induced secretion of Objective adrenal cell co-cultures. Using VPAC1 antagonist [Ac-His1, To study the current prevalence of TS and other GID in Russia. D-Phe2,Lys15,Arg16]VIP-(3-7),GH-releasing factor-(8-27)-NH2 (VPAC1-A), the Materials and methods PAC1 antagonist PACAP6-38 (PAC1-A) and VPAC2 immunoneutralized cells, in We summarized the data collected in 2006 by four Moscow clinics, experienced in vitro VIP or PACAP treated adrenal cell co-cultures, we showed that the VIP- and with GID: Research Center for Endocrinology, Moscow Center for Psychoendo- PACAP-induced steroid and peptide hormone secretion is carried out through the crinology, Russian National Research Center for Surgery, Research Center for activation of selective receptors which promote, in time dependent manner, the Psychiatry. Statistical analysis was done with STATISTICA (StatSoft Inc., USA, production of c-AMP: after 1 h of PACAP/VPAC1-A/VPAC2 immunoneutralized version 6.0) software. cells treatment, c-AMP production is 250% in relation to control. After 3 h of Results stimulation with VIP/PAC1-A/VPAC2 immunoneutralized cells, the c-AMP In 2006, there were in average 31.6 men and 30.8 women who addressed with the production was increased of 281% compared with control. After 24 h of treatment request of sex change for the first time. Among them, diagnosis of TS was neither VIP nor PACAP was able to stimulate c-AMP production. Further, we ascertained in 16.6 (52.5%) men and in 21.3 (69.2%) women. Another GID were showed that VIP enhances c-AMP production through the binding of the VPAC1 diagnosed in 15 (47.5%) men and 9.5 (30.8%) women. Hence, the MWR in receptor and PACAP increases c-AMP production through the interaction with the patients with TS formed 1:1.3 and 1.6:1 in patients with other GID, respectively. PAC1 receptor exclusively. Thus, our investigation showed that the activation of Conclusion adenylate-cyclase is required to permit the in vitro VIP and PACAP stimulation and The new data are different from reported earlier. This fact could be explained with PACAP is faster than VIP to induce c-AMP production in lizard adrenal cell the lack of accurate differential diagnostics between TS and other GID. The secretion. second aspect was that the data were prevalently estimated by surgeons and included not only transsexuals, but all people with different GID who requested for surgery. The third aspect was that the more frequent surgery in transsexuals was mastectomy in female-to-male transsexuals (because vagino- or phalloplasty P165 were more complicated and more expensive), so these patients requested to surgeons more often. Our current data reflect the situation more widely, because Chemokine CXCL10 gene polymorphisms in Addison’s disease 1 1 3 now we possess the data not only from surgeons, but also from endocrinologists Dilek Sadet , Marissa Penna-Martinez , Alina Kurylowicz , and physiatrists. Jane Paunkovic2, Heinrich Kahles1, Patrick Bru¨ck1, Klaus Badenhoop1 & Elizabeth Ramos-Lopez1 1Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine I, Frankfurt am Main, Germany; 2Department of Nuclear Medicine, Medical Center, Zajecar, Serbia; 3Department of Endocrinology, Medical Research Center, Polish Academy of Science, Warsaw, Poland. P167 Background and aims In vivo effects of chronic contamination with 137 cesium on testicular CXC chemokine ligand 10 (CXCL10) also known as chemokine interferon g and adrenal steroidogenesis inducible protein (IP-10) is a CXCR3 chemokine belongs to a group of Elise Grignard1, Yann Gue´guen1, Ste´phane Grison1, Jean-Marc Lobaccaro2, structurally related molecules, that induce the chemotaxis of diverse leukocyte Patrick Gourmelon1 &Maaˆmar Souidi1
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
1Institute for Radiological Protection and Nuclear Safety, Fontenay-aux- P169 2 roses, France; UMR Universite´ Blaise Pascal-CNRS 6547 and Centre de Endocrine effects of a coat-color mutation Star in farm-bred silver foxes Recherche en Nutrition Humaine d’Auvergne, Clermont-Ferrand, France. Vulpes vulpus Ludmila Osadchuk More than twenty years after Chernobyl nuclear power plant explosion, Institute of Cytology and Genetics, Novosibirsk, Russian Federation. radionuclides are still mainly bound to the organic soil layers. Currently, the radiation exposure is dominated by the internal exposure to gamma-radiation Captive breeding of wild animals is a first step of domestication. The process following the decay of 137Cs, due to presence of 137Cs into the food chain. 137 is accompanied by a number of adaptations to captive conditions, which Because of this persistence of contamination with Cs, questions regarding resulting in behaviour, physiological and morphological changes. One of public health for people living in contaminated areas were raised. Several studies morphological consequences of domestication is a coat-colour mutation report an increase number of various malfunctions affecting the cardiovascular, named Star (S) that is characterised by some unpigmented areas on the skin. nervous and immune systems, in addition to a large increase of thyroid cancers. 137 The dominant mutation was first revealed in farm-bred populations of silver Moreover, it has been shown that Cs accumulate in different organs such as the foxes, but the highest frequency of this mutation was observed in silver foxes endocrine glands, the heart and the spleen. 137 selected artificially for domestic behavior (nonaggression to human). The aim Up to now the effects of the radionuclides such as Cs have been poorly of the present work was to investigate effects of Star gene on hormonal investigated on the testicular or adrenal steroidogenesis. Studies on ‘liquidators’ activity of the ovaries and adrenals, and fertility in adult silver foxes selected show some modifications of sperm parameters, along with perturbations within the Z Z 137 for domestic behaviour (n 38) and unselected control (n 37). At levels of cortisol, ACTH, and testosterone have been observed following Cs 22–28 days of pregnancy and during midanoestrus, the homozygous (SS), irradiation, but the effects of chronic internal contamination has not been studied yet. 137 heterozygous (Ss) and wild-type (ss) females from selected and unselected We investigated the biological effects of chronic exposure to Cs on testicular and populations were euthanized, blood samples were taken, gonads and adrenals adrenal steroidogenesis metabolisms in rat. Animals were exposed to radionuclide in were dissected. Plasma levels of progesterone, oestradiol and cortisol, as well their drinking water for 9 months at a dose of 6500 Bq/l (610 Bq/kg per day), a dose as gonadal content of progesterone and oestradiol, and adrenal content of that can be found in contaminated areas near Chernobyl. cortisol and progesterone were measured by RIA. Fertility was estimated by Cesium 137 contamination decreases the level of circulating 17b-estradiol, and the number of corpora lutea and implantation sites in the same groups. The increases corticosterone level. In testis, several nuclear receptors messenger Star allele decreased plasma concentrations of progesterone and cortisol, expression is disrupted; levels of mRNA encoding LXRa alpha and LXR beta ovarian progesterone contents and adrenal contents of both hormones during are increased, whereas FXR mRNA presents a lower level. Adrenal metabolism pregnancy with a most pronounced effect in selected groups. We also showed presents a paradoxical decrease in cyp11a1 gene expression. In conclusion, our negative effects of this gene on the number of corpora lutea and implantation results show for the first time molecular and hormonal modifications in testicular sites in selected groups, and on ovarian and adrenal weights in both and adrenal steroidogenic metabolism, induced by chronic contamination with 137 behavioural groups. In conclusion, our results indicate that in addition to its low doses of Cs. effect on pigmentation, the S allele also causes a number of endocrine pleiotropic effects, which are more expressed in animals selected for domestic behaviour.
P168 Contamination with depleted or enriched uranium differently affects steroidogenesis metabolism in rat Elise Grignard1, Yann Gue´guen1,Ste´phane Grison1, Jean-Marc Lobaccaro2, 1 1 Patrick Gourmelon &Maaˆmar Souidi P170 1Institute for Radiological Protection and Nuclear Safety, Fontenay-aux- roses, France; 2UMR Universite´ Blaise Pascal-CNRS 6547 and Centre de Serum levels of the soluble isoform of the receptor of advanced Recherche en Nutrition Humaine d’Auvergne, Clermont-Ferrand, France. glycosylated end products (sRAGE) are increased in women with PCOS Christina Piperi1, Evangelia Tantalaki2, Sarantis Livadas2, Claire Christakou2, Xenophon Xirafis2, Christos Adamopoulos1, Uranium is the heaviest naturally occurring element found in the Earth’s crust. It Stelios Kandarakis1, Athanasios Papavassiliou1 & Evanthia Diamanti- is an alpha-emitter radioactive element that present both radiotoxicant and Kandarakis2 chemotoxicant properties. Uranium is present in environment as a result of natural 1Department of Biological Chemistry, Medical School, University of deposits and releases by human applications (mill tailings, nuclear industry and Athens, Athens, Greece; 2Endocrine Section, First Department of Internal military army). Populations could thus be exposed to uranium either through their Medicine, Medical School, University of Athens, Athens, Greece. drinking water or the food chain. Natural uranium can be radiologically enriched, the by-product of this enrichment is then called depleted uranium. Enriched uranium is three time more radioactive Serum levels of soluble RAGE (sRAGE total), the soluble isoform of the receptor than depleted uranium. of advanced glycated end products (AGEs) that lacks the transmembrane and Few studies have been conducted regarding the effects of uranium contamination intracytoplasmic domains of RAGE, has been found elevated in type 2 diabetics on reproduction or steroidogenesis. Hormonal levels were modified among and non diabetic subjects and positively correlated with AGEs levels. In women uranium miners, whereas no effects were observed in Gulf war veterans with with PCOS, while serum AGEs have been demonstrated to be elevated, sRAGE retained fragments of depleted uranium shrapnel. levels have not been determined as yet. To distinguish chemical versus radiological effects of uranium on the metabolism The aim of the present study was to determine sRAGE serum levels in of the steroids in the testis, rats were contaminated via their drinking water with PCOS women compared with the levels in healthy controls and investigate depleted or enriched uranium. Animals were exposed to radionuclides for 9 the potential associations of sRAGE with metabolic and endocrine months at a dose of 40 mg/l (560 Bq/l for depleted uranium, 1680 Bq/l for parameters in PCOS women. The study was approved by the local ethical enriched uranium). This dose represent double highest concentration find in some committee. wells of Finland. Fifty-one non diabetic reproductive-aged women with PCOS (defined by While depleted uranium did not seem to significantly affect the production Rotterdam criteria), receiving no medical treatment and 10 controls were of testicular steroid hormones in rats, enriched uranium significantly studied. sRAGE, AGEs, androgen, estradiol serum levels and homeostatic increased the level of circulating testosterone. Enriched uranium contami- assessment model (HOMA) were determined. Women with PCOS compared nation pointed out significant increases in the mRNA levels of synthesis with controls of similar age and body mass index (BMI) had significantly enzymes, while depleted uranium contamination induces no change in these increased sRAGE levels (677.1G51.57 vs 475.6G22.69 pg/ml, PZ0.019), genes expression. Moreover, expression levels of nuclear receptors, as well which were correlated positively with AGEs levels (rZ0.533, PZ0.009). as the transcription factors were modified following enriched uranium sRAGE levels did not correlate with BMI, androgen levels and HOMA. contamination. These data demonstrate, for the first time, that non diabetic PCOS women In conclusion, our results show for the first time a differential effect among depleted have increased levels of sRAGE, which correlate positively with AGEs or enriched uranium contamination on the testicular steroidogenesis. This study levels, but are independent of obesity, hyperandrogenemia and insulin didn’t show pathological consequences, but raises questions about the of uranium resistance. The role of elevated serum sRAGE levels, in PCOS remains to chronic contamination on human being. be explored.
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P171 References Effects of dietary advanced glycation end products on endocrine and 1. Morrison et al. Mol Cell Biochem 2004 261 77–82. metabolic parameters of women with polycystic ovarian syndrome 2. Morrison et al. Int J Impot Res 2007 19 509–516. Evangelia Tantalaki1, Christina Piperi2, Katerina Koulouri1, Sarantis Livadas1, Giouli Argyrakopoulou1, Fragkiskos Economou1, Giorgos Mpoutzios1, Athanasios Papavassiliou2 & Evanthia Diamanti- Kandarakis1 1Endocrine Section, First Department of Internal Medicine, Medical School, University of Athens, Athens, Greece; 2Department of Biological Chemistry, Medical School, University of Athens, Athens, Greece. P173 Anxieties of type one diabetic patients In female rats, diet enriched in advanced glycation end products (AGEs) has been Marjan Koohnavard1, Mahin Kohankari2 & Alavieh Razavi3 associated with increased serum testosterone levels and deposition of dietary 1 glycotoxins in ovarian tissue. Iran University of Medical Sciences, Tehran, Iran, Islamic Republic of Iran; 2Iran Diabetese Association, West Azarbaijan, Iran, Islamic Republic Women with PCOS present increased serum AGE levels, which are acutely 3 elevated after intake of a single meal high in AGE content. In this study the effects of Iran; Urmia University of Medical Sciences, Urmia, Islamic Republic of a hypocaloric diet and an AGE-enriched hypocaloric diet were investigated, on of Iran. the endocrine and metabolic profile of PCOS women. Eleven women with PCOS, defined by Rotterdam criteria, were assigned for two Background months to a hypocaloric regular diet followed by two months of a hypocaloric Diabetes mellitus type 1 leads to various complications which make diabetic AGE-enriched diet. At the end of each period endocrine parameters were patients anxious. In this study, anxieties of 11 diabetic patients who could take determined. their blood sugar under control were investigated and solutions were suggested PCOS women on hypocaloric diet showed a significant reduction on BMI and done. (PZ0.0276), which was followed by a significant reduction on HOMA Patients and methods (PZ0.0035), but not significant changes on AGEs (PZ0.6073) or Eleven patients with diabetes mellitus type 1 listed their anxieties and ranked Testosterone concentrations (PZ0.7857). In post hypocaloric-AGE-enriched them in matris. The most important anxiety of these patients was blood sugar level diet, without significant changes in BMI (PZ0.29) and HOMA (PZ0.1560), changes after each meal. The practical and available solution for decreasing this testosterone levels (PZ0.0007) were increased in comparison to their status anxiety was awareness of blood sugar level after meals. This solution was during hypocaloric diet and to baseline. Additionally, the difference of suggested by the patients themselves. For this purpose, the amount of calorie of AGEs levels from hypocaloric diet to high AGEs diet were significantly meals and blood sugar level after 30 to 60 min after each meal were measured by higher (PZ0.0312). the patients for 1 month. Increased dietary intake of AGEs in hypocaloric diet is associated with Results significant increases in androgen levels, contributing to abnormal hormonal Interventions resulted in decrease of anxiety about blood sugar changes after profile in women with PCOS. Since in the ovarian compartments from meals. In the end, nine patients declared that their anxiety was decreased. polycystic ovarian tissue the AGE and their receptor RAGE have been Conclusion determined immunochemically, the role of dietary AGEs in PCOS needs to Awareness and knowledge are the main factors for decreasing anxieties and be explored. participation of diabetic patients in solving their problems can improve their lifestyle.
Diabetes and cardiovascular diseases P172 Changes in the sympathetic and sensory innervation of the tail artery, adrenal gland and male reproductive organs of glucose-intolerant Goto- P174 Kakazaki (GK) rats Opportunistic screening for type 2 diabetes mellitus in the out-patient John Morrison, Subramanian Dhanasekaran & Christopher Howarth clinic: experience from Basrah, Southern Iraq Department of Physiology, FMHS, UAE University, PO Box 17666, Al Ain, Abbas Ali Mansour United Arab Emirates. Department of Medicine, Basrah College of Medicine, Basrah, Iraq.
Twelve-month-old GK rats that showed glucose intolerance were compared with Background age matched Wistar rats. The concentrations of noradrenaline (NA), adrenaline Opportunistic screening is more efficient than population screening for diabetes (ADR) dopamine (DOP), Neuropeptide Y (NPY), and calcitonin gene-related mellitus. The aim is to describe the prevalence of unrecognized diabetes peptide (CGRP) were measured in tissue samples. The objective was to assess mellitus (DM) among out-patients clinic attending in a major hospital in Basrah, whether glucose intolerance was associated with changes in the noradrenergic and Southern Iraq. peptidergic nerves innervating the tail artery (TA), seminal vesicle (SV) and Methods corpus cavernosum (CC), and the adrenal gland (AG). The tail artery was divided A cross-sectional observational study. The study conducted for the period into three segments – proximal, middle and distal – of approximately 5 cm in between January 2006 to end of July 2007. Patients, who attended the out-patient length, because these contained the nerve endings of some of the longest nerves in clinic in Al-Faiha hospital in Basrah, were enrolled in this study if they were the body of the rat. neither known diabetics nor had florid features of DM, and their age is 18 and Tail artery above. New DM diagnosis was based on FPG equal to or more than 126 mg/dl In the tail artery, (NA) was significantly increased in the distal segments but was (7.0 mmol/l) on two occasions. reduced proximally. (ADR) was unchanged proximally, but increased signi- Results ficantly in the middle and distal segments. (DOP) was always significantly less The total study sample was 15 505, of whom 7983 (51.5%) were men and than the control levels, but increased from proximal to distal segments. (NPY) 7522 (48.5%) were women. Age range was 44.83G15.83. New DM was was significantly increased in the proximal and distal segments, and (CGRP) was seen in 1036 (6.7%). Mean age was higher among those with new diabetes significantly increased throughout the length of the artery, particularly in the 52.51G12.12 vs 44.29G15.92 (P-value !0.001). No clear difference was proximal segment. seen between both sexes regarding incidence of DM (0.007). All Seminal vesicle, corpus cavernosum and adrenal gland anthropometric indices value was clearly higher among those with diabetes. (NA) increased significantly in the CC, but was reduced in the SV and AG. (ADR) At age of 45 and above, there was a clear difference between the diabetic was significantly reduced in the SV and AG, but unaffected in the CC. (DOP) was group and non-diabetics (P-value !0.001) with prevalence of DM more significantly increased in the ADR and CC, but fell in the SV. (NPY) and (CGRP) among those at age of 45 and above in both sexes. did not change in these tissues. Conclusion These changes indicate that there are significant changes in the longest Using opportunistic screening for DM in major hospital in Basrah, Southern peptidergic sensory and sympathetic axons in the 12 month-old GK rat, and the Iraq, we detected 6.7% new patients with diabetes in the screened changes in (NA) in the distal tail artery and in the CC are similar to those population. described in the streptozotocin diabetic rat1,2.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P175 Conclusions Therefore, it is concluded that adiponectin induces the release of CCL2 to CCL5 Long term N-acetylcysteine and L-arginine administration reduces endothelial activation and systolic blood pressure in hypertensive and simultaneously reduces the surface expression of the corresponding receptors patients with type 2 diabetes mellitus and thereby may prevent an autocrine or paracrine activation of monocytes as has Andi Masha1, Valentina Ramella Gigliardi1, Loredana Brocato1, been demonstrated for CCL2 herein. Enzo Manzato3, Arrigo Berchio1, Paola Massarenti1, Fabio Settanni1, Stefania Bergamini2, Anna Iannone2 & Valentino Martina1 1University of Torino, Torino, Italy; 2University of Modena and Reggio Emilia, Modena, Italy; 3University of Padova, Padova, Italy. P177 Objective Effects of the omega-3 polyunsaturated fatty acids in the treatment of Reactive oxygen species and nitric oxide (NO) have recently been considered cardiovascular autonomic neuropathy in Type 2 diabetes mellitus involved in the cardiovascular complications of patients with type 2 diabetes as patients NO is supposed to loose its physiological beneficial effects, due to the presence of Alexander Serhiyenko, Victoria Serhiyenko, Alina Urbanovich & oxygen radicals. For this reason, we tested the effects of L-arginine (ARG) and Ludmila Serhiyenko N-acetylcisteine (NAC) administration with the aim to increase NO physiological National Medical University, Lviv, Ukraine. production reducing free radical formation. Research design A double-blind study was performed on 24 male patients with type 2 diabetes and Background and aims hypertension, divided in 2 groups of 12 patients, which received randomly an oral The aim of this study was to assess the effect of docosahexaenoic (DHA) and supplementation of placebo or NACCARG (1200C1660 mg/die, respectively), eicosapentaenoic acid (EPA) on the heart rate variability (HRV), dynamics of for 6 months. such biochemical parameters in patients (pts) with Type 2 DM and cardiovascular Results aunonomic neuropathy (CAN). The NACCARG treatment caused a reduction of the mean arterial blood Materials and methods pressure, both systolic (143.3G4.0 vs 151.5G3.5 mmHg, P!0.05) and diastolic Forty-nine pts with CAN (54G5 years) were allocated in two groups. Pts of group A (84.4G2.0 vs 88.2G0.7 mmHg, P!0.05), total-cholesterol (P!0.01), LDL- (nZ17) were receiving capsules of fish oil every day (‘Epadol’: 2.0 g EPA, 2.0 g ! ! ! DHA and 0.1% a-tocopherol acetate); B (nZ14) – capsules of olive oil. The duration cholesterol (P 0.005), oxidized-LDL (P 0.05), hsRCP (P 0.05), ICAM C C (P!0.05), VCAM (P!0.01), nitrotyrosine (P!0.01), fibrinogen (P!0.01), of the study was 3 months. We investigated the protein-kinase C (PK-C), Na ,K - 2C 2C PAI-1 (P!0.05) and intima-media thickness (P!0.02) during endothelial post- ATPase, Ca ,Mg - ATPase activities, RBC’s membranes fatty acids 125 125 ischemic vasodilation. The HDL-cholesterol level increased (P!0.05). No composition, I-6-ketoprostaglandin F1a (6-ketoPGF1a)and I-thromboxane changes in the others parameters were observed. B2 (TXB2) levels in the blood plasma, platelet aggregation parameters. Conclusions Statistics The NACCARG administration seems to be a potential well-tolerated ANOVA. antiatherogenic therapy since it improves the endothelial function in hypertensive Results patients with type 2 diabetes by improving NO availability reducing the oxidative It has been discovered that manifestation of the CAN is accompanied by decrease of C C 2C 2C ! stress. Our study’s results give prominence to its potential use in the primary and the Na ,K -ATPase, Ca ,Mg -ATPase activities (P 0.001), 6-ketoPGF1a, secondary cardiovascular prevention in these patients. Further, clinical studies on EPA level, EPA/arachidonic acid ratio with simultaneously increase of TXB2 level, a larger scale are needed to support our experimental data. PK-C activity, QTc interval parameters. Analysis of aggregatory curves shows that platelets in Type 2 DM with CAN began to aggregate earlier and the speed (0.75G 0.02 U/min, P!0.001), stage of aggregation (27.78G1.15 MU/min, P!0.01) increase. After 3 months of treatment there was a decrease of TXB2 level (P!0.001), activity of PK-C (12.37G4.11 pmol 32P/mg protein per 1 min, P!0.001), degree and speed of an aggregate of thrombocytes with simultaneous C C increase of EPA, 6-ketoPGF1a levels, EPA/arachidonic acid ratio, Na ,K - P176 ATPase, Ca2C,Mg2C-ATPase activities in the group A were marked. Also, we observed significant improvement of cardiovascular autonomic tests, HRV Adiponectin stimulates monocytic release of CCL2, -3, -4 and -5 parameters, decrease of QTc interval (P!0.01). concomitantly reduces the surface abundance of CCR1, -2 and -5 Conclusions Johanna Weigert, Markus Neumeier, Hilke Bru¨hl, Cornelius Bollheimer, DHA and EPA may exert cardioprotective, antithrombic effects and may be used Roland Bu¨ttner, Andreas Scha¨ffler, Ju¨rgen Scho¨lmerich & Christa Buechler for effective treatment of diabetic CAN. Internal Medicine I, Regensburg, Germany.
Background Systemic adiponectin is reduced in patients with obesity and type 2 diabetes mellitus. Peripheral monocytes of type 2 diabetic patients are activated and show P178 a higher surface abundance of CCR2. Inflammatory markers like CCL2 are Omega-3 polyunsaturated fatty acids and simvastatin in the treatment elevated in the serum of these patients. Therefore, the influence of adiponectin on of type 2 diabetic patients with cardiomyopathy the release of CC chemokines and the abundance of the corresponding receptors Victoria Serhiyenko, Alina Urbanovich, Alexander Serhiyenko, were investigated in monocytic cells. Volodymyr Segin & Ludmila Serhiyenko Methods National Medical University, Lviv, Ukraine. Primary human monocytes were isolated and incubated with recombinant adiponectin (10 mg/ml) for 24 h. GeneChip analysis was performed and ten out of 23 known CC-chemokines were found expressed in human blood monocytes by Background and aims GeneChip analysis and the mRNA of eight of these chemokines was induced by The aim of this study was to assess the effects of simvastatin (SIM), adiponectin. eicosapentaenoic (EPA), docosahexaenoic acid (DHA) on dynamics of such Results biochemical parameters in type 2 diabetic patients with cardiomyopathy (DCMP). Elevated CCL2 to CCL5 mRNA and protein secretion were confirmed by real- Materials and methods time RT-PCR and ELISA, respectively. The p38 MAPK inhibitor SB 203580 Twenty-five patients with DM and DCMP received SIM 20 mg tid (group A); abrogated adiponectin-mediated release of CCL2 and CCL3. CCL2 binds to the B(nZ37) – capsules of fish oil (‘Epadol’: 2.0 g EPA, 2.0 g DHA and 0.1% G-protein coupled receptors CCR2, CCL3 and CCL5 to CCR1 and CCR5, CCL4 a-tocopherol acetate), C (nZ24) – SIM 10 mg plus ‘Epadol’. All patients were on 125 and CCL5 to CCR5. The surface abundance of these receptors was significantly the same diet. We investigated the lipid profile, I-6-ketoprostaglandin F1a 125 reduced in adiponectin treated monocytes. The mRNA expression of CCR1 and (6-ketoPGF1a), I-thromboxane B2 (TXB2) concentrations, liver enzymes CCR2 was not affected whereas CCR5 mRNA was slightly elevated. CCR1 activities in the blood plasma; NaC,KC-ATPase activities, fatty acids level in protein was lower in adiponectin-treated monocytes and CCR5 was increased the membranes of RBC’s. The duration of the study was 3 months. when total cell lysates were investigated by immunoblot. CCL2 had been Statistics described to induce the mRNA expression of CCR2 and TGF-beta? in human ANOVA. monocytes. However, the abundance of these mRNAs was not altered in Results adiponectin-stimulated monocytes arguing against an autocrine or paracrine Lipid disorders (high level of total cholesterol (TC), LDL-C, triglycerides (TG, effects of this chemokine. 7.3G10.1; 4.5G0.3; 2.87G0.2 mmol/l, P!0.05)) and decrease level of HDL-C
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 in the patients with DCMP are accompanied by a decrease of the NaC,KC- selected. After completion a questionnaire, evaluation of peak systolic flow ATPase activities in the RBC’s membranes. There is a considerable increase in velocity (PSV) in middle cerebral (MCA) internal carotid (ICA) and vertebral the TXB2 level and a decrease in serum 6-ketoPGF1a, EPA, DHA levels in the arteries (VA) was done by TCD. PSVO120 cm/s for MCA and ICA and PSVO RBC’s membranes. It has been discovered that the monotherapy by SIM is 100 cm/s for VA was defined as significant stenosis. It is approved by local accompanied by negative dynamics of liver enzymes activity. After 3 months of Ethical Committee. treatment there was a more significant decrease in LDL-C, TC, TG concentration, Results TXB2 level (152.5G16.9 pg/ml, P!0.001) with simultaneous increases of EPA One hundred and eight patient (51 female, 57 male) aged 62.51G7.90 (50–85) level, EPA/arachidonic acid ratio, NaC,KC-ATPase (0.04G0.003 vs 0.09G years were invited. About 22 (20.3%) patients (11 male, 11 female) had stenosis, 0.004 mmol Pi/mg protein per 1 h, P!0.001) and the concentration of 34 (31.4%) stenotic arteries were also determined (8 stenosis in ICA, 8 in VA, 18 6-ketoPGF1a in the 3rd group (P!0.001). in MCA) mean age of 22 patients with and 86 without stenosis were 62.09G6.71 Conclusion and 62.50G8.23 years respectively, PZNS. Mean duration of hypertension The combined purpose SIM and ‘Epadol’ significantly improve the lipid profile, between these two groups were 5.36G8.00 and 3.07G3.39 years respectively state of prostacyclin I2-thromboxane A2 system, lower a doze SIM, that allows to PZNS, mean duration of diabetes was 14.09G8.42 and 8.32G6.90 years recommend their combination in the rational-proved treatment of patients with respectively P!0.01. Nine out of 22 (41%) had hyperlipidemia and 6 of them had DCMP. multiple involvement, but only 1 out of 13 patients without hyperlipidemia had multiple stenosis. Conclusion More than 20% of our patients had significant stenosis. MCA was the most common involved artery. There wasn’t any relationship between occurrence of stenosis with age, sex and duration of hypertension but a significant correlation P179 was observed between prevalence and severity of stenosis with duration of Degree of control of cardiovascular risk factors (CRFs) in patients with diabetes and also hyperlipidemia. Periodic evaluation of old diabetic patients is type 2 diabetes mellitus (T2DM) stratified by diabetes therapy recommended. Francisco Javier del Canizo-Gomez1 & Maria Natividad Moreira-Andres2 1Hospital General de Vallecas, Madrid, Spain; 2Hospital Universitario 12 de Octubre, Madrid, Spain. P181 Control of CRFs in T2DM patients results in a clinically important reduction in the risk of death and complications related to diabetes. The impact of family history of type 2 diabetes mellitus on insulin Objective sensitivity in lean subjects with polycystic ovary syndrome To assess the degree of control of modifiable CRFs in treated T2DM patients, Emre Bozkirli, M Eda Ertorer, Okan Bakiner, Inan Anaforoglu, stratified by diabetes therapy. N Bascil Tutuncu & N Guvener Demirag Materials and methods Division of Endocrinology and Metabolism, Faculty of Medicine, Baskent Cross-sectional study in 574 T2DM patients who attended our clinic for a routine University, Ankara, Turkey. follow-up. Fasting plasma glucose (FPG), HbA1C, HDL-Cholesterol (HDL-Ch), LDL-Ch and triglycerides (TGs), systolic (SBP) and diastolic blood pressure Objective (DBP), BMI, waist circumference (WC), smoking status and cardioprotective Polycystic ovary syndrome (PCOS) is a common endocrine disorder, medications were extracted from over diet dose. We applied the ADA characterized by hyperandrogenism and chronic anovulation. Hyperinsulinemia recommendations for our comparisons. The use of cardioprotective medications and insulin resistance are well-documented features of the disease. In obese PCOS was also evaluated. patients, family history of type 2 diabetes mellitus (FH-DM) is shown to be Results related with a decrease in insulin sensitivity, however not much is known about G G Mean ( S.D.) age was 67.2 11.4 years. Overall, 43% patients received insulin lean PCOS cases. The aim of this study was to determine the relationship between and 57% took taking oral hypoglycaemic drugs (OHD). Insulin users tended to be FH-DM and insulin resistance in lean PCOS subjects. older, to have longer duration of diabetes, higher WC, and higher prevalence of Methods obesity, abdominal obesity, metabolic syndrome (MS), coronary artery disease Nineteen lean PCOS patients (mean body mass index-BMI: 23.06G2.71 kg/m2) (CAD) and hypertension, than subjects taking OHD. Moreover, had higher BMI were recruited into the study. Subjects were separated into two groups regarding Z Z Z Z (P 0.004), SBP (P 0.002), FPG (P 0.000), and HbA1C (P 0.000), than their FH-DM status. Mean age, BMI and metabolic syndrome parameters were patients taking OHD. The percentage of subjects who reached the HbA1C and similar between the FH-DM negative (nZ10) and FH-DM positive (nZ9) SBP target and the number of male patients who achieved the WC target was groups. Insulin sensitivity was evaluated by using the homeostasis model Z higher among subjects taking OHD than in those on insulin (P 0.000, 0.03, assessment of insulin resistance; HOMA-IR formula and the hyperinsulinemic 0.016 respectively). More subjects on insulin than on OHD were taking euglycemic clamp method from which insulin sensitivity was derived from Z Z antiplatelet therapy (P 0.001), ACEIs/ARBs (P 0.004), beta-blockers glucose disposal rate expressed as mg/kg per min and indicated as ‘M’ index. Z Z Z (P 0.0035), calcium channel blockers (P 0.0031) and diuretics (P 0.01). Results Conclusions Mean M value of the whole group was 5.97G1.58. Mean HOMA-IR and The higher prevalence of obesity, abdominal obesity, hypertension, CAD and MS, M values of the FH-DM positive and FH-DM negative groups exhibited and the poor control of the majority of CVRFs observed in our diabetic population insignificant difference; 2.02G0.86 vs 1.98G1.11 and 5.41G1.20 vs 6.48G1.77, treated with insulin, supports the need for more aggressive arrangement of their respectively (PO0.05). CVRFs. Conclusion In this study, we found insignificant difference regarding insulin sensitivity markers among lean PCOS cases with and without a family history of type 2 diabetes mellitus. We propose that a positive FH-DM had no impact on insulin sensitivity in lean PCOS subjects. P180 Determination of asymptomatic interacranial stenotic arteries in diabetic and hypertensive old patients by transcranial doppler sonography Farzaneh Sarvghadi, Mohammad Karimi & Fereidoun Azizi P182 Endocrine Research Institute, Tehran, Islamic Republic of Iran. Rapid acting insulin analogues are superior to normal human insulin in intensified insulin treatment of type 2 diabetes mellitus Eckart Jungmann & Gisela Jungmann Background St Vincent’s Hospital, D-33378 Rheda-Wiedenbru¨ck, Germany. Ischemic stroke is a major complication of diabetes mellitus. This survey was design to detect asymptomatic intracranial stenosis and determine it’s risk factors in diabetic patients older than 50 years with hypertension by transcranial doppler Postprandial hyperglycaemia is a cardiovascular risk factor in diabetic patients. sonography (TCD). Therefore, younger type 2 diabetic patients are best treated by intensified insulin Methods therapy (IIT) for effective control of postprandial hyperglycaemia. It is unclear, Between June 2003 and December 2004 all diabetic patients older than 50 years however, whether rapid acting insulin analogues were superior to normal human with hypertension and no previous history of cerebrovascular problems, were insulin when used in IIT by patients with type 2 diabetes mellitus.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
We carried out a randomised open intra-individual cross-over trial to compare blood Materials and methods glucose (BG) responsiveness to insulin analogues (preprandial versus postprandial In a randomized, double-blind, placebo controlled clinical trial, 69 type 2 diabetic injections of insulin lispro, aspart or glulisine) with that to normal human insulin patients were randomly divided into four groups, each group receiving one of the (injected 30 min versus immediately before meal). BG was measured before and one following daily supplement for 3 months; group M: 200 mg magnesium and hour after the three main meals and at bedtime. Seventy insulin-naı¨ve type 2 diabetic 30 mg zinc (nZ16), group V: 200 mg vitamin C and 150 mg vitamin E (nZ18), patients (age, 62G2 years (meanGS.E.M.), known duration of diabetes, 7G2years, group MV: minerals plus vitamins (nZ17), group P: placebo (nZ18). BMI, 30.3G1.1 kg/m2) participated at this study. Results Whereas, BG measured one hour after meal did not differ after preprandial versus Results indicate that after 3 months of supplementation mean serum levels of postprandial injections of rapid acting insulin analogues, postprandial BG was lower HDL-C and apolipoprotein A1 increased significantly in the MV group by 24% after injections of normal human insulin 30 min versus immediately before meal (50.4G19.3 vs 40.6G10.8 mg/dl) and 9% (170G34 vs 156G24 mg/dl), (171G6vs167G5mg/dland155G6vs187G7 mg/dl, respectively, P!0.05 respectively (P!0.01). Levels of fasting serum glucose decreased in MV group (ANOVA)). The averages of the 7-point BG profiles were similarly different: 145G5 (P!0.05). Malondialdehyde concentrations decreased significantly in the M and vs 142G4mg/dland138G3vs154G4 mg/dl, respectively, P!0.05). Prandial MV groups (P!0.05 and P!0.01, respectively). Arylesterase activity increased insulin requirement was lower with insulin analogues (24G2vs30G2IU/day, significantly in the M group (91G24 vs 87G24, P!0.05) There were no P!0.05). There was no hypoglycaemic event throughout the study. significant changes in the levels of these parameters in the other groups. HbA1, Whereas in IIT normal human insulin should be injected 30 min before fructosamine, insulin and HOMA score and serum levels of total cholesterol, meal, both preprandial and postprandial injections of insulin analogues can LDL-C, triglyceride, apolipoprotein B and paraoxonase activities were not altered be allowed. Since patients benefit from injecting prandial insulin after supplementation in all 4 groups. immediately before or even after meal and since less insulin is required Conclusion with rapid acting insulin analogues, insulin analogues are superior to normal It is concluded that since co-supplementation of Mg, Zn, vitamin C and E human insulin in type 2 diabetes mellitus. significantly increases HDL-C and apolipoprotein A1 and improves fasting serum glucose and lipid proxidation, supplementation of these micronutrients should be recommended for the type 2 diabetic patients based on their daily requirements. P183 Melatonin–insulin relationships in rats and humans Elmar Peschke1, Thomas Frese 1, Sabine Wolgast1, Ivonne Bazwinsky1 & Eckhard Mu¨hlbauer2 1Martin Luther University of Halle-Wittenberg, Halle, Sachsen-Anhalt, Germany; 2Saxon Academy of Sciences, Leipzig, Sachsen, Germany. P185 There is a well documented link between melatonin and insulin. Morphological, Metabolic improvement in diabetic patients under education before molecular and functional investigations have shown that the pineal hormone implantation of the insulin sibcutaneous continuous infusion (ISCI) melatonin (MT) influences the insulin secretion. The effects were mediated by Silvia Maraver, Guillermo Martinez de Pinillos, Cristobal Morales, Juan specific, high-affinity, pertussis-toxin-sensitive, G-protein-coupled MT1- as well Manuel Garcia-Quiros, Monica Tome, Isabel Serrano, Teresa Garcia, as MT2-membrane receptors which were detected in pancreatic tissue and islets Carmen Cuesta & Angel Sendon of rats and humans and additionally in rat insulinoma cells INS1. Using the Virgen Macarena Hospital, Seville, Spain. Gi-protein-adenylylcyclase-cAMP- and possibly the cGMP-pathway, MT decreases the insulin secretion, whereas using the Gq-phospholipase C-IP3- Introduction pathway MT increases the insulin secretion. ISCI treatment is useful to optimize treatment in patients with DM1. Before For further analysis of MT-insulin-interactions, plasma MT levels were implantation, is necessary the education of patients, as in technical aspects so in measured in diabetic rats and humans. In this context, own recent the handling of diabetes with this therapy. investigations have proven that type 2-diabetic rats and humans displayed Objective a decreased MT level whereas type 1-diabetic rats (induced by Evaluate the results of the diabetological education previous to the implantation streptozotocin, STZ) showed an increased plasma MT level. In addition, of the ISCI and the repercussion of this program in patients metabolic control. the rate-limiting enzyme of the MT synthesis, the arylalkylamine-N- Material and method acetyltransferase (AANAT), was investigated by quantitative RT-PCR Forty-seven diabetic patients with indication of insulin pump were educated. analysis. Furthermore, plasma catecholamines by HPLC technique, pineal They were distributed in 4–5 people groups. Age: 31.7 years G12.45 (12–64). insulin-receptor and adrenoceptor status in addition to clock gene transcripts Fifty-six percent women and 44% men. Evolution of diabetes: 16.2 years G10 (Per1 and Bmal1) and the clock output gene dbp were analyzed in a (4–40). Indication of pump determined by bad metabolic control in 21 patients circadian series by RT-PCR. In conclusion, the results emphasize that (44.6%), hypoglycemia in 15 (31.7%), gestation in 7 (14.8%) and glycemic increased insulin levels, which were observed in some forms of type instability in 4 (8.5%). It was organized in classes of 1.5 h, 1 or 2 afternoons 2-diabetes, are combined with a decreased MT level. On the other hand, weekly, with theoretical and practical contents. The program consisted of decreased insulin levels of STZ-induced type 1-diabetes are combined with 6 classes: approach to the therapy (indications, advantages and disadvantages), a higher MT plasma level. Astonishingly, the drastic metabolic disturbances basic concepts (factor of sensitivity, ratio, basal line and bolus), feeding by CH of diurnal rhythmicities of the parameters investigated were maintained. The countings, daily and pump life (deports, disconnection, trips, hour change), acute conserved melatonin rhythm combined with an unchanged day-night- complications and technical handling of the pump. rhythmicity of AANAT reflect that the master clock, the hypothalamic Results nucleus suprachiasmaticus, was not affected. Once completed program, the average HbA1c descended respect to 2 months previous one (K0.67%), being higher when in the group in whom the pump was indicated by bad metabolic control (1.12%).
P184 Total Bad metabolic Glycemic inest- Pregnancy Hypoglycemias Effects of micronutrients supplementation on lipid peroxidation in Type HbA1c (%) (nZ47) control (nZ21) ability (nZ4) (nZ7) (nZ15) 2 diabetes Maryamsadat Farvid1, Mahmoud DJalali2 & Feraydoun Siassi2 Pre 8.48G2.49 10.12G2.74 7.75G0.70 7.58G1.60 6.79G0.86 1 Post 7.81G1.99 9.00G2.09 7.40G0.52 7.10G2.07 6.58G0.97 Faculty of Nutrition Sciences and Food Technology, Shaheed Beheshti P !0.001 !0.001 0.10 0.19 0.12 University of Medical Sciences, Tehran, Iran, Islamic Republic of Iran; 2Faculty of Public Health, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran. Conclusions In candidates to pump by bad control, a program of diabetological education Objective served to improve this control before initiate this therapy. The educative programs The present study designed to assess the effect of MgCZn, vitamin CCE, and make an improvement in the metabolic control and a motivation in the self-care of combination of these micronutrients on glycemic control, lipid profile and lipid the patient. Its application to all the diabetics would be advisable. peroxidation in type 2 diabetic patients.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P186 Comparison of patient’s life quality between inhalated insulin therapy (Exubera) and conventional treatment Period 1 Period 2 (blind) (R.T) P Monica Tome, Isabel Serrano, Cristobal Morales, Silvia Maraver, Guillermo Martinez de Pinillos, Juan Manuel Garcia-Quiros, Average glyc 157.17G34.30 137.49G21.99 0.053 (110–224) (115–203) Carmen Cuesta & Angel Sendon Variability 73.72G19.60 48.23G13.20 !0.005 Virgen Macarena Hospital, Seville, Spain. (38–103) (25–75) % High 32.56G19.25 19.90G13.87 !0.05 (7.0–75.0) (1.23–56.03) Objectives % Euglycemia 55.49G17.79 74.98G14.22 !0.005 (25.0–86.0) (43.97–98.77) To evaluate satisfaction with treatment in diabetic patients under therapy with % Low 11.94G8.04 5.10G5.16 !0.005 inhaled insulin (exubera). (0.00–29.00) (0–17.00) Material and methods Thirty-seven diabetic patients were evaluated, 27DM1 (75%) and 9DM2 Guardian P CGSM (25%) that initiated treatment with Insulin inhaled (EXUBERA) between Satisfaction 4.2 NS 3.8 August and October 2007. Twenty-five men (69.4%) and 11 women Recommendable 5.1 !0.,05 4.1 (30.56%), between 18 and 71 years old (38.4G16.4) and with a time of system evolution of diabetes between 0 and 47 years (13.9G9.9). They presented Uncomfortability 3.8 NS 3.1 G Anxiety 1.8 NS 1.9 an HbA1c average: 8.13 2.1%. They filled the DTQ1s before beginning the Interferences with treatment (group 1/G1) and 1 month later (group 2/G2). It was made a non- Job 1.3 !0.05 2.5 parametric test to match the results (Wilcoxon). Social life 1.1 !0.05 2.1 Physical activity 2.7 NS 3.1 Results Sexual life 2.5 !0.05 3.5 Eight aspects were valuated that patients had to score in a scale between 0 and 6. Sleep quality 1.5 NS 2.3 Satisfaction with present treatment: G1 3.50G1.1, G2 5.83G3.8, P!0.001. Frequency of hyperglycemias G1 3.02G1.8, G2 1.80G1.5, P!0.01. Frequency G G of hypoglycemias G1 1.6 1.6, G2 1.27 1.6 non significance. Convenience of The monitoring in real time could be useful tool at the time of assuring a better G G ! treatment G1 4.44 1.5, G2 5.77 0.4, P 0.001. Flexibility of treatment G1 metabolic control and to diminish the exhibition to hypoglycemias. G G ! G 4.33 1.6, G2 5.19 0.9, P 0.001. Knowledge of diabetes G1 4.58 1.5, G2 GURADIAN RT did not generate greater anxiety than the GCMS interfering to a G ! G 5.52 0.6, P 0.001. Recommend treatment to other G1 3.72 1.4, G2 lesser extent in the daily life of our patients. 6.0G0.0, P!0.001. Disposition of continuing treatment G1 2.22G1.8, G2 6.0G0.0, P!0.001. Conclusions Diabetic patients showed more satisfaction with the inhalated insulin therapy than with their previous treatment. There were no significant differences in the perception of hypoglycemias but they did appreciate less episodes of hyperglycemias. The greater satisfaction with inhaled insulin therapy is shown by the disposition to continue the treatment and to recommend it P188 to other patients. Metabolic control and quality of life in patients with DM1 and insulin pump therapy Isabel Serrano, Cristobal Morales, Silvia Maraver, Guillermo Martinez de Pinillos, Juan Manuel Garcia-Quiros, Monica Tome, Carmen Cuesta & Angel Sendon Virgen Macarena Hospital, Seville, Spain.
Objectives To value the quality of life improvement and metabolic control in patients with DM1 in the 2 first years of treatment with insulin pump therapy. Material and methods P187 We studied 33 DM1 patients, 16 men (48.5%) and 17 women (51.5%), with Satisfaction degree and metabolic control in patients with glucose average age of 34.2G12.2 and 16.3G10.21 years of disease. Pump indication was continuous monitoring system hypoglycemia in 10 (30.3%), badly metabolic control in 14 (42.4%), pregnancy in Cristobal Morales, Guillermo Martinez de Pinillos, Juan Manuel Garcia- 5 (15.2%) and glycemic inestability in 4 (12.1%). Following parameters pre- Quiros, Monica Tome, Silvia Maraver, Isabel Serrano, Carmen Cuesta & treatment were valued to the 3, 12 and 18 months: HbA1c, total insulin (IU/kg), Angel Sendon BMI, glycemia average, hypoglycemias and number of controls/day. All filled the Virgen Macarena Hospital, Seville, Spain. WHO questionnaire of treatment satisfaction previous to implantation of I.S.C.I., to 6 and 12 months. Results Objective To study the improvement of metabolic control and patients satisfaction with glucose continuous monitoring systems (Guardian real time). Material and method Pre Beginning 6 m 12 m 18 m Fifteen DM1 patients studied (age: 33.8G13.40, years of evolution: 17.06G HbA1c 8.0G1.9 7.5G1.6† 6.8G1.3† 6.4G0.5* 6.3G0.7 11.32) in intensive treatment (5 multidoses, 10 insulin pump) which were made IU/kg 0.76G0.3 0.56G0.3† 0.57G0.2† 0.65G0.3 0.45G0.1 BMI 25.4G4.3 25.05G4.0 25.37G3.9 25.14G3.2 25.89G2.6 one 4 days long blind monitoring Period 1 (blind period) with sensor CGMS Gold. Glycemia 157.2G32 155.4G24.5 151.7G50.1 156.5G52.1 151.4G12.3 Next another monitoring was made with a real time system with alarms of Variability 86.7G20.3 83.2G20.7 73.3G23.8* 96.5G45.2 79.1G15.1 hyperglycemia and hypoglycemia, Guardian RT, Period 2 (real time period). Hypoglyce- 8.1G6.5 10.6G8.2 4.5G3.9* 6.08G5.2* 4.20G2.4 mias/month These 2 monitorings were consecutive in each patient, establishing in the second Controls/day 1.76G0.8 3.59G1.9 4.14G1.6 3.2G1.2 3.46G0.5 period the levels of alarm of hypoglycemia in 50 mg/dl and hyperglycemia in 200 mg/dl. We studied in both periods: average glycemia, glycemia variability, *P!0.05; †P!0.01. percentage of time in hyperglycemia (O180), normal glycemia and hypogly- cemia (!70). A satisfaction questionnaire about the systems of continuous monitoring was made. Conclusions Results A significant reduction of HbA1c was obtained in patients with insulin pump, specially during the first month. The HbA1c descended before treatment in Conclusions relation to the educative program. The number of hypoglycemias decreased three We observed during the monitoring in real time: months after the beginning. A greater satisfaction with I.S.C.I was observed at the – Longer time in normal glycemia with less frequency of hypoglycemia and 6 and 12 months. hyperglycemia. – Smaller glycemia variability.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P189 the test group, we showed an educational video film, and after one month, the Utility of ambulatory blood pressure monitoring in diabetological second application was completed by the two groups. consulting Results Juan Manuel Garcia-Quiros, Isabel Serrano, Cristobal Morales, In the first application, the two groups didn’t have good knowledge about risk Guillermo Martinez de Pinillos, Silvia Maraver, Monica Tome, factors for cardiovascular diseases like obesity. In the second application, the control group did not obtain good knowledge, but in test group their knowledge Carmen Cuesta & Angel Sendon ! Virgen Macarena Hospital, Seville, Spain. increased significantly (P 0.001). The comparison of knowledge between the two groups, showed statistically important difference (P!0.001). Objectives Conclusion To check possible advantages of ambulatory blood pressure monitoring (ABPM) This study showed that the society’s knowledge about risk factors for in diagnosis and disease control respect to blood pressure conventional cardiovascular diseases like obesity is minimal, and the educational video film measurement ways. had an important effect on increasing the society’s knowledge about it. Also to study the circadian rhythm of each patient to detect higher cardiovascular risk situations. Material and methods One hundred and nine patients were included in this study: 44% male, 56% female. ABPM were indicated in four different situations: hypertension diagnosis (45%), treatment efficacy (44%), pheocromocytoma (2.8%), miscelanous (8.2%). P191 Daytime blood pressure values and the night decrease were studied to catalog them as deeper, non-deeper or raiser. ABPM values and consulting ones were Mediterranean-style diet attenuates inflammation and atherosclerosis compared. Finally, we compared non-deeper/raiser frequency between treated markers in type 2 diabetic patients patients and people who acceded for diagnosis. Yuriy Karachentsev1, Maryana Gorshunska2, Eugene Jansen3, Results Nataliya Krasova1 & Viktoriia Poltorak1 In the hypertension screening group, 17 of 49 were confirmed, from them 25 1Institute of Endocrine Pathology Problems, Kharkiv, Ukraine; 2Kharkiv (51.03%) were deeper and 24 (48.97%) were non-deeper/raiser. Postgraduate Medical Academy, Kharkiv, Ukraine; 3National Institute for In the treatment efficacy group, 23 of 43 were wrongly controlled. Nine were Public Health and the Environment, Bilthoven, The Netherlands. deeper (15%) and 36 were non-deeper/raiser (75%). Blood pressure values to consider hypertension were over 135/85 during the day Type 2 diabetes mellitus (T2DM) is an insulin-resistant state characterized by an and over 120/70 during night. We considered deeper if blood pressure decreased increased low-level inflammation and oxidative stress which are probably the more then 10%. Non-deeper if these values decreased less tan this value and raiser initiation of diabetes-related cardiovascular complications. The aim of the study if there was an increasement of blood pressure. was to evaluate the impact of Mediterranean-style diet on inflammation and Forty of the 109 patients included in the study took benefits by initializing or atherosclerosis markers in T2DM patients. Twenty-five overweight/obese T2DM modifying their current treatment. patients (age 54.1G1.9 years, diabetes duration 7.8G1.3 years, HbA1cR7.0%) were following (within 3 months) isocaloric dietary recommendation on food intake, i.e. rich in olive oil, fish, vegetables and fruits. Insulin resistance (IR) was Deeper Non-deeper Raiser Total calculated using Homeostasis Model Assessment (HOMA). The two-tailed t-test Screening group was applied for statistical analysis. In T2DM patients, starting values of No hypertension 18 12 2 22 (44.8%) adiponectin, HDL-cholesterol, paraoxonase activity (PON) and erythrocyte Hypertension 7 8 2 17 (34.69%) reduced glutathione (GSH) were significantly (P!0.05–0.001) decreased Treatment efficacy group whereas levels of sICAM, C-reactive protein (CRP), ferritin and insulin were Good control 5 12 3 20 (46.51%) significantly enhanced (P!0.05–0.001) compared to healthy subjects. Adipo- Bad control 4 14 5 23 (53.48%) nectin was increased after dietary intervention (PZ0.018) whereas tumor necrosis factor alpha (TNF-a) and sICAM were decreased (PZ0.004, PZ0.007, respectively), serum ferritin was also diminished (PZ0.028). There were no Conclusions significant differences in CRP, HbA1c, HOMA-IR before and after the diet. But ABPM was useful to: HDL-cholesterol, PON and GSH levels were enhanced after diet therapy 1. Diagnose hypertension when this is not possible by common ways. (PZ0.001, PZ0.03, PZ0.004, respectively). Thus, consumption of the 2. Evaluate antihypertensive treatment efficacy and, if necessary, make changes in Mediterranean-style diet within 3 months by T2DM patients induced this treatment. geterogenous anti-inflammatory and anti-atherogenic effects against the back- 3. Identify ‘non-deeper and raiser’ patients, to value possible treatment that could ground of stable glycaemic state. These finding may implicate a potential use of improve cardiovascular risk. Mediterranean-style diet as effective non-pharmacological mean for aggressive intervention against diabetes-associated cardiovascular risk factors.
P190 P192 The knowledge of society about risk factors for cardiovascular diseases Endothelin-1 is correlated with TGF-b1 but not with glycemic control like obesity and prevention of it in normotensive subjects with type 2 diabetes Bereliant Bozorgmehr, Shideh Fatahi & Morteza Abdollahi Serkan Yener1, Pinar Akan2, Abdurrahman Comlekci1, Baris Akinci1, Shaheed Beheshti University of Medical Sciences, Tehran, Islamic Republic Firat Bayraktar1 & Sena Yesil1 of Iran. 1Division of Endocrinology and Metabolism, School of Medicine, Dokuz Eylul University, Izmir, Turkey; 2Department of Biochemistry, School of Medicine, Dokuz Eylul University, Izmir, Turkey. Aims Increasing the nutritional knowledge of society about risk factors for diabetes mellitus like obesity and cardiovascular diseases. Objectives Background Endothelial dysfunction contributes to the development of atherosclerosis in Cardiovascular diseases are one of the most important cause of death between the diabetic subjects. Endothelin-1 (ET-1) is an endothelium derived vasoconstrictor. people in many countries, and obesity is one of the important causes for It has been shown that ET-1 levels are increased in a variety of situations such as cardiovascular diseases. So the society’s knowledge about risk factors for it like diabetes, hypertension and obesity. Transforming growth factor beta1 (TGF-b1) obesity is very important to prevention of cardiovascular diseases. is an important cytokine for the development of renal injury in type 2 diabetic Methods patients and associated with hyperglycemia and insulin resistance. Cell culture The method was the clinical trial on 84 occupied men. The sampling was at studies showed that TGF-b may upregulate ET-1 production. Our aim was to random. After selecting the samples, the first application was completed by the demonstrate the possible relations between ET-1 and TGF-b1 in type 2 diabetic samples. Then the samples were divided into two groups (42 control, 42 test). For patients.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Methods Material and methods Forty Type 2 diabetic subjects without any micro or macrovascular diabetic Ninety-two pts (33F; 59 M), aged 34–82 mean 63.5G12.0 years. In whole group, complications, hypertension or microalbuminuria were enrolled. The patients there were 20 (21.7%) pts with previously diagnosed diabetes. In the time of were being treated with glimepride for at least 12 weeks. Patients treated with admission into Intensive Care, glucose and homocysteine levels applying other oral antidiabetics or insulin, anti-hypertensive drugs, anticoagulants or anti- chemiluminescence method (IMMULITE, DTC) in the venous blood had been obesity drugs were not included. measured. Results Results The mean values were; A1c: 7.8%, fasting plasma glucose: 167.9 mg/dl, BMI: In the whole group, myocardial infarct was diagnosed in 52 (56.5%) pts and ACS 27.5 kg/m2, waist circumference: 91.0 cm, TGF-b1: 29.68 ng/ml and ET-1: without acute cardiac necrosis in 40 pts. Mean admission glucose and 0.33 fmol/ml. ET-1 levels were not associated with glycemic parameters or homocysteine levels in diabetic patients group were 163G62.8 (range 86–264) anthropometric features. ET-1 levels did not differ between males and females. mg% and 13.1G6.5 (range 6.9–34.3; F 13.8G8.3; M 12.6G4.8) mmol/l ET-1 levels were found to be correlated with TGF-b1 levels (rZ0.358 P!0.05). respectively. Merely in 12 (16.4%) non-diabetics with ACS admission glucose Conclusion level didn’t exceed 100 mg% (group 1). Mean level glucose and HC in these Our results demonstrate that ET-1 expression is associated with TGF-b1 in type 2 group was 95.7G3.8 mg% and 12.2G2.6 (F10.9G2.5; M 12.9G2.4) mmol/l, diabetic people. Neither glycemic parameters nor anthropometric features were respectively. In the other patients without previously diagnosed diabetes: in 27 found to effect ET-1 levels in type 2 diabetic people without diabetes related (40%) subjects randomly measured glycemia at admission ranged from 101 to complications. A possible explanation for this finding may be the strict enrolment 130 mg% (mean 112.1G8.1 mg%) and mean HC 13.8G5.8 (F 13.9G4.9; M criteria for the study. Because of the inclusion of patients without diabetes related 13.7G6.3) mmol/l (group 2); in 16 (21.9%) patients between 131 and 160 mg% complications, ET-1 levels might be found to be unrelated with glycemic (mean 139.9G7.2 mg%) and HC 15.6G6.4 (F 16.3G4.9; M 15.4G7.0) mmol/l parameters. (group 3); in 18 (24.6%) above 160 mg% (mean 201.6G34.1) and HC 18.0G 9.8 mmol/l (F 17.4G12.8; M 18.5G8.0) (group 4). The myocardial infarction was diagnosed in the 25; 51.8; 56.3 and 72.2% patients of studied groups without diabetes and in 70% of diabetics. Conclusion The higher levels of ABG have been connected with the higher HC blood levels as well as with the higher percentage of patients with myocardial infarction.
P193 Use of three dose premixed aspart: clinical correlates Sanjay Kalra, Bharti Kalra, Amit Sharma & Bhavika Chhabra Bharti Hospital, Karnal, India. P195 Objective Premixed aspart is being used in once, twice and thrice-daily regimes in persons K121Q PC-1 gene polymorphism is not associated with postpartum type with diabetes. This study was designed as a cross-sectional, observational study to 2 diabetes in gestacional diabetes mellitus patients Jime´nez Gonza´lez Amalia, Fornieles Gonza´lez Constanza, Yeste Doblas assess the need for three-dose premixed aspart in different subsets of subjects with a a type 1 and type 2 diabetes attending an endocrine OPD. M Carmen, Escobar Jime´nez Fernando & Ferna´ndez Soto M Luisa Methods Hospital Universitario ‘San Cecilio’, Granada, Spain. Records of 200 consecutive patients receiving premixed insulin were assessed to determine the frequency of insulin dosage and its clinical correlates. Women suffering gestational diabetes mellitus (GDM) are a risk group for type 2 Results diabetes. The genetic determinants are not widely known and controversial data Of the 200 records studied, 188 were of type 2 diabetes, 4 of gestational exists about association between K121Q PC-1 gene polymorphism and early type diabetes (GDM) and 8 of type 1 diabetes. Single-dose insulin was prescribed 2 diabetes and/or IR. to 38 type 2 diabetes subjects; two-dose to 136 type 2, 2 GDM and 2 type 1 The aim of the study was to investigate the relationship between K121Q PC- 1 diabetes patients; and three-dose regime to 14 type 2, 2 GDM and 6 type 1 gene polymorphism and the glucose metabolic alterations, IR or metabolic diabetes subjects. syndrome in GDM women in the postpartum period. Three dose regime was more commonly used, with respect to the average Patients and methods frequency (11%), in men (13/96: 13.5%) in persons with recently diagnosed ! O Fifty-seven women with previous GDM were reclassified by means of oral diabetes ( 1 month) (2/8: 25%), persons with weight 100 kg (9/9: 100%) glucose tolerance test (OGTT) in the early postpartum using diagnostic criteria of , with renal transplant (1/2: 50%), with foot infection (2/10: 20%), with NDDG. Anthropometric and biochemical parameters and systolic and diastolic urinary tract infection (2/11: 19%), and with type 1 diabetes (75%) or GDM BP were studied. K121Q PC-1 polymorphism was studied by PCR amplification (50%). O of the gene ENPP1 (exon4), including the c.361 position which represents the It was less often used in elderly subjects 60 years (0/48: 0%), in women place for the K121Q nucleotide changes. SPSS 12.0 v.s. was used as statistical (7/104: 6.7%), and in persons with associated hypothyroidism (0/22: 0%). analysis. Results The different genotypes prevalence are shown on table. No significant differences in K121Q polymorphism have been found between the group of patients with glucose intolerance and the patients with normal tolerance.
P194 OGTT Relationship between admission blood glucose (ABG) and homocysteine Allelic frequencies Normal (nZ34) Intolerance (nZ23) (HC) levels in patients with acute coronary syndromes (ACS) Genotype Prevalence %
Maria Kurowska, Marta Dudzinska, Iwona Kaznowska-Bystryk, Position c.361 Codon 121 AA121 Jerzy S Tarach, Janusz Kudlicki & Joanna Malicka A/A (no mutation) AAG K 22 (65%) 17 (74%) Medical University, Lublin, Poland. C/C (homozygosis) CAG Q 3 (9%) 1 (4%) A/C (heterozygosis) AAG/CAG K/Q 9 (26%) 5 (22%)
Introduction The admission glucose may be a predictor of survival and is independently associated with infarct size and higher mortality in patients with ACS. Hyper- There were not statistical differences in anthropometric and biochemical homocysteinemia in patients with ischaemic heart disease represents a strong parameters between patients with and without the presence Q allele. predictor of vascular morbidity. The role of glucose increase above normal levels Conclusion in non-diabetic patients with ACS is not adequately defined. The aim was the The results showed that the K121Q PC-1 gene polymorphism is not associated assessment of dependence between admission blood glucose and homocysteine with type 2 diabetes or glucose intolerance in women with previous GDM. concentrations in patients with ACS.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P196 ongoing to understand the significance of this serum marker and whether it can be Improvement of exercise capacity, muscle strength and insulin used to monitor therapies for beta cell regeneration. resistance in elderly patients with heart failure after treatment with long acting testosterone: a randomized clinical trial Giuseppe Caminiti, Giuseppe Marazzi, Rosalba Massaro, Marco Miceli, Maurizio Volterrani & Giuseppe Rosano San Raffaele IRCCS, Rome, Italy. P198 Influence of ethnicity on prevalence of gestational diabetes Background Giuliana Trifiro Patients with congestive heart failure (CHF) show muscle mass wasting and San Giuseppe Hospital, Milano, Italy. decreased testosterone levels. Long-term testosterone supplementation improves walking distance and glucose metabolism of patients CHF. No studies have The prevalence of gestational diabetes (GD) continues to increase worldwide, as investigated the integrated effects of testosterone on exercise oxygen uptake diabetes mellitus type 2, with the increasing overweight and age of pregnancy. muscle strength and glucose metabolism in patients with CHF regardless of the The Caucasian race is the group with a low risk factor in addition to age !25 presence of hypogonadism. years and BMI!25. In Italy, the recent immigration of different ethnies with high Aim natality have changed in the last decade the epidemiologic profile of pregnant To assess the effect of a 12-week testosterone administration on maximal exercise women. We assessed the prevalence of gestational diabetes in the view of ethnic capacity, muscle strength and insulin resistance in elderly CHF patients. modification. Methods From January 2004 to June 2006, we evaluated 2400 mother–newborn pairs. G Seventy elderly patients with stable CHF, mean age 71 8 years, ejection fraction Glucose challenge test (GCT) was performed at 27–28th week of gestation. If the G 00 34 1%, NYHA class II/III 38/32, were enrolled. Of these, 35 were randomized test was positive (O140 mg/dl at 60 ) an oral glucose tolerance test (100 g of to receive testosterone therapy (through intramuscular injection every 6 week) glucose) for 3 h was performed and Carpenter-Coustan criteria were followed. and 35 to receive placebo both on top of maximal medical therapy. At baseline Seventy-five percent pregnant women were Italian and 25% non Italian. In the last and after 12 weeks all patients underwent echocardiogram, cardiopulmonary test, group, only 13% were European women; among extra-European group 37.1% of 6-min walking test (6MWT), quadriceps maximal isometric and isokinetic women came from Asia, 36.5% from South America, 22.2% from Africa and 4% strength. from USA. Results GD diagnosed by GCT in 182 cases (7.5%) was confirmed by OGTT in 132 At baseline 30% of patients had hypogonadism. Peak VO2 (r 0.44; P 0.02) and (5.5%). The incidence of GD has been 4.7% in Italian women and 9% in extra- quadriceps isometric strength (r 0.39; P 0.01) were both positive related to serum European women showing a significant difference (P!0.001). Only in 7.5% G G testosterone concentration. After three months, peak VO2 (13 4vs16 1 glucose intolerance was associated with weight increase in pregnancy more than G G G P 0.02), VE/VCO2 (33 7vs29 5 P 0.01) distance walked at 6MWT (420 45 20 kg. Asian women were at the highest risk (15%) also compared to women from G vs 480 51 P 0.001), significantly improved from baseline in the testosterone South America (11%). Neonatal complications were hypoglycemia (5.8%) and group while were unchanged in the control group; HOMA-IR was significantly respiratory distress (3.4%). G G reduced in the testosterone group (2.6 1.4 vs 1.8 0.8, P 0.002). Maximal Immigrant women are at high risk of impaired glucose tolerance with a higher G G quadriceps isometric (130 28 vs 166 32, P 0.04) but not isokinetic strength incidence of cesarian sections and complications of their newborns. The ethnic was significantly increased at three months in the testosterone group. Increase in factor is an independent risk factor in developing impaired glucose tolerance. testosterone levels were significantly related to improvement in peak VO2. No significant changes in left ventricular function were found. Conclusion Long-acting testosterone therapy improves exercise capacity, muscle strengthed glucose metabolism in men with moderately severe heart failure. Testosterone benefits seem to be mediated by metabolic and peripheral effects. P199 24 h glycemia variability correlates with arterial structure alteration in type 1 diabetes P197 Manuela Carla Colombo, Pierluigi Gamba, Monica Failla, Felice Paleari, Mauro Rigoldi, Rita Perego, Cristina Giannattasio & Giuseppe Mancia Circulating Reg1-a plasma levels: potential marker of beta cell Clinica Medica Ospedale S. Gerardo, Univerista` Milano Bicocca, regeneration? Monza, Italy. Chiara Guglielmi1, Fabrizio Battistoni1, Luciana Valente1, Elisa Astorri1, Dario Pitocco2 & Paolo Pozzilli1 1University Campus Bio-Medico, Rome, Italy; 2University Cattolica, Rome, Objective Italy. Diabetes mellitus is characterized by vascular complications associated with arterial thickening. Although strict glycaemic control is clinically beneficial, limited or no evidence exists as to whether arterial damage is positively related to Reg and Reg-related genes are members of a multifunctional family. Under blood glucose levels and variability. physiological conditions Reg protein is not expressed in pancreatic beta cells, Methods although the Reg protein receptor is expressed. When islets are damaged, the Study purpose was to asses the relationship between arterial thickness and 24 h expression of Reg gene is increased in the islets of Langherans. In type 1 diabetes mean and S.D. of blood glucose in type 1 diabetes. Fifteen type 1 diabetic patients (T1D), insulin secretion may be still detectable in some subjects with long- aged 39G1 years (meansGS.E.M.) were enrolled; diabetes aged for 18 years standing disease indicating the existence of a small population of surviving beta (means). Patients were all normotensive (blood pressure, 128G4/75G2 mmHg) cells or continued renewal of beta cells. Beta cell apoptosis has been shown in and devoided of clinically evident macro and microvascular complications. pancreas of subjects with long standing T1D indicating that continued source of Average fasting blood glucose was 160G19.26 mg/dl while Hb1Ac was 7.8G beta cell replenishment may take place. No measurement is available in vivo up to 0.35%. Twenty-four hours blood glucose was measured over 24 h every 5 min by now of this phenomenon. The aim of this study was to evaluate circulating levels a glucometer. The S.D. of blood glucose levels over the 24 h was used as an index of Reg1-a in T1D subjects as a potential marker of beta cell regeneration. We of blood glucose variability. Arterial stiffness was measured in two manners: 1) investigated serum samples of newly diagnosed T1D (nZ31) (mean age 18.8 carotido-femoral pulse wave velocity (cfPWV) (Complior), 2) arterial diameter yearsG7.4), long standing T1D (nZ46) (mean age 36.8 yearsG11.8), type 2 changes/pulse pressure (Reneman Formula, CarDist) the former being measured diabetes (nZ63) (mean age 63.1 yearsG10.4) and in a group of control (nZ50) by an echo-tracking device and the later by a tonometer (pulsepen). Common (mean age 32.7 yearsG12.5). Carotid artery IMT was measured by standard ecocolor Doppler, 3 cm under Levels of Reg1-a were measured using an enzyme linked immunoabsorbent bifurcation. assay. A significant difference was detected in Reg1-a circulating levels between Results long standing T1D and controls (PZ0.03), between newly diagnosed and CarDist (4.0G0.4, 1/mmHg 10K2), cfPWV (10.1G0.6 m/s) and IMT (0.54G longstanding T1D (PZ0.04), between T2D and newly diagnosed T1D 0.02 mm) showed no correlation with glycated hemoglobine. Only CarDist (PZ0.002) and between T2D and controls (PZ0.0001) No correlation were significantly correlated with fasting blood glucose (rZ0.57, P!0.02). IMT found between Reg1-a levels and typical markers of diabetes (C-peptide, HbA1c shows no relationship with mean blood glucose both when assessed in the clinical and duration of diabetes). setting and when averaged over the 24 h. In contrast, there was a direct In conclusion, raised circulating levels of Reg1-a are detectable in T1D and T2D relationship between the IMT value and the standard deviation of 24 h mean indicating the presence of active expression of Reg1-a gene. Further studies are blood glucose (rZ0.4, Spearman correlation, P!0.05).
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Conclusions effect. This resulted for the EPIC-cohort in a relative risk under 0.72 or above 1.35 In type 1 diabetes 24 h variability values of blood glucose seem to be a more and for the MeSyBePo-cohort under 0.66 and above 1.44. important determinant of large artery structural alteration than fast and mean In conclusion there is no strong effect of the one htSNP in the SOCS3 gene on the blood glycaemia. development of T2DM. However, the impact of genetic variants on complex diseases is usually quite small. Thus a small effect might still exist, which has not been detected by our cohorts, although a total of more than 4000 individuals was investigated.
P200 Relationship between nerve conduction velocity with uncoupling protein 2 promoter polymorphism -866G/A and A allele frequency in type 2 diabetic patients with diabetic peripheral neuropathy P202 Sebnem Aktaran 1, Ersin Akarsu1, Aylin Hengirmen Akcalı2 & Atherosclerosis in premenopausal diabetic women with or without Sibel Oguzkan3 polycystic ovary syndrome 1Division of Endocrinology and Metabolism Disease, Medical Faculty, Andromachi Vryonidou1, Anastasia Christodoulou1, Athanasios Gaziantep University, Gaziantep, Turkey; 2Gaziantep University, Papatheodorou2, Georgios Karapostolakis2, Nikolaos Giannoulakos2, Neurology, Gaziantep, Turkey; 3Gaziantep University, Medical Biology, Vicky Loi1, Thomais Terzi1 & Constantinos Phenekos1 Gaziantep, Turkey. 1Department of Endocrinology, Red Cross Hospital, Athens, Greece; 2Department of Radiology, Red Cross Hospital, Athens, Greece. Progression of the diabetic peripheral neuropathy (DPN) demonstrated differences in the individual considered the contribution of genetic predisposition. Background and aims We aim to study the relationship between the K866G/A polymorphism in the It is well recognized that insulin resistance and type 2 diabetes (T2DM) are promoter region of the uncoupling protein 2 (UCP2) which enhances associated with an increased risk for cardiovascular disease especially in women, transcriptional activity and A allele frequency with nerve conduction velocities while the role of sex steroids is still controversial. Women with polycystic ovary (NCV) and clinical factors. We compared 370 type 2 diabetic patients with syndrome (PCOS) represent a unique biological model for the study of the impact healthy control. Subjective neuropatic symptoms, neurologic examination and of all these factors on cardiovascular system. We aimed to evaluate the degree of electrophysiologic measurements were evaluated. Diabetic patients were divided low-grade inflammation and atherosclerosis in premenopausal diabetic women into two groups Group 1: (G/G) and Group 2: (G/ACA/A) according to genotype. with or without PCOS by measurement of C-reactive protein (CRP) and common Clinical features and NCV were compared and also independent risk factors of the carotid intimal-medial thickness (IMT). DPN were defined. The comparison of two independent group was performed Subjects and methods with Mann–Whitney U-test or Fisher’s Exact test. Relationship between NCV We studied 40 women with T2DM (mean age 43.2 years) treated with metformin with UCP2 genotype and cinical factors assessed through multiple regression and/or sulfonylourias and 30 healthy, normal cycling, age-matched women. analysis (MRA) and ANOVA. Pearson correlation was performed for correlation According to gynaecological history (menstrual cycles%8 per year) and the analysis. DPN was present in 46.2% of the cases. DPN was significantly presence of hyperandrogenism (clinical or biochemical), diabetic women were correlated with HbA1c, duration of DM, age at DM onset, retinopathy and divided in two groups: group 1 diabetic women with normal cycles and group 2 nephropathy. The proportions of the individuals carrying genotype (-866G/A and diabetic women with PCOS. We measured BMI, waist circumference (WC) and A/A) and A allele frequency were significantly higher in the diabetic patients with systolic blood pressure (SBP). Blood samples were collected after an overnight DPN than that in the controls respectively (P!0.009, P!0.004). Group 2 had an fast, during the 2–6 day of the cycle and hormones, lipids, glucose and CRP levels early age at DM onset (P!0.0001) and high proportion of retinopathy (PZ0.03). were determined. Carotid IMT was assessed by B-mode ultrasound imaging. NCV was significantly lower in Group 2 than that in Group 1. MRA showed that Results UCP2 genotype and HbA1c were related with the impairment of NCV No difference was found between diabetic and control women in age, smoking independently of other clinical factors. HbA1C, and retinopathy. In conclusion, habits and the presence of hypertension. Diabetic women had significantly higher higher A allele frequency with DPN and early age at DM onset in the Turkish BMI (34.5G6.39 vs 27.9G6.1, P!0.001), WC (105.3G14 vs 86.9G11.2 cm, diabetic population might partly indicate the genetic predisposition. Higher UCP2 P!0.001), hirsutism score (1.78G0.9 vs 1.15G0.3, P!0.01) and a positive activity related to A allele which was independent risk factor in the impairment of family history for T2DM (82.5% vs 34.6%, P!0.002). Additionally, they NCV may contribute to reduce NCV via decreased ATP production in presented higher total testosterone (0.62G0.21 vs 0.45G0.11 ng/ml, P!0.001), mitochondria. On the other hand, increased UCP2 in the DPN may be a marker insulin (17.8G11.9 vs 9.8G3.6 mIU/ml, P!0.002), triglycerides (131G23 vs of an inadequate antioxidant effect of the UCP2 in the chronic oxidative stress. 95G67 mg%, PZ0.02) and LDL-cholesterol (132G31 vs 114G23 mg%, Investigation of the genetic tendency for DPN may guide to define the risk factors PZ0.025) levels and lower SHBG (34.3G16.2 vs 53.9G18.7 nmol/l, and also in the new insights for the treatment. P!0.001) and HDL-cholesterol (47.1G12.8 vs 57G10.9 mg%, P!0.001) levels compared to control women. Between diabetic women, patients in group 2 reported higher percentage of Pregnancy Diabetes (37.5% vs 8.3%, P!0.05) were younger at disease diagnosis (32.8G5.7 vs 39.7G6.1 years, P!0.001) and they had higher WC (115G12.8 vs 99G11.1 cm, P!0.01). Furthermore, they presented higher total testosterone (0.75G0.22 vs 0.54G0.16 ng/ml, PZ0.01) P201 and insulin (24G15.8 vs 14.4G7.5 mIU/ml, P!0.05), and lower SHBG (26.1G No genetic impact of the SOCS3-gene on T2DM 9.5 vs 39.8G17.6 nmol/l, P!0.001) and HDL-cholesterol (41.4G11.2 vs 50.8G Antje Fischer1, Eva Fisher2, Matthias Moehlig1, Martin Osterhoff1, Martin 12.6 mg/%, P!0.001) levels. Duration of T2DM and glycaemic control was the O Weickert1, Andreas FH Pfeifer1, Heiner Boeing2 & Joachim Spranger1 same in both groups but women in group 2 were younger (39.9G6.3 vs 44.5G3.6 1Department of Clinical Nutrition, German Institute of Human Nutrition and years, P!0.02). Diabetic women had higher CRP levels (1.4G0.4 vs 0.8G Department Endocrinology, Diabetes and Nutrition, Charite´ Medical 0.2 mg/dl, P!0.05) and carotid IMT (0.065G0.007 vs 0.056G0.008 mm, School, Nuthetal/Berlin, Germany; 2Department of Epidemiology, German P!0.001) compared to controls, while no difference was found between the two Institute of Human Nutrition, Nuthetal, Germany. groups of diabetic women. Conclusions Premenopausal diabetic women have low-inflammation and accelerated The diabetic epidemic is increasing worldwide. The suppressor of cytokine atherosclerosis. High androgen levels do not seem to aggravate this process as signaling 3 (SOCS3) provides a link between cytokine action and their negative in the case of diabetic women with PCOS. consequences on insulin signaling. This potential influence on the development of T2DM makes the gene a potential candidate gene for type 2 diabetes. We investigated the one haplotype tagging single nucleotide polymorphism (htSNP) rs4969168 to examine the impact on T2DM in two independent study populations; one prospective case-cohort study and one cross-sectional cohort. In the prospective cohort a total of 2,242 individuals (669 had developed T2DM during the follow-up period) were analyzed. In the dominant model there was no P203 effect of the polymorphism on diabetes risk (hazard ratio (95% CI): 0.86 (0.66– Effects of testosterone and sildenafil on cytokines and angiogenic 1.13); PZ0.3). In the second, cross-sectional MeSyBePo-cohort 1,897 subjects factors: a randomized controlled trial (325 had T2DM) were investigated. Accordingly to the prospective results, no Andrea M Isidori, Antonio Aversa, Carlotta Pozza, Elisa Giannetta, association with T2DM was found (odds ratio (95% CI): 0.78 (0.54–1.12); Gianni Spera, Vincenzo Bonifacio, Andrea Fabbri & Andrea Lenzi PZ0.8). We also calculated the power in our cohorts, to estimate the detectable Sapienza University, Rome, Italy.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Ageing in men is accompanied by a decline in serum testosterone (T) levels and We determined the glycemia by the method GOD-PAP (glucose oxidase). increased risk of cardiovascular disease, osteopenia, visceral obesity and impaired Results metabolism. These conditions have complex aetiologies that may share a common Correlation between glucometer and laboratory test (L): pro-inflammatory state. We investigated the impact of T therapy on cytokines and L-A: 0.980; L-B: 0.979; L-C: 0.986; L-D: 0.973; L-E: 0.977; L-F: 0.89 angiogenic factors involved in atherosclerosis and bone loss, in hypogonadal men Capillary glycemia average: who underwent androgen replacement. We carried out a 6 months, randomized, A: 131.9G56; B: 139G61; C: 124.4G64; D: 139G64; E: 127.8G69.6; double-blind, controlled, crossover trial of T gel (50 mg/d)CSildenafil(S) (50 mg) F: 141.9G66.4. vs Placebo(P)C(S) in a group of 25 men (age, 52G6 years) with hypogonadism and Blood glycemia average differences between laboratory test and differents erectile dysfunction. All patients had penile CDU, IIEF, CES-D, AMS and EDITS glucometers: questionnaires, DEXA for BMD, routine biochemistry and measurement of serum L-A: K50.7G43; L-B: K28.37G27.6; L-C: K19.1G35.2; L-D: K62.95G cytokines (IL-1, IL-6, IL-10, IL-12, TNF) and angiogenic factors (FGF, PDGF, 41.57; L-E: K16G20; L-F: K78.56G54.8. All of them had significant difference VEGF, HGF) evaluated at baseline and at the end of each treatment period. In the (P!0001). TCS arm serum T levels rose from 2.6G2.3 to 3.8G2.2 ng/dl (P!0.05) with Capillary glycemia average differences between several glucometers: improvement in penile Peak Systolic Velocities (from 26G7.3 to 34G8.9 cm/s, Statistically significant differences were obtained from the following gluco- P!0.01). TCS also induced a significant reduction in serum pro-inflammatory meters: A and B: K7.07G11.8 (P!0.001); A and C: 7.55G13.6 (P!0.001); IL-1b (K27G8%; P!0.05) and TNF-a (K23G6%; P!0.05) and an increase in A and D: K7.12G13.23 (P!0.01); B and C: 14.62G11.2 (P!0.001); B and E: anti-inflammatory IL-10 (45G9%; P!0.05). Sildenafil alone induced a reduction of 11.2G17 (P!0.001); B and F: 8.74G14.5 (P!0.01); C and D: K14.67G12.37 FGF and VEGF, compared with the association of TCSildenafil (respectively, (P!0.001); C and F: K5.06G13.27 (P!0.05); D and E: 11.25G17 (P!0.001); K18G8% and K22G9%, P!0.05), while the reduction in PDGF was inconsistent D and F: 8.74G14.54 (P!0.01). (K13G8%, PZ0.05). These data suggest that: 1) T in men plays an immune- Conclusions modulatory effect shifting circulating cytokine toward a favourable anti- 1. All glucometer had an excellent correlation with blood glycemia obtained in inflammatory state; 2) PDE5 inhibitors (PDE5i) reduces markers of vascular our laboratory (O0.9) but our blood glucose levels were significantly lower. damage; 3) the association of T and PDE5i in hypogonadal subject could potentiate 2. We found significant differences in capillary glycemia values obtained with the positive endothelial and vascular effects of PDE5i and counteract the pro- different glucometers which is important for an estrict metabolic control. angiogenic effects of T. These data disclose future indications for the combined 3. Glucometer E gives closer values to our laboratory ones and introduces lower treatment of androgen and PDE5i in the rehabilitation of patients with hypogonadism variability. and cardio-vascular disease.
P206 P204 Evaluation of continuous subcutaneous insulin infusion in type 1 diabetes Smoking shortens insulin-free interval in type 2 diabetics ¨ Cristina Coserria, Jose´ Ortego, Inmaculada Gavila´n, Mar Roca, Tijen Yesim, Unsal Durupinar, Sema Ucak, Tayyibe Saler & Gloria Baena, Isabel Torres, Isabel Valencia, Amor Garcı´a, Manuel Cayo´n Yuksel Altuntas & Manuel Aguilar Sisli Etfal Education and Research Hospital, Istanbul, Turkey. Endocrinology Service, Puerta del Mar Hospital, Ca´diz, Spain.
Smoking is a modifyable risk factor in the incidence of impaired glucose Objective tolerance and type 2 diabetes, but the data concerning the effect of smoking on the To evaluate continuous subcutaneous insulin infusion (CSII) in type 1 diabetes course of type 2 diabetes is limited. In this study, we aimed to investigate a using the analysis of epidemiological variables, treatment indications, metabolic possible relationship between smoking and the need of insulin therapy in patients results, acute and chronic complications and causes for therapy suspension. with type 2 diabetes. 470 patients with type 2 diabetes were assessed for smoking Methods habitus, marital and educational status, duration of diabetes, duration of insulin- A retrospective descriptive study of patients with type 1 diabetes treated with naive interval, alcohol consumption, adherence to treatment, body-mass index CSII therapy in our institution. (BMI) and HbA1c. The nonsmokers both never and former were significantly Results older than the smokers’ group. Duration of diabetes was significantly longer in A total of 49 type 1 diabetic patients who had been treated with CSII were nonsmokers than smokers. Insulin treatment was more often in smokers than evaluated (age: 31.9G8.3 years; female: 67.3%, time of evolution of diabetes: nonsmokers. The smokers had significantly higher HbA1c levels than both never- 16.5G8.1 years). Before starting CSII, retinopathy was present in 46.9%, and former-smokers. Never smokers and former smokers had similar HbA1c microalbuminuria in 8.2%, macroalbuminuria in 4.1%, polineuropathy in 2.0% levels. Duration of diabetes was similar in both groups and insulin-naive interval and vasculopathy in 2.0% of the subjects. The indications for CSII treatment was significantly shorter in smokers and former smokers than never-smokers. were: brittle diabetes (38.7%), poor metabolic control (32.6%), pregnancy Adherence to treatment was better in smokers than nonsmokers. BMI was (16.3%), pregnancy planning (8.2%) and hypoglycemias (4.1%). Patients significantly higher in nonsmokers than smokers. Alcohol consumption was received CSII therapy during 22.2G12.1 months. Hemoglobin A1c before reported in smokers, but not in nonsmokers. In conclusion, the need for insulin starting CSII therapy was 8.3G1.2% and improved significantly during treatment was more frequent and earlier in smokers, which could be explained by treatment: 7.1G0.9% after 3 months, 7.3G1.2% after 9 months, 7.4G0.9% hyperglycemia induced by smoking and increased toxicity in the microenviron- after 12 months, 7.6G1.4% after 18 months and 7.5G1.4% after 24 months of ment of pancreatic islets. CSII therapy (P!0.001). CSII also reduced the frequency and severity of hypoglycemias. During CSII therapy 3 patients had diabetic ketoacidosis (6.1%), 4 developed retinopathy (8.2%), 3 microalbuminuria (6.1%) and in 5 patients the previous retinopathy progressed (10.2%). Seven patients discontinued CSII: 3 for patient wish, 3 due to the end of pregnancy and one because treatment failure. P205 Conclusions The most frequent indications for CSII therapy in patients with type 1 diabetes in Glycemic variability analyze with different glucometers our institution are brittle diabetes and poor metabolic control, and the most Guillermo Martinez de Pinillos, Silvia Maraver, Isabel Serrano, frequent causes for therapy suspension are the patient wish and the end of Cristobal Morales, Carmen Cuesta & Angel Sendon pregnancy. CSII is a safe and effective treatment to optimize metabolic control in Virgen Macarena Hospital, Seville, Spain. type 1 diabetic patients.
Introduction Currently self-glycemic control by the patient is essential to achieve a right metabolic control of diabetes. Nowadays, there are different systems that have P207 proved useful for this aim. Objectives Elevated plasma fatty acid levels are associated with myocardial Valuing any possible differences between systems and the relation with glycemia triglyceride accumulation and diastolic dysfunction in type 2 diabetes identified in our laboratory. mellitus which can be reversed by acipimox Material and methods Joahnnes Smit, Sebastiaan Hammer, Rutger van der Meer, Albert de Roos, We took blood samples by vein-puncture to 41 patients, and simultaneously we Hildo Lamb & Johannes Romijn measured capillary glycemia using 6 different glucometer (A, B, C, D, E and F). Leiden University Medical Center, Leiden, The Netherlands.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Background P209 Although it has been conceived that type 2 diabetes mellitus (DM2) is associated Relationship of insulin sensitivity with carotid intima media thickness in with increased myocardial triglyceride (TG) accumulation, it is unknown whether patients with type 2 diabetes mellitus this can be influenced by modifying plasma non-esterified fatty acids (NEFA) Angel Marinchev & Petya Kamenova levels. We therefore determined in uncomplicated DM2 whether modifications in University Specialized Hospital for Active Treatment in Endocrinology plasma NEFA influence myocardial TG content and myocardial function. ‘Acad. Iv. Penchev’, Sofia, Bulgaria. Research design and methods Myocardial TG content and left ventricular (LV) function were determined using proton magnetic resonance spectroscopy and MRI respectively at 1.5 T Objective (Gyroscan ACS/NT15, Philips) in 11 subjects with uncomplicated DM2 (mean The study was to establish the association between insulin sensitivity (IS) and 2 ageGS.D.: 59.8G5.4 years, BMI 26.2G0.9 kg/m , HbA1c: 6.0G0.2%) before carotid intima media thickness (CIMT) in type 2 diabetic patients (T2D pts). and after 3 days of a very low calorie diet (VLCD, 473 kcal/day, to increase Materials and methods plasma NEFA levels) and after 3 days of a VLCD complemented with the 40 (21 f,19 m) T2D pts aged 58.1G10.2 years, BMI 30.1G5.8 kg/m2 (meanG administration of acipimox (4!250 mg during the last day of caloric restriction, S.D.); 36 (19 f, 17 m) normal glucose tolerant (NGT) subjects of mean age 57G to decrease NEFA levels). The percentage (%) of myocardial TG was calculated 10.1 years, as a control group in terms of IS, and 38 (20 f, 18 m) NGT subjects of as TG/water!100. Myocardial function was calculated as ejection fraction (EF) mean age 57.6G9.4 years, as a control group in terms of CIMT, participated in for systolic function, and the ratio between early and atrial filling phase (E/A the study. IS was measured with a manual hyperinsulinaemic euglycaemic clamp ratio) for diastolic function. technique and expressed as a glucose disposal rate (M; mg/kg per min). CIMT Results was assessed using B mode sonograph ‘Ultrasonix’, M’Ath Software in both right A VLCD increased plasma levels of NEFA, from (meanGS.E.M.) 0.50G common carotid artery (CCAr) and left common carotid artery (CCAl). The study 0.08 mmol/l (baseline) to 0.91G0.15 (PZ0.023), associated with myocardial TG was approved by Local Ethical Committee. accumulation (from 0.66G0.09% (baseline) to 0.98G0.16% (PZ0.028), and a Results decrease in E/A ratio (from 1.00G0.05 (baseline) to 0.90G0.06 (PZ0.002). IMTCCAr 0.76G0.15 mm and IMTCCAl 0.82G0.21 mm of T2D pts were After the VLCD with acipimox, plasma NEFA levels decreased (to 0.24G significantly higher than IMTCCAr 0.59G0.12 mm and IMTCCAl 0.58G 0.05 mmol/l, PZ0.002) and myocardial TG content and diastolic function 0.10 mm of NGT subjects, both P!0.001. IS (M) of T2D pts significantly returned to baseline values. inversely correlated with IMTCCAr rZK0.51 and IMTCCAl rZK0.57, both Conclusion P!0.001, independently of age, BMI, waist circumference, blood pressure, A short-term VLCD induces myocardial TG accumulation in patients with triglycerides, LDL cholesterol and HDL cholesterol. According to the median uncomplicated DM2, and is associated with changes in diastolic function. level of M 6.118 mg/kg per min of NGT subjects, T2D pts were divided into Administration of acipimox during the VLCD reduced myocardial TG insulin sensitive (IS) and insulin resistant (IR). There was a significant difference accumulation together with plasma NEFA level in conjunction with diastolic between IMTCCAl 0.87G0.20 of IR pts and IMTCCAl 0.62G0.23 of IS pts, heart function. These data stress the relation between plasma NEFA levels and P!0.01. There was a significant difference in CIMT between IR pts and NGT myocardial TG accumulation in DM2. subjects, whereas we did not find a significant difference in CIMT between IS pts and control group. Conclusion Insulin resistance could be considered as an important factor for increased carotid intima media thickness in type 2 diabetic patients.
P208 May testosterone therapy be the key to metabolic syndrome (MS) P210 treatment in men? Diabetic survival with HD: 10-years follow-up Yuliya Tishova1, George Mskhalaya1, Farid Saad2 & Svetlana Kalinchenko1 Dusica Toljic-Suluburic, Jovan Bakovic, Suncica Skapina, 1Research Center for Endocrinology, Moscow, Russian Federation; 2Bayer Nikola Sretenovic & Dragana Bubanja Schering Pharma, Department of Men’s Healthcare, and Gulf Medical 1Health Center, Cacak, Serbia; 2Medical Center, Pozarevac, Serbia; University School of Medicine, Ajman, United Arab Emirates. 3Clinical Center, Kragujevac, Serbia.
Background Background Impaired glycaemic control, resulting in diabetes mellitus type 2 (DMT2), is Diabetic nephropathy affects 20–40% diabetics. It is the most common cause of one of the MS components. In 1998 the UKPDS study showed that over 10 ESRD in Europe. In Serbia, 10–18% of the patients requiring HD are diabetics years of observation there were no significant changes in haemoglobin A1c and that number is constantly increasing. (HbA1c) in intensive insulin therapy group compared with conventional Methods therapy group. Therefore, we still need new options to treat DMT2. We made a retrospective study of the survival of both diabetic and non-diabetic Testosterone is well-known for it’s lipolytic activity; obesity leads to insulin patients requiring HD treatment during two 5 years long periods. resistance and DMT2. Results Objective During the first period 92 patients were followed-up and during the second 93 To study the glycaemic status in men with androgen deficiency (AD), MS and patients. There was not any statistically significant age difference between DMT2, treated with testosterone/placebo. diabetics and non-diabetics with HD therapy, and between disease duration before Materials and methods HD therapy among diabetics type 1 vs type 2, in none of the analysed periods. Twenty-eight men with MS (IDF criteria), DMT2 (nine patients were on insulin During the first period survival of diabetics on HD was shorter at a highly therapy) and AD (total testosterone (TT) !11 nmol/l) received 3 injections of statistically significant level compared to non-diabetics 2.3G2.6 years for DM testosterone undecanoate (Nebido, Schering) or placebo. Patients were divided compared to 4.7G3.9 years for non-DM, but it was not statistically significant into two groups according to TT levels 12 weeks after the third injection of when we compared patients with type 1 and type 2 DM. During the second period testosterone/placebo: in group 1 (nZ17)TTwasnormalizedupto15.8(13.0– survival of patients with HD therapy was highly statistically shorter for diabetics 21.0) nmol/l and in group 2 (nZ11), TT was not normalized (8 (6.5–10.3) vs non-DM 1.4G1.5 vs 4.1G2.7 years, and for DM type 2 compared to type 1 nmol/l (normal range (NR) 11–33)). Fasting plasma glucose (FPG) was DM 0.9G0.4 vs 2.8G2.3 years. Between 1991 and 1995, 19 diabetics – 21% measured before and after 30 weeks. Statistical analysis was performed using started HD therapy, between 1996 and 2000, 14 diabetics – 15% and between Wilcoxon test. 2001 and 2005, 28 diabetics – 22% started HD therapy. That increase is especially Results significant in 2005, 12 out of 21–57%. In group 1, FPG decreased from 6.7 (6.3–9.3) to 6.3 (5.3–877) (PZ0.01). In Conclusion three patients, insulin was no longer needed. In group 2, FPG increased from Prognosis for ESRD patients caused by diabetic nephropathy is extremely bad. 6.71 (6.4–7.0) to 7.0 (6.1–7.5), but these changes were not significant (PZ0.53). That is why all preventive measures should be taken, not only regarding the basic Conclusion disease, DM, but also in terms of primary and secondary prevention of diabetic AD correction in men with MS and DMT2 improves glycaemic parameters. nephropathy.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P211 P213 Markers of oxidative stress and antioxidant status in patients with Patients with type 2 diabetes mellitus have intima media thickness gestational diabetes of carotid artery wall equal to that of a decade older non-diabetic Lo´pez Cristina, Garcia Amor, Bartha Jose Luis & Aguilar Manuel patients Hospital Universitario Puerta del Mar, Cadiz, Spain. Angel Marinchev University Specialized Hospital of active treatment in endocrinology ‘Acad. In. Penchev’, Sofia, Bulgaria. Objective Evaluate the markers of oxidative stress and antioxidants status in patients with gestational diabetes (GD). Background Material and methods High resolution real-time B-mode ultrasound diagnostic and off-line computer- We performed a nested case-control study within a sample of a total of 126 ized measurement of vasculature can precisely assess the intima-media thickness pregnant women between the 24 and 29 weeks. Of the 126 women studied we (IMT) of the vascular wall and the presence of atherosclerotic plaque. compared 63 with GD and 63 control pregnant women. Both groups were Aim of the study analyzed for demographic data, perinatal and obstetrics results and the levels of To determine whether there is a difference in IMT of common carotid artery wall the markers oxidative stress and antioxidants status (lipid peroxides, glutathione (CCA) between patients with diabetes mellitus type 2 (DM2) and non-diabetics peroxidase, glutathione reduced, catalase and superoxide dismutase). (nonDM). Results Materials and methods Maternal age studied for the control group was 29.95G5.03 years old and Three hundred and sixty patients are examined – mean age 55.47G11.97 year, 31.57G4.1 years in patients with GD. Results showed 23% of the control group male – 120, female 240, DM2 – 195, non-diabetic – 175. The difference in age and 26% in patients with GD presented a history of abortion or macrosomia. The between diabetics and non-diabetics with equal IMT measure is calculated. IMT pre-pregnancy BMI was 23.46G3.73 kg/m2 in the control group and was assessed by sonograph ‘Ultrasonix’, linear transducer 7.5–12 MHz and 28G3.6 kg/m2 in GD (PZ0.0001). M’Ath Software. In reference to the perinatal and obstetrics results, the final week of pregnancy Results was 39.62G1.2 in the control group and 39.02G1.8 in GD. The rate of cesarean delivery was 10% in the control group and 33% in the patients with GD (PZ0.0001). The rate of macrosomia was 8% in the control group and 16% in GD Male DM2 Male non-DM Female DM2 Female non-DM (PZ0.3). Z Z IMTcca-left (mm) 0.747 0.675 0.727 0.605 Levels of lipid peroxides (P 0.001), peroxidase glutation (P 0.01), catalase IMTcca-right (mm) 0.785 0.675 0.758 0.617 (PZ0.04) and dismutase superoxide (PZ0.0001) were statistically siginificant. In the multivariance analysis the levels of lipoperoxides (PZ0.03), catalase (PZ0.006) and superoxide dismutase (PZ0.003) were significantly associated Linear regression analysis (Stepwise method). with the dependent variable GD. Z C ! C ! Conclusions IMTcca-left 0.229 0.008 Age 0.105 DM – male – 13.1 years. IMTcca-leftZ0.244C0.007!AgeC0.100!DM – female – 14.3 years. Women with GD present a higher probability of developing higher risk markers Z Z of cardiovascular disease expressed as higher levels of lipid peroxides Age (years), DM 1 for DM2, DM 0 for nondiabetic. and descending levels of antioxidants such as the catalase and superoxide Conclusions dismutase. Male with DM2 have IMTcca-left equal to that of non-diabetic male that are 13.1 year older than them. Women with DM2 have ITMcca-left equal to that of non- diabetic female that are 14.3 year older than them. IMT of the left CCA is significantly thicker than IMTcca-right. The presence of diabetes mellitus precipitates early thickening of the vascular wall.
P212 Adipokine profile in gestationa diabetes mellitus Lopez Cristina, Garcia Amor, Bartha Jose Luis & Aguilar Manuel Hospital Universitario Puerta del Mar, Cadiz, Spain.
Objective P214 Evaluate the proinflammatory and anti-antinflamatory adipokines in patients with Kidney transplantation and diabetes mellitus: continuous monitoring of gestational diabetes (GD). glucose Material and methods Carla Baptista1, Margarida Bastos1, Joana Guimara˜es1, Patricia Leita˜o1, We performed a nested case-control study within a sample of a total of 126 Miguel Melo1, Jacinta Santos1, Luisa Barros1, Carlos Bastos2, Rui Alves3, pregnant women between the 24 and 29 weeks. Of the 126 women studied we Francisco Carrilho1, Alfredo Mota2 & Manuela Carvalheiro1 compared 63 with GD and 63 control pregnant women. Both groups were 1Endocrinolgy, Diabetes and Metabolism Department, HUC, Coimbra, analyzed for demographic data, perinatal and obstetrics results and the plasma Portugal; 2Urolgy and Transplantation Department, HUC, Coimbra, levels of the tumor necrosis factor (TNF-a), Interleukin (IL-6), adiponectin and Portugal; 3Nephrology Department, HUC, Coimbra, Portugal. leptin. Results Maternal age studied for the control group was 29.95G5.03 years old and Introduction 31.57G4.1 years in patients with GD. Results showed 23% of the control group The benefits of intensive management of type 1 and type 2 diabetes have and 26% in patients with GD presented a history of abortion or macrosomia. been well established in several studies, as DCCT and UKPDS, and include The pre-pregnancy BMI was 23.46G3.73 kg/m2 in the control group and reduced of long term complications. Current guidelines target of A1c!7% 28G3.6 kg/m2 in GD (PZ0.0001). is also to achieve in diabetic patient with kidney transplant. Methods to In reference to the perinatal and obstetrics results, the final week of pregnancy improve patient’s ability to achieve this goal are being explored. Continuous was 39.62G1.2 in the control group and 39.02G1.8 in GD. The rate of cesarean monitoring of glucose in interstitial fluid allows the identification of delivery was 10% in the control group and 33% in the patients with GD glycemic excursions and general patterns of glucose levels in a manner not (PZ0.0001). The rate of macrosomia was 8% in the control group and 16% in GD available with self-monitoring blood glucose. Knowledge of these excursions (PZ0.3). and patterns may be used to make appropriate changes in treatment of Levels of TNF-a (PZ0.002), leptin (PZ0.001) and adiponectin (PZ0.04) were diabetes. statistically significant. In the multivariance analysis the levels of adiponectin Patients and methods (PZ0.026) and the pre-pregnancy BMI (0.01) were significantly associated with Continuous monitoring of glucose in interstitial fluid with MiniMed-CGMS was the dependent variable GD. performed in two patients with type 1 diabetes and a kidney transplant. Both Conclusions patients had A1cO7% and were under intensive therapy. Women with GD present a higher probability of developing higher risk markers of Results cardiovascular disease expressed as a higher pre-pregnancy BMI and descending Reported CGMS download were analyzed. We identified ‘down phenomen’, levels of adiponectin. undetectable hypoglycaemia events, incorrect adjustments insulin therapy. Therapy adjustments based on this information were done. No mechanical
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 device or local complaints were reported. After six month, glycemic control Results improved (A1c!7%). At baseline LT group had a significant lower peak oxygen uptake (VO2)(K2G Conclusions 0.6; P 0.01) and had shorter exercise time (K2.6G1.3; P 0.04) than HT pts and Continuous monitoring of glucose is an important tool in intensive management placebo group. After three months LT group had a significant greater of diabetes. This technology should be performed in all diabetic patients when improvement from baseline of peak VO2 (18% vs 9%; P 0.02), VE/VCO2 goals are not achieved. It helps health team to make therapy adjustments and can (K14% vs K4%; P 0.01) HOMA index (K16% vs K4%; P 0.03) and maximal improve patients’ glycemic control. This is the way to stopped progression of isometric strength (19% vs 2%; P 0.03) than HT group. Distance walked at macro and microvascular complications that are present in diabetic patients as 6MWT and isokinetic strength improved in a similar rate in both LT and HT those with kidney transplant. groups (PO0.05). There was not significant change in any endpoint in the placebo group. Conclusion Effects of TA in male with CHF on both exercise capacity and glucose metabolism seem to be greater in those pts with testosterone deficiency.
P215 Metabolic changes induced by glucose infusion in persons with Glu23Lys polymorphism P217 Thomas Bobbert, Marc Mittag, Knut Mai, Antje Fischer, Ayman Arafat, AFH Pfeiffer & Joachim Spranger GC-tofMS metabolite profiling in the pancreatic beta cell line INS-1 Charite´, Berlin, Germany. under chronic glucose stress conditions Isabel Go¨hring1, Gareth Catchpole2,A¨ nne Eckardt2, Lothar Willmitzer2, Andreas FH Pfeiffer1 & Joachim Spranger1 The development of diabetes mellitus type 2 (T2DM) is affected by genetic and 1Department of Clinical Nutrition, German Institute of Human Nutrition, lifestyle factors. Polymorphisms within the KIR6.2 gene seem to be associated and Department of Endocrinology, Diabetes and Nutrition, Charite´- with a higher risk for T2DM. The protein encoded by this gene represents a University Medicine Berlin, Campus Benjamin Franklin, Potsdam- potassium channel, which plays an essential role in insulin and glucagon secretion Rehbru¨cke/Berlin, Germany; 2Max-Planck-Institute of Molecular Plant by the pancreas. Physiology, Potsdam-Golm, Germany. A hyperglycaemic clamp without insulin was performed over 2 h in 10 healthy persons with the Kir6.2 E23K wild type Glu/Glu, 10 age-, BMI- and sex-matched persons being heterogenous at Kir6.2 E23K (Glu/Lys) and 10 persons with the Background Lys/Lys genotype. Effects on insulin and glucagon secretion were analysed. Long term exposure of INS-1 beta cells to elevated glucose concentrations has Insulin values were not different, although the maximum peak of the insulin been observed to impair insulin expression, a phenomenon termed as glucose answer was delayed for the Lys/Lys group (Glu/Glu-peak: 2.5 min, Lys/Lys- toxicity. Despite its potential relevance in the progression of diabetes, the peak: 5 min). Glucagon was at baseline significantly different between Glu/Glu underlying mechanisms is not yet fully understood. (39.1G2.9 pg/ml) and Lys/Lys (30.3G1.6) individuals (PZ0.015). In addition, Aim Glucagon decreased significantly in the Lys/Lys group after 2 h (85.9G2.3%; Target analysis of single, or a sub-group of metabolites has until now been the P!0.001) and the AUC values for the glucagon time course showed significant method of choice in mammalian cells to investigate the pathological state in terms lower results (4218G332 vs 3321G194; PZ0.035) compared to the Glu/Glu of small molecule composition. We therefore aimed to show that metabolite group. profiling is useful to detect multitude changes in metabolism in INS-1 cells after In conclusion we demonstrated in this study for the first time lower glucagon chronic high glucose exposure. We further suggest that mitogen-activated protein levels in healthy persons with the Glu23Lys variant in the KIR6.2 gene. In kinases (MAPK) participate in the regulation of insulin gene expression. addition a stronger reduction in glucagon suppression after i.v. glucose was found. Methods These results in healthy individuals indicate that specifically effects on glucagon INS-1 cells were incubated with medium containing 3 mM and 16 mM glucoseG secretion might contribute to the development of type 2 diabetes. MAPK inhibitor for 48 h. Insulin mRNA was measured using quantitative real time RT-PCR. Intracellular metabolites were extracted with a chloroform:metha- nol:water mixture and analysed by GC-tofMS. Results Insulin gene expression is significantly reduced after exposure of INS-1 cells to chronic high glucose levels. The application of INS-1 extracts to GC-tofMS allowed the relative quantification of several hundred biological peaks. The use of principal component analysis demonstrates a clear differentiation of cells treated P216 with low or high glucose. Further in-depth analysis revealed details of glucose- derived changes in single metabolites. The inhibition of MAPK results in a Effects of testosterone administration in male patients with heart failure restoration of insulin gene expression at high glucose levels that may be explained with and without hypogonadism due to improvement of specific metabolite levels. Rosalba Massaro, Giuseppe Marazzi, Giuseppe Caminiti, Marco Miceli, Conclusion Maria Cristina Ribaudo, Maurizio Volterrani & Giuseppe Rosano Metabolite profiling allowed the identification of core metabolites which were San Raffaele IRCCS, Rome, Italy. present at significantly different levels in low and high glucose treated INS-1 cells and which may participate in the regulation of insulin gene expression. Background Testosterone administration (TA) can improve exercise capacity and glucose metabolism of males patients (pts) with chronic heart failure (CHF). It is not known whether testosterone supplementation benefits only CHF subjects with hypogonadism. Aim P218 To compare effects of TA in male pts with CHF with and without testosterone Diabetes management and metabolic control are below expectations in deficiency. specialist diabetes practice in Portugal Methods ´ G G Salvador Massano Cardoso, Rui Duarte, Jose Manuel Boavida, Fifty-six males patients (median age 64.2 9.6), ejection fraction (EF) 36 9.4, Carvalheiro Manuela, Carvalho Davide & Gardete Luı´s NYHA class II/III (31/25), were enrolled. Of these 38 were randomized to receive Sociedade Portuguesa de Diabetologia, Lisbon, Portugal. TA, intramuscular injection of testosterone undecanoate, every 6 weeks (Nebido, Bayer Shering Germany) and 18 to receive placebo both on top of maximal medical therapy. Treated patients were than divided, according to median value of In Portugal, no relevant epidemiologic data exists relative to the management and testosterone, into two groups with Low (LTZ14 pt) or high (HTZ24 pt) level of control of diabetic patients. testosterone levels. At baseline and after 12 weeks all patients underwent TEDDI, a non-interventional cross-sectional study, allowed to characterize the glycometabolic assessment through HOMA index, cardiopulmonary test, usual management of type 1 (T1D) and type 2 (T2D) diabetes using a 6-minute walking test (6MWT) and quadriceps maximal isometric and isokinetic standardized questionnaire in 1775 patients (F: 47.5%; T2D: 80.8%) aged 18 strength. years or older, visiting their diabetes specialist (nZ180).
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Data was obtained for metabolic control and risk factor prevalence. Main results Material and methods are as follows (CI 95%): We performed ANOVA comparisons and computed Pearson correlations/linear regressions between womens’ age and BMI, O’ Sullivan test, OGTT 0 h, 1 h, 2 h and 3 h, new born weight and the need of insulin. non-FBG, Results n HTN, % High LDL, % Low HDL, % High TGs, % mg/dl HbA1c, % BMI was similar in both groups (mean value AZ24.6 kg/m2, BZ24.9 kg/m2, P ns). T1D, 29.9 30.8 36.6 16.5 176.4 8.0 O’Sullivan test measures were significantlyhigher in group B as compared to group A G G 336 (25.2–35.0) (26.0–36.0) (31.5–42.0) (12.9–20.9) ( 85.9) ( 1.7) BZ AZ PZ T2D, 70.1 51.2 40.6 35.0 183.7 7.6 (mean values 166 mg/dl, 151 mg/dl, 0.04). There was a positive 1395 (67.7–72.4) (48.5–53.9) (38.0–43.3) (32.5–37.5) (G73.0) (G1.5) correlation (rZ0.272) between these measures and age (PZ0.028). We found no significant differences across OGTT measures between these groups. Birth weight was significantly lower in group B compared to group A (mean values BZ3.190 kg, Severe hypoglycaemic crises (requiring emergency care) were reported by 3.4% AZ3.480 kg, PZ0.03). Insulin therapy was given more often in group B as of patients (T1D: 7.5%; T2D: 2.3%) in the preceding month. In these, an average compared to group A (35.5% and 8.6% respectively, PZ0.011, c2 test). of 2.4 crises per patient was determined. Conclusions In T2D, level of insulinization was 47.0%, and 31% were treated simultaneously Age was not correlated with BMI and OGTT for any of the groups. with oral hypoglycaemic, antihypertensive, antidyslipidemic and anti-platelet The older group had significantly higher levels of O’Sullivan test. Maternal age drugs. In T1D, 16.1% of patients used LA insulin, while metformin was used as an influenced the need for insulin. In the older group birth weights were lower, probably adjuvant therapy in 15.2%. due to the better glycaemic control, given the more aggressive insulin therapy. Although old barriers in diabetes management (insulin for T2D and LA insulin and metformin for T1D) are overcome, metabolic control is still below expectations.
P221 SelS/Tanis controls insulin sensitivity and is regulated by acute phase and diet Mette Stoedter, Kostja Renko, Josef Ko¨hrle & Lutz Schomburg P219 Institut fu¨r Experimentelle Endokrinologie, Charite´ Universita¨tsmedizin Glucose metabolism alterations in non-diabetic patients undergoing Berlin, Berlin, Germany. cardiac rehabilitation programs Rosalba Massaro, Giuseppe Caminiti, Giuseppe Marazzi, Lucia Gatta, Background Adelaide Carluccio, Maurizio Volterrani & Giuseppe Rosano Selenoproteins contain the 21st proteinogenic amino acid selenocysteine (Sec) and San Raffaele IRCCS, Rome, Italy. exert important biological functions. Selenoprotein S (SelS) has only recently been identified and appears to be implicated in type 2 diabetes and inflammation. In vitro Background studies have shown that SelS expression is controlled by circulating cytokine and Effects of cardiac rehabilitation (CR) on glucose metabolism of coronary artery glucose levels. Mechanistically, SelS participates in the retro-translocation during disease (CAD) patients (pts) without diabetes has not been assessed. quality control in the ER and the ER-associated degradation pathway. Aim Hypothesis Evaluate effects of an intensive CR program on glucose metabolism of SelS is a selenoprotein and as such its translation depends on the selenium (Se) no-diabetic CAD pts with. supply. mRNA levels may fail to reliably reflect SelS protein levels, especially if Methods the organism is stressed by an acute phase response (APR). Therefore, Sixty non-diabetic pts (M/F 53/7), age 71.2G9.2, were submitted to a 3 week CR Se-deficiency and/or APR may impair the regular SelS expression. program. Oral glucose tolerance test (OGTT), HOMA index, six minute walking Material and methods test (6mwt) were performed at baseline (T0), three weeks (T1) and after three We have injected male and female mice on different Se status with months (T2). At discharge a dietetic and exercise program was recommended. lipopolysaccharide (LPS) to induce an APR. SelS levels were determined by Results qPCR and Western blot analysis in liver, fat and muscle. At T0 28.3% had normal glucose tolerance, 41.6% IGT, and 30.1% were diabetic Results (DM). At T1 there was a significant reduction of BMI (29.8G3.4 vs 29.0G3.8 SelS biosynthesis turned out to be intensively regulated on the posttranscriptional P 0.001), waist circumference (81.0G34.1 vs 79.1G33.4 cm P 0.006), HOMA-R level by both the APR and the Se status of the organism. In liver, fat and muscle (2.6G1.4 vs 1.8G0.8, P 0.002). 64.7% of previous diagnosed IGT pts had normal tissue, we observed a tissue-specific increase of SelS protein concentrations in well- glucose tolerance (P 0.04), and 77% of previous DM resulted IGT. At T2 BMI, supplied animals (up to 20-fold induction of SelS protein) but only marginal effects fasting glicemia, HOMA-R increased to similar values than baseline. on SelS mRNA. This Se-dependent expression was characteristically altered during Overall at T1 distance walked at 6MWT improved significantly (287G107.9 vs the APR. 482G117.8, P 0.001). IGT pts had a worst performance than pts with normal Conclusion glucose tolerance at baseline and discharge 6MWT (291.1G83.4 vs 344.4G87.1; Since SelS is involved in glucose metabolism, diabetes and oxidative stress P!0.04; and 444.9G102.3 vs 510.7G84.7, P!0.02 respectively). No difference defence, sufficient dietary Se is needed for the regular biosynthesis of SelS, and was found between IGT and DM pts at baseline (291.1G83.4 vs 264.7G86.3 m; thereby may impact onto the individual insulin sensitivity and APR. PO0.05) and discharge 6MWT (444.9G102.3 vs 457.8G100 m, PO0.05). Supported by Deutsche Krebshilfe (10-1792 SchoII) and DFG (SCHO 849/2-1). Conclusion OGTT is usefull to identify gluco-metabolic state in CAD pts. IGT pts have a worse functional capacity than normo-glicemic. CR program improves glucose metabolism and insulin resistance in cardiac pts with impaired OGTT. However results are lost when CR is stopped. P222 Atherosclerotic factors, low antioxidant defense and cardiovascular diseases in retinal occlusions and anterior ischemic optic neuropathy Branko Sreckovic1, Vesna Dimitrijevic-Sreckovic2, Natalija Kosanovic- Jakovic3, Predrag Djordjevic2, Emina Colak4, Fadil Canovic2, Svetislav Milenkovic3, Jecka Stojanovic2 & Mirko Resan3 P220 1Institute of Cardiovascular Diseases, Clinical Center of Serbia, Belgrade, GDM in women younger and older than 28 years: are there any Serbia; 2Institute of Endocrinology, Diabetes and Metabolic Diseases, differences in phenotype and biochemical markers? Clinical Center of Serbia, Belgrade, Serbia; 3Institute of Ophtalmology, Sandra Paiva, Luisa Ruas, Jacinta Santos, Elvira Marta, Ermelinda Sobral, Clinical Center of Serbia, Belgrade, Serbia; 4Institute of Medical Anto´nio Lobo, Manuela Carvalheiro & Paulo Moura Biochemistry, Clinical Center of Serbia, Belgrade, Serbia. Coimbra University Hospital, Coimbra, Portugal. Aim Goal The aim of the study was to examine the existence of cardiovascular diseases The aim of this study was to find different characteristics between GDM women (CVD), atherosclerotic factors and antioxidant defense in patients with central aged under (GDM A nZ23) and above 28 years (GDM B nZ107), followed in retinal artery and central retinal vein occlusions (CRAO, CRVO) and anterior our department in 2005. ischemic optic neuropathy (AION).
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Materials and Methods One of the proposed mechanisms responsible for Diabetes mellitus (DM)- The study included 38 obese individuals with CRAO, CRVO and AION. associated erectile (ED) dysfunction is overactivity of RhoA/ROCK signalling. Glycoregulation disorders were determined by OGTT. Lipid status was Because statins may decrease RhoA activation, we investigated whether determined by spectrophotometry. Serum CRP was measured by immunometric atorvastatin ameliorated DM-induced ED in alloxan-treated (100 mg/kg) rabbits assay. Microalbuminuria was determined by nephelometry. Activities of markers (in vitro studies) and streptozotocin-treated (STZ, 50 mg/kg) rats (in vivo studies). of antioxidant defense, superoxide dismutase (SOD) and glutation peroxidase A subgroup of diabetic animals received atorvastatin 5 mg/kg per daily 2 weeks (GSH-Px) were determined in erythrocytes. before sacrifice. In diabetic animals, atorvastatin treatment did not affect Results glycaemia, cholesterol blood levels and the diabetes-induced hypogonadal state. Disorder percentages in observed patients were as follows: CRAO 46.4%, CRVO In alloxan-rabbits, atorvastatin did not ameliorate DM-induced acetylcholine 35.7%, AION 17.9%. CRAO, CRVO and AION patients had the following hypo-responsiveness, while normalized DM-induced hypersensitivity to the respective values of the following disorders: hypertension 63.3%, 60.0%; 80.0%; contractile effect of Endothelin-1 and to the relaxant effect of the ROCK inhibitor obesity 69.2%, 70.0%, 60.0%; hyperlipoproteinemia 84.6%, 100.0%, 80.0%; Y27632. In STZ-rats penile tissue, ROCK1 mRNA resulted increased, nNOS metabolic syndrome (MS) 69.2%, 70.0%, 80.0%; angina pectoris 30.8%, 10.0%, mRNA decreased. These effects were not normalized by atorvastatin, which, in 40.0%; miocardial infarction 0%, 10%, 40%; impaired fasting glucose (IFG) contrast, completely restored the DM-induced hypersensitivity to Y27632, 30.8%, 10.0%, 20.0%; diabetes mellitus type 2 (T2DM) 15.4%, 40.0%, 60.0%. intracavernously injected. Moreover, atorvastatin ameliorated the DM-induced LDL/HDL ratio was 3.3G1.4, 3.3G0.7 and 3.0G0.7. Lp(a) was 0.37G0.77, impairment of penile erection obtained by electrostimulation of the cavernous 0.43G0.38 and 0.13G0.1. Microalbuminuria was 21.7G14.7, 112.9G166.9 and nerve and normalized the sildenafil effect on erectile function, decreased by DM. 13.0G4.8. CRP was highest (P!0.01) in CRAO patients (3.7G1.4; 1.9G1.0; We then studied in vitro effect of atorvastatin on RhoA/ROCK in human foetal 0.9G0.7 mg/l). Decreased antioxidant defense was present in all disorders. penile SM cells (hfPSMCs) activated by increasing concentration of glucose Conclusions (5, 22 and 40 mM). In hfPSMCs, high-glucose (22 and 40 mM) stimulated RhoA Visceral obesity, hypertension, hyperlipoproteinemia are associated with activation, along with migration, proliferation and RhoA-mediated gene accelerated atherosclerosis and CVD, which was most frequent in CRAO transcription. Atorvastatin (1 mM) restored all the high glucose-induced effects, (highest CRP as inflammatory factor, highest atherogenic risk factor LDL/HDL, whereas was ineffective in the presence of geranyl–geranyl pyrophosphate, the high Lp(a)) and AION patients (most frequent T2DM with poor glycoregulation product reduced by statins and required for RhoA activation. Accordingly, in and MS with all its characteristics). Low antioxidant defense is associated with atorvastatin-treated hfPSMCs RhoA was less expressed at the membrane (active atherosclerosis and various vascular complications. form) and RhoA-dependent genes (ROCK2, myocardin, MKL1, SM22a, desmin, and a-SMA) was down-regulated. In conclusion, atorvastatin, most probably by inhibiting RhoA, is able to decrease the DM-induced ED and also to restore sildenafil responsiveness. This data are in keeping with clinical reports showing that atorvastatin ameliorates sildenafil-induced erections, in otherwise unres- P223 ponsive subjects. Glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide in polycystic ovary syndrome Jana Vrbikova1, Martin Hill1, Karel Vondra1, Bela Bendlova1, Tereza Grimmichova1, Katerina Dvorakova1, Sonja Stanicka1 & Giovanni Pacini2 1Institute of Endocrinology, Prague, Czech Republic; 2ISIB CNR, Padova, Italy.
Insulin hypersecretion during oral or intravenous glucose tolerance test (OGTT, P225 ivGTT) was described previously in women with polycystic ovary syndrome (PCOS). Little attention was given to the regulation of insulin secretion in these Circulating endotoxin as a potential biomarker and mediator of subjects. We aimed to study the secretion of incretins (glucose-dependent inflammation: influenced by diabetic therapies Nasser Al-Daghri1, Khalid Al-Rubeaan2, Omar Al-Attas1, Nancy da Silva3, insulinotropic polypeptide, GIP, glucagon-like peptide 1, GLP-1), during OGTT 1 3 3 1 in normoglucose-tolerant PCOS women. Shaun Sabico , Sudhesh Kumar , Philip Mc Ternan & Alison Harte 1King Saud University, Riyadh, Saudi Arabia; 2Diabetes Research Center, After signing written informed consent approved by the local Ethical Committee, 3 women with PCOS (nZ21,age 25.8G4.1 years, BMI 21.6G1.7 kg/m2) and control Riyadh, Saudi Arabia; University of Warwick, Birmingham, UK. healthy women (CT nZ13, 28.5G7.2 years, 20.3G2.5 kg/m2) underwent OGTT with sampling for blood glucose, insulin, C-peptide, total GIP and active GLP-1. Recent studies suggest that endotoxin from gut flora, may be key to development Insulin sensitivity was assessed in fasting (QUICKI) and in dynamic conditions of inflammation by stimulating the secretion of an adverse cytokine profile from 2 (OGIS; ml/min per m ). Two-sample t-tests or repeated measures ANOVA followed adipose tissue. The study investigated the relationship between endotoxin and G by LSD were done. Values are given as mean S.D. various metabolic parameters of diabetic patients to determine if anti-diabetic Basal glucose, insulin and C-peptide did not differ between PCOS and CT. Similarly, therapies exerted a significant effect on endotoxin levels and adipocytokine stimulated glucose and insulin did not differ significantly between PCOS and CT as profiles of T2DM subjects. Fasting blood samples were collected from consenting 2 well as QUICKI and OGIS.During OGTT, PCOS had higher levels ofC-peptide than Saudi Arabian patients (BMI: 30.2G (S.D.) 5.6 kg/m , nZ413), consisting of non- ! CT irrespective time (ANOVA PCOS vs CT P 0.05, PCOS vs time interaction diabetics (controls, nZ67) and T2DM subjects (nZ346). The diabetics were Z G G Z P 0.76), higher AUCCP (370 113 vs 325 104 nmol/180 min P 0.05) along divided into 5 subgroups based on 1 year treatment regimes: dietcontrol (nZ36), ! Z with higher levels of GIP (ANOVA PCOS vs CT P 0.001; PCOS vs time P 0.76) metformin (nZ141), rosiglitazone (RSG, nZ22), a combined fixed dose of G G Z and with higher AUCGIP (39 250 16 680 vs 29 890 7000 pg/180 min; P 0.06). metformin/rosiglitazone (Avandamet nZ100) and insulin (nZ47). Lipid profiles, Total active GLP-1 was not higher in PCOS; however, GLP-1 pattern of PCOS was fasting serum glucose, insulin, adiponectin, resistin, TNF-a, leptin, C-reactive significantly different from CT being lower at 180 min (ANOVA PCOS vs time protein (CRP) and endotoxin concentrations were determined. Regression ! P 0.008). analyses revealed significant correlations between endotoxin levels and In conclusion, enhanced insulin secretion in normotolerant women with PCOS is triglycerides (r2Z0.42; P!0.0001); total cholesterol (r2Z0.10; P!0.001), associated to a general augmentation of GIP and to a late-phase decrease of GLP-1. glucose (r2Z0.076; P!0.0001) and insulin (r2Z0.032; P!0.001). Endotoxin Elevated incretin secretion and the concomitant insulin hypersecretion could be early showed strong inverse correlation with HDL-cholesterol (r2Z0.055; P!0.001). markers of not yet fully expressed prediabetic state. Endotoxin levels were elevated in all of the treated diabetic subgroups compared Supported by Ministry of Health of Czech Republic, grant NR 8759-3. with control, but only RSG group did not differ significantly from control (Control: 4.2G1.7 EU/ml, RSG: 5.6G2.2 EU/ml). Both Avandamet and RSG treated groups had significantly higher adiponectin levels than all the other groups, with RSG group expressing the highest levels overall. In conclusion, sub- P224 clinical inflammation in T2DM may, in part, be mediated by circulating endotoxin. Furthermore, that whilst the endotoxin and adipocytokine profiles of Atorvastatin ameliorates penile erection and sildenafil responsiveness diabetic patients treated with different therapies were comparable, the RSG group in two distinct animal models of chemical diabetes and inhibits high demonstrated significant differences in both adiponectin and endotoxin levels. We glucose-induced alterations in human penile smooth muscle cells confirm an association between endotoxin and serum insulin and triglycerides and Annamaria Morelli, Sandra Filippi, Linda Vignozzi, Xin-Hua Zhang, an inverse relationship with HDL. Lower endotoxin and higher adiponectin in the Rosa Mancina, Benedetta Fibbi, Aravinda Chavalmane, Enrico Silvestrini groups treated with RSG may be related and indicate another mechanism for the & Mario Maggi effects of RSG on insulin sensitivity. University of Florence, Florence, Italy.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P226 P228 Serum adiponectin concentration is not dependent on inflammatory Vitamin D deficiency is associated with heart failure and sudden cardiac process of periodontium in patients with primary hypertension: death: cross-sectional and mortality data of 3299 patients referred to preliminary results coronary angiography Edward Franek1, Klamczynska Ewa3, Ganowicz Ewa4, Blach Anna2 & Stefan Pilz1, Winfried Ma¨rz2, Astrid Fahrleitner-Pammer1, Hans P Dimai1, Gorska Renata4 Bernhard O Boehm3 & Harald Dobnig1 1Department of Endocrinol, Medical Research Center, Polish Academy of 1Department of Internal medicine, division of Endocrinology and Nuclear Sciences, Warsaw, Poland; 2Department of Endocrinol and Diabetol, Medicine, Medical University of Graz, Austria, Graz, Austria; 2Department Central Clinical Hospital MSWiA, Warsaw, Poland; 3Department of of Public Health, Social and Preventive Medicine, Mannheim Medical Cardiology, Central Clinical Hospital MSWiA, Warsaw, Poland; Faculty, University of Heidelberg, Mannheim, Germany; 3Department of 4Department of Periodontologyi, Medical University of Warsaw, Warsaw, Internal Medicine I, Division of Endocrinology and Diabetes, Ulm Poland. University, Ulm, Germany.
Introduction Background Patient with chronic periodontitis (CP), especially those with its advanced The myocardium is a target tissue for vitamin D, that was shown to exert several forms, have higher cardiovascular risk compared to those with healthy effects on cardiac contractility and calcium homeostasis. We aimed to elucidate periodontium. They are also characterized by higher hs-CRP levels, greater whether insufficient vitamin D status is associated with heart failure and sudden left ventricular mass, greater intima-media thickness. Adiponectin, a hormone cardiac death (SCD). excreted by fat tissue, is involved in insulin sensitivity regulation and in Methods and Results atherosclerotic processes. The aim of the study was to assess a relationship We measured 25-hydroxyvitamin D [25(OH)D] in 3299 Caucasian patients that between chronic periodontitis and serum adiponectin concentration in patients were all routinely referred to coronary angiography at baseline (1997–2000). with primary hypertension. 25(OH)D was not associated with the prevalence of coronary artery disease Material and methods (CAD) but was negatively correlated with N-terminal pro-B-type natriuretic Two groups of patients were included into the study: 28 patients with no or only peptide (NT-pro-BNP), and was an independent predictor for higher NYHA moderate CP (Community Periodontal Index of Treatment Risk–CPITN – score Z classes and impaired left ventricular function. During a median follow-up time of 0–2, mean age 49.6G5.9 years, BMI 30.6G5.2 kg/m2), and 25 patients 7.75 years, 116 patients died due to heart failure, 90 due to myocardial infarction with advanced CP (CPITN score 3–4, mean age 50.9G4.5 years, BMI 28.6G and 118 due to SCD. After adjustment for cardiovascular risk factors, the Cox 3.1 kg/m2). In both groups other than periodontium potential sources of infection proportional hazard ratios (with 95% confidence intervals) for death due to heart were carefully excluded. Serum adiponectin concentration was assessed by EIA failure and for SCD were 2.84 (1.20–6.74) and 5.05 (2.13–11.97), respectively, (Alpco Diagnostics). Mann–Whitney test was used for between groups comparison, when comparing patients with severe vitamin D deficiency [25(OH) and Spearman rank test for correlation assessment. D!10 ng/ml)] with the normal range group [25(OH)DR30 ng/ml]. 25(OH)D Results was not independently associated with the risk for fatal myocardial infarction. For Serum adiponectin concentration did not differ between CPITN 0–2 and CPITN all statistical analyses we obtained similar results for 25(OH)D and for 1,25- 3–4 groups (12.4G5.0 mg/ml vs 12.2G3.9 mg/ml), the same was true for serum dihydroxyvitamin D [1,25(OH)2D]. hsCRP level (2.99G3.89 mg/ml vs 2.14G2.33 mg/ml, respectively). No significant Conclusions correlation between adiponectin concentration and mean or maximal CPITN Low levels of 25(OH) and 1,25(OH)2D are independently associated with heart score was shown. There was also no correlation between adiponectin and failure and SCD but not with fatal myocardial infarction and prevalent CAD, hsCRP levels. suggesting that possible cardioprotective effects of vitamin D might directly affect Conclusion the cardiomyocytes and less the coronary vessels. From those preliminary results one can conclude that there is no relationship between serum adiponectin concentration and inflammatory process of periodontal tissue. However, a small number of included patient and no difference between hs-CRP level between the groups limit power of the study.
P229 Retrovirally transduced, antigen-specific T cells for therapy of type 1 diabetes Nonsikelelo Mpofu, Nadja Saal, Matthias Hardtke-Wolenski, Michael P Manns & Elmar Jaeckel P227 Hannover Medical School, Hannover, Germany. The association between adipocytokine profiles and insulin resistance in obese subjects C C Omar Al-Attas1, Nasser Al-Daghri1 & Reem Sallam2 In vitro expanded antigen specific CD4 CD25 regulatory T cells (Tregs), 1King Saud University, Riyadh, Saudi Arabia; 2King Khalid University have been shown to suppress autoimmune diabetes, suggesting a novel Hospital, Riyadh, Saudi Arabia. approach to cellular immunotherapy for autoimmunity. However to interfere with ongoing disease requires at least 106 in vitro expanded antigen specific Tregs which are difficult to obtain from a polyclonal repertoire. Hence an This study aims to explore the baseline adipocytokine profiles of adult alternative approach would be to instruct naı¨ve or antigen specific CD4CT Saudis and evaluate their relationship in the development of insulin cells to obtain regulatory function. Indeed retroviral transduction of antigen resistance. Three hundred adult Saudis with varying glucose tolerance specific T cells withFoxp3, a Treg lineage specific transcription factor, were recruited. They were grouped into NGT, IGT and DM. Anthropo- results in the generation of Tregs that can interfere with established metrics, glucose and lipid profiles were analyzed by routine methods; leptin, autoimmunity in a non-lymphopenic nonobese diabetic (NOD) mouse model. adiponectin, resistin and CRP were measured by ELISA. Insulin resistance However, conditions for transduction into NOD T cells have not yet been was significantly correlated with levels of CRP (R 0.32, PZ0.02) in the optimized. Furthermore very little is known about the in vivo effect of these NGT; with leptin levels (R 0.46, PZ0.001) in the IGT; and with Foxp3 transduced antigen specific T cells. Here we show that ecotropic adiponectin levels (R 0.25, PZ0.001) in all groups. In males, resistin and pseudotyped viruses are more efficient at transducing NOD CD4CTcells CRP exhibited significant correlations to insulin resistance (R 0.33, than VSVG pseudotyped viruses. In addition retroviral transduction of PZ0.005); in females significant correlation was demonstrated between Foxp3 into NOD CD4C primary T cells carrying the transgenic TCR from insulin resistance and adiponectin (R 0.32, PZ0.003). Significant associ- an islet Ag-specific T cell clone, BDC2.5, confers a Treg phenotype on ations exist in the adipocytokine profiles of adults with different glucose these cells as they exhibit Treg signature characteristics such as in vitro tolerance. Certain adipocytokines can be used not only as promising markers anergy, suppressive capacity and upregulation of CD62L, CD25 and GITR. but as potential adjunct therapy with regards to insulin sensitivity and Adoptive transfer of Foxp3 transduced BDC T cells into NOD recipients obesity. shows that the cells home and proliferate in an antigen specific manner.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P230 Conclusion Induction of autoantigen-specific tolerance by retroviral transduction of CAN was observed in 53.85% of the patients; peripheral sensory dysfunction hematopoetic stem cells with GAD65 prevalence here was higher (35.9%), than in general population. Undiagnosed Elmar Jaeckel1, Philipp Ivanyi1, Markus Busch1, Harald von Boehmer2 & hyperglycemia that may be asymptomatic and untreated for years, may explain Michael P Manns1 why at diagnosis CAN and peripheral sensory dysfunction are present in many 1Hannover Medical School, Hannover, Germany; 2Harvard Medical School, patients. Boston, MA, USA.
Transfer of hematopoetic stem cells from mice transgenically overexpressing the islet autoantigen insulin could prevent type I diabetes in NOD mice. We tested if such an approach of tolerance induction could be employed by means of retroviral P232 gene transfer of autoantigens into syngeneic hematopoetic stem cells (HSCs). We used glutamic acid decarboxylase 65 (GAD) as the autoantigen as T cell Severity of depression in patients with type 1 and type 2 diabetes and its responses against GAD are more easily detected in NOD mice and as it has been relation to the level of glycemia control and anti-depressive therapy previously difficult to establish tolerance against this antigen. We generated Liana Tsutskiridze, Ramaz Kurashvili, Natalia Asatiani, Givi Kurashvili, retroviruses expressing GAD modified for optimal presentation by antigen Maia Khelashvili, Maia Nishnianidze, Elena Shelestova & Mzia Dundua presenting cells followed by eGFP. Retroviruses expressing just eGFP served a Georgian Diabetes Center, Tbilisi, Georgia. control. We developed a protocol for efficient in vitro transduction of NOD- HSCs. Mice reconstituted with GAD transduced bone marrow exhibited a long- Background and aims lasting, multi-lineage hematopoetic chimerism as shown by eGFP. Percentage of There are consistent findings about increased prevalence of depressive disorders eGFP positivity of HSCs correlated with eGPF expression in thymic and in in diabetes. The aim of the study was to reveal prevalence of depression in peripheral dendritic cells. Mice receiving eGFP transduced HSCs showed a strong patients (pts) with type 1 (DM1) and type 2 (DM2) diabetes. T cell response against GAD and its peptide epitopes while animals getting GAD Materials and methods transduced HSCs were completely tolerant. Chimerism of just 5% with GAD Totally, 157 pts with DM were questioned. To assess depression degree Beck’s transduced HSCs was still sufficient to induce complete GAD-specific tolerance. scale was used, and 83 depressive pts (scoresO10), were allocated into 2 groups Recipients of secondary bone marrow transplants were also tolerant against GAD (Gr.): Gr.1 (nZ44)-DM2 pts (m20/f24), mean age 57.5G8.4 years, diabetes thereby proving that tolerance was due to transduction of HSCs rather than of duration 6G2 years, HbA1c-8.8G1.3%, Gr. 2 (nZ39)–DM1 pts (m16/f23), committed progenitors. Despite complete tolerance against GAD mice still mean age 30G5 years, diabetes duration-7G2 years, HbA1c-9.2G1.9%. developed type I diabetes with unchanged kinetics and incidence as compared to Assessment scores: Gr.1 (m) O55 (7 pts/35%), 30–50 (8 pts/40%), R10 mice receiving eGFP transduced HSCs, thereby proving that GAD65 is not an (5 pts/25%); (f) O60 (11 pts/45.8%), 30–50 (8 pts/33.4%), O15 (5 pts/20.8%). essential autoantigen in the NOD mouse. We prove for the first time that retroviral Gr.2(m) O50 (8 pts/50%), 30–50 (7 pts/43.7%), R10 (1 pts/6.25%); (f) O60 transduction of HSCs with autoantigens can lead to complete T cell tolerance. (12/52.2%), 30–50 (8/34.8%), O20 (3/13%). Eighteen Gr.1 pts were treated with Similar approaches with other autoantigens could have a huge potential in the insulins and oral hypoglycemic agents (OHAs); 26-only with OHAs. Intensive therapy of type I diabetes. Meanwhile the model will be suitable for testing insulin therapy was used in 22 Gr.1 pts. Tianeptin 3 tablets/daily was used for the importance of potential antigens without the need of creating transgenic depression treatment in both groups. animals. Results Repeated examination at month 3 post study initiation showed: HbA1c dropped by 7.3G0.9%; PZ0.000 (Gr.1), and by 6.5G0.6%; PZ0.000 (Gr.2). Beck’s scores were: Gr.1 (m): 30–40 (7 pts), 20–30 (8 pts), 0 (5 pts); (f): 50–60 (11 pts), 20–30 (8 pts), R10 (5 pts). Gr.2 (m): 30–40 (8 pts), R20 (7 pts), 0 (1 pts); (f): 50– 60 (12 pts), 20–25 (8 pts), R8 (3 pts). At entry there was no statistically evident difference in depression severity between the groups (PZ0.177; PZ0.537, P231 respectively). Post treatment there was statistically evident correlation between decline in HbA1c levels and depression severity in both groups, this evidence was Cardiac autonomic and peripheral neuropathy in newly diagnosed relevant for males and females: Gr.1 (m) rZ0.948, PZ0.000; (f) rZ0.909, type 2 diabetic patients PZ0.000. Gr.2 (m) rZ0.915, PZ0.000; (f) rZ0.921, PZ0.000. 1 1 1 Givi Kurashvili , Ramaz Kurashvili , Maia Khelashvili , Conclusion 1 1 2 Liana Tsutskiridze , Elena Shelestova & Manoni Kobaidze We conclude: (1) There was no statistically evident difference in depression 1 2 Georgian Diabetes Center, Tbilisi, Georgia; State Medical University, severity between the DM types. (2) There is statistically evident post-treatment Tbilisi, Georgia. correlation between glycemia control level and depression degree in both groups.
Background and aims At diagnosis 20–30% of patients (pts) with type2 diabetes (T2DM) have neuropathy, that often goes unrecognized. Cardiac autonomic neuropathy (CAN) is associated with 5-fold risk of mortality. As today there is no specific treatment for overt neuropathy, it is important to use prevention and timely revealing. The goal of the work was to evaluate prevalence of peripheral neuropathy and CAN in P233 pts with newly diagnosed T2DM. Quality of diabetes shared care in patients with diabetes type 2 in the Materials and methods diabetes clinic of Fredericia hospital We observed 39 pts with newly diagnosed T2DM without known CV disease, Laima Sadauskiene, Ulla Linding Jørgensen, Jette Pedersen, Charlotte ketoacidosis, alcoholism and/or chronic liver disease and non-diabetic nerve Chrois Møller, Ellen Grodum & Hans Jørgen Gjessing damages, not taking medications affecting CAN reflex tests. Ewing’s standard Diabetes Clinic, Fredericia Hospital, DK-7000 Fredericia, Denmark. reflex tests were performed, severity of CAN was evaluated according to Jermendy, 1995. Standardized evaluation was conducted (Neurometer, Balti- more, MD), that discriminates between neuropathic and non-neuropathic pts and Aim tests different nerve fiber types. Electric current perception threshold was To evaluate the quality of diabetes group-based education followed by shared measured at: 5, 250 and 2000 Hz. Measurements were obtained from hallux deep care. The diabetes education programme had a duration of 4 days and included and superficial peroneal nerves. Forced choice method was used to confirm screening for diabetes late complications. Patients with microvascular compli- minimum intensity, which was considered as current perception threshold. cations should visit the diabetes clinic four times a year. Patients without Clinical data of the study population: males/females-27/12, mean age – 49.3G3.6 microvascular complications should visit their general practitioner every third years; HbA1c 8.3G1.73%; BMI 24.4G2.6 kg/m2. month and the diabetes clinic once a year. Results Methods CAN test scores – 0 -1 -18 cases (46.15%), 2–3 (mild) – 17 pts (43.59%) and 4–6 Retrospective data on 100 newly referred patients with type 2 diabetes with (moderate) – 4 pts (10.26%) CAN. No severe CAN were registered. CPT quality standards shown in parenthesis. abnormalities had 14 pts: 8 (20.5%) hyperesthetic and 6 (15.4%) hypoesthetic, 12 Results of them had CAN. Positive correlation was demonstrated between prevalence of Eighty-six percent (80%) of the patients visited our diabetes clinic 2 years after CAN and HbA1c (P!0.001); CAN and peripheral sensory dysfunction the diabetes group-based education and 73% (80%) visited their general (P!0.001). practitioner.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
After 2 years, HbA1C and blood pressure were assessed in 100% of the patients Subjects and methods (O95%), while urinary albumin was measured in 99% (O95%). One hundred and forty-four patients (59 M/85 F), mean age 61.4G0.9 years, Optimal control with HbA1C!7% increased from 36 to 55% (O60%), and treated 2.4G0.2 years with amiodarone were assessed for TSH, TT3,TT4 moderate good control with HbA1C!8% increased from 75 to 83% (O80%) (immunoradiometric assays) and FT4, TPO Ab (microenzymatic immunoassays). 2 years after diabetes education. Thirty-three patients were residents in areas with mild/moderate iodine deficiency Optimal control of blood pressure %130/80 mmHg was found in 35% (O60%) at and 111 patients from areas with normal iodine intake. Kaplan Meier curves were the diabetes group-based education and in 40% 2 years after the diabetes group- used for estimation of cumulative incidence and timing of AITD. based education. Blood pressure%140/90 mmHg was found in 59% (80%) at the Results diabetes group-based education and in 62% (O80%) 2 years later. AITD occurred in 89/144 patients (61.8%): 60 patients (41.7%) developed Micro- and macroalbuminuria was shown in 9% at the diabetes group-based thyrotoxicosis (AIT), 29 patients (38.1%) hypothyroidism. Type 1 and education and 8% 2 years later. Total cholesterol ! 4.5 mmol/l in 31% (O80%) mixed forms of AIT prevailed (43 patients, 71.6%). Estimated mean time at the diabetes group-based education and in 57% (O80%) 2 years later. for AITD was 3.8G0.33 years; estimated cumulative incidence was 25% at Conclusions 1 year, 50% at 2 years and 75% at 5 years of treatment. Patients from The quality of the organization of diabetes care was good with high scores of iodine-deficient areas developed thyroid dysfunction significantly more appearance in the diabetes clinic and measurement of clinical variables. The frequent (25% at 0.5 years, 50% at 2 years and 75% at 4 years) and quality of clinical results was good concerning glycaemic control while, quality earlier (2.2G0.3 years) as compared to those from iodine sufficient areas goals for the management of blood pressure and cholesterol values were not (25% at 1.5 years, 50% at 3 years and 75% at 7 years), mean time 4.2G0.4 accomplished. years, PZ0.001, log rank Mantel-Cox. Patients with TPO Ab R 100 IU/ml developed thyroid dysfunction significantly more frequent (25% at 0.75 years, 50% at 1 year and 75% at 2.5 years) and earlier (2.2G0.7 years) as compared to those with TPO Ab ! 100 IU/ml (25% at 1.1 years, 50% at 3 years and 75% at 5 years), mean time 3.9G0.5 years, PZ0.046. No differences regarding age, gender, cumulative amiodarone dose were P234 noticed. Cardiac autonomic neuropathy in relation to some components of Conclusion metabolic syndrome in newly diagnosed type 2 diabetic patients Iodine deficiency and thyroid autoimmunity are the main risk factors for Ramaz Kurashvili, Givi Kurashvili, Liana Tsutskiridze, Elena Shelestova & amiodarone-induced thyroid dysfunction in Romania. Mzia Dundua Georgian Diabetes Center, Tbilisi, Georgia.
Background and aims Components of metabolic syndrome (MS) carry an increased risk for cardiovascular disease (CVD). People with abnormal glucose regulation are more prone to develop complications. At diagnosis 20–30% of type 2 diabetic (T2DM) patients (pts) already have neuropathy-one of the most dangerous P236 complications. Cardiac autonomic neuropathy (CAN) is associated with five-fold risk of mortality. Our aim was to study possible relation between CAN and some Changes in glucose profiles in fasting patients with type 2 diabetes components of MS in newly diagnosed T2DM pts. mellitus during Ramadan: analysis of CGMS data in patients in the UAE Materials and methods 1 2 4 We observed 33 T2DM pts with Grade 1/2 arterial hypertension (AH) (ESH/ESC Nader Lessan , Ilham Saadane , Al-Mousawi Haidar & Abdullah AbdulRidha3 Guidelines), increased BMI, but without known CVD, ketoacidosis, alcoholism 1 2 and/or liver disease. males/females-21/12, mean age-47.5G4.8 years.; mean AlZahra Hospital, Sharjah, United Arab Emirates; Department of Internal HbA1c-8.1G2.04%; mean BMI-29.6G3.3 kg/m2). Ewing’s standard reflex tests Medicine, Ma´xima Medisch Centrum, Eindhoven, The Netherlands; 3School of Medical Physics and Engineering, Eindhoven, The Netherlands; were performed; severity of CAN was evaluated according to Jermendy et al. 4 1995. Lipid profile, resting blood pressure (BP), pulse pressure (PP) and heart rate University of Sharjah, Sharjah, United Arab Emirates. (HR) were assessed. Results Introduction Response CAN reflex tests were normal in 15 cases (45.4%); 13 pts (39.4%) had Many Muslim patients with diabetes observe dawn to dusk fasting during the mild, and 5 (15.1%) – moderate CAN. No severe CAN was registered. There was month of Ramadan. In an observational prospective study, we have used ! positive correlation between prevalence of CAN and HbA1c (P 0.001); CAN continuous glucose monitoring system (CGMS) to investigate the changes in ! ! and mean heart rate (P 0.001), CAN and mean SBP/PP (P 0.05). Only 7 pts glucose profiles amongst Muslim patients during Ramadan fasting. G had normal lipid profile. High total cholesterol levels (mean 5.59 0.84 mmol/l) Methods G were registered in 18 cases, elevated LDL levels (mean 3.86 1.10 mmol/l)-in 4 CGMS was applied to patients with type 2 diabetes mellitus (nZ14) attending G pts; low HDL levels (mean 0.89 0.69 mmol/l)-in 21 pts; high triglycerides AlZahra Hospital Sharjah for three consecutive days, before (non-fasting) G (mean 2.91 0.54 mmol/l)-in 8 pts. No statistically evident correlation was and then during Ramadan (fasting). Necessary changes to timing and dosing of observed between CAN severity and lipid profile indices. medication were made. Two CGMS curves were constructed by pooling Conclusion complete individual 24 h glucose datasets in fasting and non-fasting periods. CAN was registered in 54.5% of patients; compared to general population For each period, area under the curve (AUC), low blood glucose index (LBGI) abnormal lipid profile indices were observed more frequently (78.9%) in the study and high blood glucose index (HBGI) were calculated using methods previously population. We can presume, that in newly diagnosed T2DM hyperglycemia, that described. For non-diabetic subjects the same procedure and analyses were may be asymptomatic and not treated for years, plays more important role in CAN performed. development than lipid disorders. Results Among the diabetic patients studied (3 female, 11 male, age 45.2G7.4 HbA1c 7.8G2.0%, BMI 30.9G4.1 kg/m2) and also amongst non-diabetic subjects (nZ2), there were no significant differences in AUC for glucose curves during fasting (1389 mmol/l!5 min daytime, 1354 mmol/l!5 min night-time) and non-fasting (1346 mmol/l!5 min daytime, 1432 mmol/l!5 min night-time) periods. Mean glucose profile during fasting was characterized by a small peak in P235 early morning (corresponding to pre-dawn meal), lower glucose for part of the Cumulative incidence, timing and risk factors for thyroid dysfunction in day and a rapid rise in glucose level with a large peak in the evening (evening 144 Romanian patients treated with amiodarone meal). LBGI in both fasting and non-fasting periods were below 4. HBGI was Raluca-Alexandra Trifanescu, Simona Fica, Oana-Gabriela Ion & higher in the evening during Ramadan. Mihail Coculescu Conclusion ‘Carol Davila’ University of Medicine and Pharmacy, Bucharest, Romania. During Ramadan fasting, in the group studied there was a common problem with hyperglycaemia after the evening meal; hypoglycaemia occurred rarely. Major emphasis on dietary advice and a more appropriate adjustment in Aim antidiabetic treatment could help in achieving better glycaemic control with To assess cumulative incidence and risk factors for amiodarone-induced thyroid Ramadan fasting. dysfunction (AITD) in a large cohort of Romanian subjects.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P237 P239 Diabetic ketoacidosis in two periods: XX–XXI centuries Subclinical alterations of blood pressure associated to clasical Laura Fajar Rodrı´guez, M Concepcio´nPa´ramo Ferna´ndez, Reyes cardiovascular risk factors in patients with type 1 diabetes Luna Cano, Anna Castera`s Roma´n, Beatriz Mantin˜a´n Gil, Javier De la Francisco Vı´lchez-Lo´pez, Florentino Carral-Sanlaureano & Fuente & Ricardo Vı´ctor Garcı´a-Mayor Manuel Aguilar-Diosdado Hospital Xeral, Vigo, Spain. Universitary Hospital Virgen De La Victoria, Malaga, Spain.
Despite advances in the management of last years, diabetes and its complications Objectives are still the most frequent cause of admission in Endocrine Departments. To evaluate the prevalence of subclinical hypertension detected by ambulatory Nowadays, in our Hospital, 60% of admissions are due to Diabetes, and more than blood pressure monitoring (ABPM) and its relationship with some clinical and a half of these are diabetic ketoacidosis (DKA) (35.4%). epidemiological factors in normotensive and normoalbuminuric patients with Objective type 1 diabetes. Analize DKA episodes in our medical area in the last 12 years and compare them Patients and methods divided in two periods. Transversal study that included patients with type 1 diabetes, older than 18 years, Methods with clinic blood pressure lower than 130/80 mmHg and absence of Divide DKA episodes in two periods of 6 years: A: XX century (January 95– microalbuminuria. Twenty-four hours blood pressure monitoring was performed December 00) and B: XXI century (January 01–December 06) according to ADA (SPACELABS 90217). We considered normal ABPM those with mean systolic diagnostic criteria. We retrospectively analyzed medical charts. and diastolic blood pressure (sBP and dBP) over 24 h and daytime lower than Results 130/80 mmHg and over night-time lower than 120/70 mmHg. Subjects with a A (XXc): 117 episodes (56 patients); Type 1 diabetes 95.7%; Mean age: 26.48G nocturnal fall in either sBP or dBP of less than 10% of daytime values were 15.26 years; Gender: 59% men; Precipitating factors: infections 32.2%, classified as non-dippers. inadequate insulin or diet 28%, drugs 5.1% corticoids 0.8%, unknown cause Results 33.1%, other 0.8%; DKA- new onset diabetes 12%; evolution of disease Eighty-five type 1 diabetic patients (55% women) aged 27.9G6.1 years, with a (months) : 102.03G81.08; pH: 7.11G0.11; HCO3: 9.79G4.4; Glycemia: 522.62G disease duration of 12.3G6.5 years. Mean HbA1c since diagnosis was 8.3G 204.71; Intensive care unit assistance: 6.8%; Admission days: 9.88G6.9. 1.4%. In 32% of patients (nZ27), mean sBP or dBP was altered over daytime and B (XXIc): 108 episodes (60 patients); Type 1 diabetes 92.6%; Mean age: 31.8G 41.6% of them (nZ36) were non-dippers. Blood pressure burden was more 16.25 years; Gender: 61.1% men; precipitating factors: infections 27.1%, inadequate prevalent in men. BMI was higher in patients with mean sBP elevated over insulin or diet 30.8%, drugs 14%(PZ0.02), corticoids 0.9%, unknown cause 22.4%, daytime (26.4G3.4 vs 23.5G2.7 kg/m2, P: 0.002). Non-dippers showed worse other 4.7%; DKA- new onset diabetes 6.5%; evolution of disease (months): 134.68G metabolic control since diagnosis (HbA1c 8.6G1.4% vs 7.9G1.4%; PZ0.046). 107.7; pH: 7.10G0.12; HCO3: 9.04G3.94; Glycemia: 569.51G225.54. Intensive HDL-cholesterol level was lower and triglycerides level higher in subjects with care unit assistance: 12%; Admission days: 9.01G8.3. altered sBP or dBP over daytime (HDLc: 55.9G14.4 vs 66.8G13.8 mg/dl, P: Conclusions 0.003; TG: 97.9G52.5 vs 65.7G13.5 mg/dl, P: 0.003). We observe an increase in drug abuse as a precipitating factor for DKA in the last Conclusions years, however we haven’t demonstrated other differences in clinic and (1) Normoalbuminuric and normotensive type 1 diabetic patients present high biochemical DKA episodes profile. prevalence of subclinical alterations of blood pressure so ABPM is appropriate to detect them. (2) Burden BP was more frequent in men, in patients with elevated BMI, with worse metabolic control and lipid profile. Association of altered ABMP and classical cardiovascular risk factors suggests that cardiovascular risk factors should be treated soon and intensively, as in type 2 diabetes.
P238 Endothelin-1 and diabetes: influence of cronic metabolic control P240 Villar Vicente, Cancer Minchot, Gonzalez P de Villar, Canovas Molina & Cognitive dysfunction in diabetics: can we predict it, can we protect Rodriguez Robles them? Hospital Fuenlabrada, Madrid, Spain. Marek Derkacz & Krzysztof Marczewski John Paul II Hospital, Zamosc, Poland. Background Diabetes mellitus leads to endothelium dysfunction and an accelerated The aim of this work was to estimate chosen cognitive functions in diabetics and progression of atherosclerosis. Vascular complications of diabetes mellitus can to investigate possible correlations between cognitive abilities and chosen clinical affect not only large and medium arteries resulting in coronary heart disease and and biochemical parameters. peripheral arteries diseases, but also small vessels leading to retinopathy and The research was conducted among 122 patients with diabetes type 1 or 2 and 140 nephropathy. clinical healthy people. Cognitive tests such as MMSE test, Clock Drawing Test, Endothelin-1 is mainly synthesized by the vascular endothelial cells and acts on Trial Making Test were applied. the vascular smooth muscle. Because of its vasoconstrictor and mitogenic effects In almost 40% of examined diabetics, the significant but mild cognitive it plays a role in the development of vascular diseases. In diabetes mellitus impairment was noticed. Cognitive functions impairment and dementia were atherosclerosis is accelerated. We summarize the available data of the role of only observed in people over 50 and were more likely to occure in patients with endothelin-1 and ANF, in type 1 and type 2 diabetes mellitus and the development diabetes type 2. It seems, that diabetes can mostly influence visuo-spatial of diabetic complication. functions, attention, psychomotor velocity and recent memory. The better results Methods and patients in people with good metabolic control suggest that deficits in cognitive functions We analysed 21 diabetic patients, 8 woman and 13 men, with ages (XCDS) are strongly associated with degree of metabolic control such as HbA1c 61.3G12.6 years and 8.4G9 years of diabetes evolution. Two were diabetic 1 (PZ0.012468), total cholesterol (PZ0.029565), HDL (PZ0.022713) and LDL and 19 type 2. The control group were 34 subjects. ET1 and ANF were measured (PZ0.038056). The significant impact on cognitive deterioration had a period by RIA. from stating the diagnosis (P!0.000001), presence of chronic complications Results (P!0.000001) and the social and demographic factors like education There were no statistically significant differences between ET-1 and Hba1c levels. (P!0.000001). Protective effect of the longer period of education, young age (rZ0.21; PZ0.24).Neither were observated correlation between ANF levels and and place of living was stated. Cognitive impairments were more likely to occur Hba1c (rZ0.05; P: 0.79) nor between ANF and ET-1 (rZ0.16 years PZ0.43). in patients living in the country but the young age of patients (P!0.000001) was a There were a weak correlation between microvascular disease and ET-1 level protective factor. The relationship between cognitive function quality and BMI (although not statistically significant), but not with ANF levels. (PZ0.004118) was confirmed, but it was determined more by the height Conclusion (PZ0.00019) than weight of examined patients (PZ0.632958). ET-1 and ANF levels not seems to be affected only by metabolic control of It is supposed that in diabetic patients over 50, there is a need to estimate their diabetes, measured by Hba1c levels. It is possible that other factor could also cognitive abilities and taking into consideration eventual dysfunctions in the plan influence these endothelium dysfunction markers. of treatment and education.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P241 monocytes did not differ among A1 and A2 groups and was significantly lower in Iliofemoral arterial occlusion in type 2 diabetics shortens life duration those both than in controls. There were no significant correlations between CD36 to the greatest extent: 10 years follow up study expression and BMI, WHR and IR indices. Dragan Tesic1, Svetolik Avramov2 & Pavle Pantelinac1 Conclusions 1Clinic of Endocrinology, Diabetes and Metabolic Diseases, Novi Sad, Expression of scavenger receptor CD36 on monocytes in obese women is Serbia; 2Clinic of Vascular Surgery, Novi Sad, Serbia. significantly lower than in lean individuals. IR indices in obese women show no significant influence on CD36 expression. Obesity significantly reduces CD36 expression and coexisting IR has no infuence on CD36 expression. Background and aim We have sought to determine factors associated with age at death in patients with type 2 diabetes (T2DM) investigated for peripheral arterial disease (PAOD). Materials and methods There were nZ167 T2DM, 140 with PAOD(G1-4) and nZ27 Controls; patients P243 were monitored from Jan-1997 till Dec-2006. CW-Doppler examination and segmental pressures showed: 35pts with crural PAOD (G1), 28 popliteocrural Gestational diabetes has no additional effect on plasma thrombin- (G2), 36 femoropopliteal (G3) and 41 iliofemoral (G4). G1-4 and Controls were activatable fibrinolysis inhibitor antigen levels beyond pregnancy comparable in age and diabetes duration. Baris Akinci, Tevfik Demir, Saba Saygili, Serkan Yener, Inci Alacacioglu, Results Fatih Saygili, Firat Bayraktar & Sena Yesil At the begining there was no difference either in their age or the duration of Dokuz Eylul University, Izmir, Turkey. the diabetes for G1-4 and Controls (65.9G9.2 vs 66.4G9.3, P 0.72; 16.8G8.1 vs G G 18.2 7.4, P 0.27). However at the end G1-4 died earlier (69.4 8.9) versus Pregnancy is a prothrombotic condition with increased levels of several G Controls (74.1 7.4; P0.045). At the end of this study, only 10 out of 167pts with circulating coagulation factors. The aim of the present study is to investigate 2 ! PAOD (5.9%) and 7 out of the 27 Controls (25.9%) (X , P 0.001) were the effect of gestational diabetes on plasma thrombin-activatable fibrinolysis alive. Comparison of G1-4 subgroups and Controls concerning age at death: G1 inhibitor (TAFI) antigen levels. Z (P 0.85), G2 (P 0.11), G3 (P 0.07), G4 (P 0.01). T-test between G4 (n 21 died Plasma TAFI and PAI-1 antigen levels were measured in 26 pregnant women with Z G G pts) and Controls (who died, n 20): 67 8.4 vs 74.1 8.95, P 0.01, at the time of gestational diabetes, 25 pregnant women with normal glucose tolerance, and age G G ! 9 G death; Lec 9.4 2.5 vs 7.3 2.3 10 /l, P 0.05; insulin dependens after 12.8 7.7 matched 24 non-pregnant women with no history of gestational diabetes. G 2 vs 18.8 7.9 years, P 0.05. X test: male 76 vs 52%, P 0.04; stroke 24% vs 10%, Increased plasma TAFI antigen levels were found in pregnant women compared O ! P 0.03. NDS(neuropathy disability scor) 4 86% vs 60%, P 0.01; smoking to non-pregnant controls. However, no statistically significant difference in TAFI ! 90% vs 40%, P 0.01. In univariate analysis of both G4 and Control groups antigen levels was observed between women with gestational diabetes and ZC ! shorter life expectancy was connected with: HDL (r 0.41, P 0.01), tg/HDL pregnant controls. Plasma PAI-1 antigen levels were higher in gestational ZK ZK ZC (r 0.32, P 0.04), BMI before DM (r 0.28 P 0.04), DM begining (r diabetes than pregnant and non-pregnant controls. ! ZC ! 0.63, P 0.01), IRI (isnulinemia) 9 h (r 0.40, P 0.01), age starting insulin We suggest that pregnancy is associated with enhanced coagulation and impaired ZC ! ZC ! therapy (r 0.87, P 0.01); Thigh segmental pressure (r 0.42, P 0.01), fibrinolysis. Despite increased PAI-1 antigen levels associated with gestational ZK ! cigarette number (r 0.54, P 0.01). In multiple logistic regression analysis diabetes, the effect of gestational diabetes on TAFI antigen levels is lacking. statistically significant remaind: shorter DM duration, earlier insulin dependance and number of cigarettes per day. Conclusion PAOD, which reduced the life span most significantly was noticed in iliofemoral region; it was characteristic of diabetics whose disease started at earlier age, who were insulin restistant (tg/HDL) and whose pancreas was not as potent (IRI9h). P244 Early introduction of rapid insulins is a very speculative therapeutic option. Psychological symptoms and quality of life among diabetic patients: a comparative study Mosaku Samuel, Kolawole Babatope, Mume Celestine & Ikem Rosemary Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria.
P242 Objective Influence of obesity and insulin resistance on scavenger receptor CD36 The aim of this study was to compare psychological symptoms between diabetic expression on monocytes in young women patients, asthmatics and healthy individuals and also to determine the effect of Justyna Kuliczkowska-Plaksej, Grazyna Bednarek-Tupikowska, these and other variables on quality of life among diabetes patients. Alicja Filus & Andrzej Milewicz Method Department of Endocrinology, Diabetology and Isotope Treatment, For each respondent the questionnaire on socio-demographic and clinical Wroclaw Medical University, Wroclaw, Poland. variables was completed. Each respondent also completed the General Health Questionnaire (GHQ 30), Zung’s Self Rating Depression Scale and, the State Trait Anxiety Inventory (STAI 1). All diabetic patients also completed the Introduction Diabetic Well-Being Questionnaire. Mechanisms by which visceral obesity and insulin resistance (IR) contribute to Results atherogenesis are complex and not entirely known. One of the atherogenic factors Depression was more prevalent among diabetic patients (20%) compared to involved in foam cells formation is scavenger receptor CD36 expressed on asthmatics (12%) and healthy individuals (4%), while anxiety was more prevalent monocytes, endothelial cells, adipocytes and platelets, participating in oxidized among asthmatics (34%) compared to diabetics (20%) and healthy individuals LDLs absorption and foam cells formation – processes that initiate atheroslerosis. (8%). Predictors of depression include early age of onset of diabetes, poor Many factors can influence the expression of receptor CD36. glycaemic control, and the presence of co morbid medical conditions. Factors that Aim correlated significantly with diabetic general well-being include depression, To assess the impact of type of obesity and IR on CD36 expression on peripheral anxiety, duration of diabetes, fasting blood glucose level and presence of co blood monocytes. morbid medical conditions. Depression and the presence of co morbid medical Materials and methods conditions significantly predicted a low quality of life. The study population consisted of 75 women aged 25–45 years was divided into 3 Conclusion groups: A1 – 30 obese women with IR, A2 – 30 obese women without IR and control Psychological factors have significant effects on the diabetic patients’ quality of life. group C – 15 nonobese women. Physical examination included body mass, body mass index (BMI), waist and hip circumferences and waist to hip ratio (WHR) evaluation. CD36 expression was evaluated using flow cytometry. Oral glucose tolerance test (OGTT) with concomitant insulin evaluation was performed. Glucose concentration was measured using enzymatic method and insulin with chemi- fluorescence method. IR (HOMA, FIRI) and insulin sensitivity (QUICKI) indices P245 were estimated. Correlation between inflammation markers and plasma fasting glucose Results in overweight and obese women BMI, WHR, total insulin and total glucose levels during OGTT, HOMA and FIRI Faruk Kutluturk1, Taner Bayraktaroglu2, Adil Azezli3 & Yusuf Orhan3 were significantly higher in A1 group than in groups A2 and C. In contrast, QUICKI 1Gaziosmanpasa University, Tokat, Turkey; 2Zonguldak Karaelmas was significantly lower in group A1 than in A2 and C. Expression of CD36 on University, Zonguldak, Turkey; 3Istanbul University, Isatanbul, Turkey.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Introduction decreased significantly. Both mothers were sucessfully transferred to Elevated levels of the inflammatory markers are associated with increased risk for glibenclamide as well. CVD and diabetes mellitus. There is accumulating evidence indicating that Summary inflammatory markers as C-reactive protein (CRP) is associated with insulin In this family, a rare genetic form of neonatal diabetes with neurological resistance. The aim of the study is to evaluate the correlations between serum development delay and heterogenous genotype-phenotype correlation occurred in inflammatory markers and plasma fasting glucose (PFG) in overweight and obese combination with a primarily described SUR 1-mutation. women. Methods Overweight (25!BMI!30 kg/m2) and obese (BMIO30 kg/m2) 2846 women were enrolled into the study. Anthropometrical parameters were measured. Leukocyte, CRP, ferritin and sedimentation rate were evaluted. Subjects were P247 measured during minimum 12 h fasting period. The subjects were divided into Continuous subcutaneous insulin infusion with U-500 insulin is better Z ! two groups: Group 1 (n 1982); women with PFG 100 mg/dl, Group II than pramlintide in highly insulin resistant patient with type 2 diabetes Z R (n 864); women with PFG 100 mg/dl. Indrajit Talapatra, Ann Ollerton & IPM O’connell Results Royal Albert Edward Infirmary, Wigan, UK. CRP levels were higher with group II than in Group I (6.13G4.34 vs 5.2G 3.09 mg/l; PZ0.012). Serum ferritin levels were higher Group II than in Group I (50.10G46.68 vs 37.51G35.26 ng/ml; P!0.001). Leukocyte count and We describe a 37-year-old woman with a BMI of 32 kg/m2 who presented with eritrocyte sedimentation rate were higher Group II than group I (7.73G3.71 vs poorly controlled type 2 diabetes (HbA1c of 10.3%). She was requiring 138 units 7.40G1.85/mm3, PZ0.002 and 26.67 vs 22.33 mm/h, PZ0.001). The results are of insulin (Aspart 20, 24 and 30 units pre meal and glargine 64 units at night documented on Table. daily). She previously had diarrhoea with metformin and an allergic reaction to glimepiride. Rosiglitazone was discontinued because of worsening liver function. Her insulin requirement increased in a year to 1650 units daily owing to insulin Table Comparison of inflammation markers within two groups. resistance. She was receiving actrapid 250, 350 and 350 units pre meal and humulin I (changed from glargine) 400 units in the morning and 300 units in the nZ nZ P Parameter Group I ( 1982) Group II ( 864) value evening. She was commenced on U-500 actrapid insulin to ameliorate the Leukocyte (/mm3) 7.40G1.85 7.73G3.71 0.002 discomfort in sustaining daily insulin injection of 16.5 ml. Subsequently she was CRP (ng/ml) 5.20G3.09 6.13G4.34 0.012 tried on pramlintide (symlin) 30 mcg s/c before each meal containing at least 30 g Ferritin (ng/ml) 37.51G35.26 50.10G46.68 !0.001 of carbohydrate, while still on insulin. Four months later the patient was on U-500 G G ESR (mm/h) 22.33 12.08 26.67 15.58 0.001 actrapid 250, 300 and 250 units pre meal and humulin I 250 units in the morning and 200 units in the evening with pramlintide of 180 mcg before each meal (containing at least 30 g of carbohydrate). She lost 5 kg following administration Conclusions of pramlintide with only slight reduction in her insulin requirement. Her HbA1c This study shown that increased concentrations of PFG are associated with was 8.2%. Thereafter she was commenced on CSII (continuous subcutaneous elevated inflammatory markers in overweight and obese women. Inflammation is insulin infusion) while still on pramlintide. Later she came off pramlintide and is closely associated with endothelial dysfunction and cardiovascular risk factors. currently on CSII alone requiring much lesser dose of insulin:U-500 actrapid 1.6 The Women’s Health Study has shown that high CRP levels predict type 2 units/h between 0 and 5 h, 1.5 units/h between 5 and 8, 3 units/h between 8 and 9 diabetes. The investigators also have shown that high CRP levels are predictors of and 4.7 units/hour at other times of the day (total daily basal dose: 430 units) with the development of type 2 diabetes. a bolus dose of 0.6 units for every 10 g of carbohydrate and with better control of her diabetes(HbA1c 7.5%).
P248 P246 Systematic exercise can further improve glycaemic control and physical Phenotypically heterogenous neonatal diabetes within one family fitness in physically active women with type 2 diabetes caused by a new mutation in the sulphonylurea receptor SUR1 Kalliopi Kotsa2, Anna-Maria Touvra1, Christos Zois1, Ioannis Yovos2 & (ABCC8) Savas Tokmakidis1 Dorothee Deiss1, Olga Kordonouri2, Walter Burger1, Mathias Herr1, 1Department of Physical Education and Sport Science, Democritus Sarah Flanagan3, Sian Elliard3, Andrew Hattersley3 & Klemens Raile1 University of Thace, Komotini, Greece; 2Department of Endocrinology, 1Center of Paediatric Endocrinology and Diabetology, Charite´, Campus Ahepa Hospital, Aristotelean University, Thessaloniki, Greece. Virchow-Klinikum, Berlin, Germany; 2Childrens Hospital Diabetes Center for Children and Adolescents auf der Bult, Hannover, Germany; 3Peninsula Medical School, Exeter, UK. Background and aims Exercise intervention programs have been proved beneficial for inactive type 2 diabetes patients by improving physical fitness, anthropometric parameters, Background glycaemic control and lipid profile. The aim of this study was to examine the Neonatal diabetes (ND) is a rare, mostly sporadic disorder diagnosed within the additional benefits of a supervised systematic exercise program in physically first 6 months of life that can either be transient or permanent. We report on a active postmenopausal women with type 2 diabetes. family of four phenotypically heterogenous subjects with ND characterized by a Materials and methods new heterozygous missense mutation (D212I) in exon 5 of the ABCC8 gene Ten physically active, postmenopausal women with type 2 diabetes under medical encoding the SUR1 subunit of the KATP channel. treatment (57.4G4.8 years old; 10.6G6.1 years diabetes duration; 3.3G3.0 years Patients of training experience) participated in a supervised systematic program (4 In each of small-for-gestational-age (SGA) female monocygous twins, ND sessions per week for 6 months) combining aerobic (60–80% maximum heart occurred at the age of 3 months requiring transient insulin therapy for 4 months. rate) and strength training (70% 1 repetition maximum). Physical fitness, At the age of 14 years, clinical diabetes relapsed and insulin treatment had to be anthropometric and biochemical parameters were measured at baseline and after 6 restarted. Both twins got one offspring, each. The daughter of the first twin was months of exercise. diagnosed with ND at the age of one month and treated with insulin using Results continuous subcutaneous insulin infusion (CSII) until 6 months with continuous Systematic exercise improved physical fitness (VO2 peak (ml/min per kg): 17.7G remission thereafter. Learning disability was diagnosed at the age of 6 years. The 3.4 vs 19.9G3.3; power (W): 128.6G30.4 vs 160.7G24.4; muscle strength (kg): son of the second twin was born with SGA and had postpartal hyperglycaemia. upper 26.3G6.9 vs 35.6G4.2, lower 26.9G8.0 vs 35.6G5.0; P!0.05). Exercise CSII was started at day 11 after birth. Furthermore, neurological features with training decreased HbA1c (7.6G0.5 vs 6.7G0.8%; P!0.05) and triglycerides motor and social development delay were present. Molecular genetic analysis was (124.7G44.8 vs 92.6G29.9 mg/dl) whereas there was no change on total performed reveiling an identical new mutation in all subjects. After molecular cholesterol, HDL, LDL and fibrinogen. Furthermore, body mass was reduced diagnosis, treatment of the boy was transferred from insulin (HbA1c 5.8%) to oral (81.5G8.6 vs 79.0G9.7 kg; P!0.05), as well as waist circumference (102.8G sulfonylureas. Fast reduction of insulin and switch of therapy to high-dose 11.8 vs 99.8G11.1 cm; P!0.05). glibenclamide was done for the first time completely under ambulatory conditions Conclusion using real-time continuous glucose monitoring. Metabolic control improved Supervised systematic exercise combining both aerobic and strength training (HbA1c 5.3%) and glycaemic fluctuations as well as frequency of hypoglycaemia significantly improves oxygen consumption, power and muscle strength, has
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 additional benefits on glycaemic control, body composition and lipid profile and Objectives therefore ameliorates the health status of physically active women with type 2 To know the frequency of hypertension in a group of males with type two diabetes diabetes. without the antecedent of hypertension, by means of ambulatory blood pressure monitoring (ABPM). To assess the possible differences between the subjects with and without hypertension in age, time of duration of diabetes, obesity and the features of metabolic syndrome. Methods P249 We included consecutively 55 males with type two diabetes without the Early major complications at diabetics in coronary care unit antecedent of hypertension. We made an anthropometric and analytic evaluation Erduan Sefedini1, Kocinaj Dardan1, Gashi Masar1, Berisha Venera1, and an ABPM during 24 h. For the diagnostic of hypertension we used the ‘VII Berisha Merita2, Ramadani Naser2 & Kocinaj Allma1 Report of the Joint National Committee on prevention, detection, evaluation and 1University Clinical Center of Kosova, Prishtina, Kosova, Albania; treatment of high blood pressure’. For the diagnosis of metabolic syndrome we 2National Institute of Public Health of Kosova, Prishtina, Kosova, Albania. used the ‘NCEP ATP III guidelines’. Results We detected high blood pressure in 20 patients (36.4%). The most part (50%) had Early and late complications of acute myocardial infarction are common at elevated systolic and diastolic rates, 35% only systolic and 15% diastolic. The diabetics compared to nondiabetics. The blood sugar level can be one of relevant blood pressure reduction during sleep was different between the groups with and factors to determine the outcome of patients with acute coronary syndrome. without hypertension: dipper (62 vs 20%), non dipper (60 vs 32%) and riser (20 vs The aim of our study is to determine the early hospital mortality at diabetics 6%), c2 PZ0.01. The patients with hypertension had metabolic syndrome in 90% experiencing an acute coronary syndrome. vs 48% of the patients without it (c2 P!0.01). The data were collected in the coronary care unit of our Institution, for the Conclusions subgroup of diabetic patients presenting with an acute coronary syndrome as an One third of diabetic patients without antecedent of hypertension had it, inclusion criteria. During analyzed period the total number of patients diagnosed discovered with ABPM. The most common was the increment of both systolic as acute myocardial infarction was 465, male/female ratio was 2.72, with the most and diastolic. The blood pressure reduction during sleep was pathologic in 80% of presented group age of the analyzed 56–65 years old. The early death during first patients with hypertension and 33% without it. The most part of the patients with days of hospitalization for an acute coronary syndrome occurred in 56 (12.04%) high blood pressure had metabolic syndrome. patients, 12.5% of whom were diabetics. Diabetes mellitus is not only a risk factor of coronary heart disease but a very important one in determining the occurrence of fatal complications at acute coronary syndromes.
P250 Nebivolol in diabetic patients with chronic heart failure P252 Tinatin Akhobadze, Ramaz Kurashvili, Liana Tsutskiridze, Concentrations of steroid hormones different from estradiol may Elena Shelestova, Mzia Dundua & Lela Dzneladze constitute risk factors of coronary artery disease in women Georgian Diabetes Center, Tbilisi, Georgia. Zbigniew Sablik1, Anna Samborska-Sablik2, Jan Henryk Goch1 & Krzysztof Kula3 1I Department of Cardiology and Cardiac Surgery of Medical University of Background and aims Lodz, Lodz, Poland; 2Department of Emergency Medicine and Disaster The aim of this study was to study the effect of Nebivolol on clinical course and Medicine of Medical University of Lodz, Lodz, Poland; 3Department of heart rate variability (HRV) parameters in type 2 diabetes (T2DM) patients (pts) Andrology and Fertility Medicine of Medical University of Lodz, Lodz, with coronary heart disease (CHD) and Chronic heart failure (CHF) of III-IV FC. Poland. Materials and methods Participants were 35 T2DM pts with CHD and CHF/ III-IV FC. The pts were divided into 2 groups (Gr.) Gr.1 (nZ15, 10m/5f, mean age 59G7 years) on basic Abstract therapy. Gr.2 (nZ20, 13m/7f, mean age 61G4.5 years) – Nebivolol was added to The aim of our research was to find different from estradiol steroid hormones the basic therapy. Treatment was initiated with 2.5 mg/daily, dose increased that changes in their concentrations may be risk factors of coronary artery to 5 mg/daily. Nebivolol was administered for 3 months. Echocardiography, to disease (CAD) in women. study end-diastolic diameter of LV, EF and FS and Holter ECG to assess Material and methods myocardial ischemia (MI) episodes, HRV and arrhythmia were performed. YM-CAD-38 menstruating women in the age of 42.6G3.4 years with past Results myocardial infarction and angiographically proven arteriosclerosis. YM-H- 15 In both groups treatment resulted in improvements in CHF course, reflected by healthy menstruating women in the age of 41.1G3.5 years. PW-CAD- 26 decrease in FC of CHF. EDV evidently dropped in both groups, though for Gr.2 it postmenopausal women in the age 59G7 years with angiographically proven was more pronounced, than for Gr.1 (20.3% vs 17.3%) EF and FS increased by CAD. 75% of them suffered from myocardial infraction. PW-H- 17 healthy 21.3% and 23.8%, respectively (Gr.1) and 26.1 and 29.9% respectively (Gr.2). postmenopausal women in the age 66G9 years. From all of the women venous The use of Nebivolol resulted in improvement of HRV parameters – SDNN blood samples were taken ones at 0800, in 4–7 day of menstrual cycle from (PZ0.000) and triangular index (PZ0.000). HRV parameter improvement was women in the reproductive age. Using immunological methods blood significant in Gr.2 when compares to Gr.1. SMI episodes also became less concentrations of estradiol, testosterone, dehydroepiandrosterone sulphate frequent in Nebivolol group. Post-treatment complex ventricular arrhythmias (DHEAS), follicle-stimulating hormone, luteinizing hormone, progesterone and were observed more frequently in Gr.1. than Gr.2 (33.3 vs 20%). cortisol were measured. Conclusion Concentration of the hormones were compared between YM-CAD and YM-H Nebivolol in T2DM pts with CHD and CHF positively effects the clinical course of and between PW-CAD and PW-H. Logistic regression analysis (LRA) was CHF, LV systolic function and ventricular rhythm impairment, decreases MI, applied to find a relation among concentrations of the hormones and occurrence increases HRV parameters. Nebivolol does not deteriorate lipid and carbohydrate of CAD. metabolism makes it possible to successfully use it in T2DM pts with CHD and CHF. Results Testosterone was the only hormone of significantly different concentration between YM-CAD and YM-H (3.5G1.5 vs 2.4G1.0 nmol/l, P!0.014). There was a trend in PW-CAD to higher than in PW-H concentration of cortisol (497G138 vs 414G166 nmol/l, P!0.07) and lower concentration of DHEAS P251 (2.04G2.07 vs 2.77G2.19 mmol/l, P!0.08). In LRA relation to occurance of CAD was revealed for level of testosterone Frequency of hypertension studied by ambulatory blood pressure O3.7 nmol/l in young women (OR 2.5, P!0.021) and for concentration of monitoring in type two diabetes DHEAS ! 2.58 mmol/l in postmenopausal ones (OR 4.8, P! 0.027). Katherinne Garcia-Malpartida, Jesus Yanini-Garcia, Celia Ban˜uls-Morant, Conclusion Eva Sola-Izquierdo, Carlos Morillas-Arin˜o, M Luisa Martinez-Triguero & Elevated concentration of testosterone in young women and diminished level of Antonio Hernandez-Mijares DHEAS in postmenopausal women may constitute risk factors of CAD. Endocrinology Service, Hospital Universitario Dr Peset, Valencia, Spain.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P253 phenotypes. The above data suggest that serum AGEs is a distinct finding The stress-related protein p8 protects beta cells from streptozotocin characterizing only women suffering from PCOS. (STZ)-induced cell death in vitro Gu¨nter Pa¨th, Nikolaos Perakakis, Susanne Ehler, Sandra van Loosen, Marcus Alt, Timm Stahl & Jochen Seufert Division of Endocrinology and Diabetology, Endocrine Research Lab (B9), Department of Internal Medicine II, University Hospital of Freiburg, P255 Freiburg i.Br., Germany. Importance of vasopressin and aldosterone for clinical outcome of patients after cardiac arrest 1 2 4 Within the exocrine pancreas, p8 expression is induced by pancreatitis and Anna Samborska-Sablik , Zbigniew Sablik , Wojciech Gaszynski , Jan Henryk Goch2 & Krzysztof Kula4 protects exocrine tissue from inflammatory damage via inhibition of NFkB. 1 In previous work, we investigated the role of p8 within the endocrine pancreas Department of Emergency Medicine and Disaster Medicine of Medical University of Lodz, Lodz, Poland; 2I Department of Cardiology and Cardiac and characterised p8 as a glucose-dependent mediator of beta cell proliferation. 3 Here we investigate the hypothesis that p8 protects beta cells from cell damage by Surgery of Medical University of Lodz, Lodz, Poland; Department of Andrology and Fertility Medicine of Medical University of Lodz, Lodz, the diabetogenic drug STZ. We investigated native and transiently transfected 4 INS-1E and beta-TC3 beta cells. For transfections, we used a CMV-driven p8 Poland; Chair of Anestesiology and Intensive Therapy of Medical expression plasmid or an empty plasmid control (mock). STZ-induced p8 gene University of Lodz, Lodz, Poland. expression and viability of cells were established with a MTS assay and qPCR using commercially bench-tested primers, respectively. Initially we characterised Aim time and dose response of cell lines to 6, 12, and 24 h STZ. Mouse beta-TC3 (24 h Assessment of possible role of arginine vasopressin (AVP) and aldosterone (Ald), LD50, 5 mM) were substantially more resistant to STZ than rat INS-1E (24 h hormones managing blood pressure and water-electrolyte balance, for clinical LD50, 0.7 mM). In both cell lines, 6 h exposure to STZ dose-dependently state and survival of patents after cardiac arrest (CA). enhances endogenous p8 gene expression to a maximum of about 4-fold at 24 h Material and methods LD50 concentrations. Further increase of STZ dosages continuously reduces p8 Fifty-two patients after CA in the age 62G13 years, 29 patients after out- gene expression indicating that endogenous p8 cannot be induced in lethally of-hospital CA, 23 after in-hospital CA. Twenty-eight patients died after CA damaged beta cells. Furthermore, transient p8 overexpression enhances cell (CA-D), 24 survived (CA-S). In each day after CA clinical state of the patients viability after 24 h exposure to STZ below 24 h LD50 dosages in both INS-1E and was assessed by common scales applied in intensive care: GCS, APACHE II, beta-TC3 about 20% despite only low efficiency of liposomal gene transfer (INS- SAPS II and MODS. Just after CA and in 2 following days at 8.00 a.m. blood 1E, 30–50%; beta-TC3, 10–30%). The protective effect of ectopic p8 expression venous samples were taken from each patient to measure typical laboratory is abolished at dosages higher than 24 h LD50 indicating that enhanced p8 levels parameters and concentration of AVP and Ald. cannot protect lethally damaged cells. In conclusion, these results demonstrate Results that, in beta cells, p8 is a stress-induced factor, which exerts protection against Mean concentration of AVP was higher in CA-D than in CA-S in each day after STZ-induced cell death. Whether p8 mediates its protective effects only via CA. Significant correlations were found among concentrations of AVP in first two stimulation of cell proliferation or also via inhibition of apoptosis is under current days after CA and values of the scales. In CA-D, compared to CA-S, research. concentration of Ald was higher in each day, significantly in the 3rd one after CA (500G507 vs 235G230 pmol/l, P!0.04). Significant relation to fatal outcome was found for concentration of AVPO83 pmol/l, assessed just after CA, in logistic regression analysis (LRA) (ORZ0.23 for survival, P!0.01) and in Kaplan–Meyer survival analysis (SurA) (P!0.02), and for concentration of Ald O222 pmol/l, measured in the 3rd day after CA, in LRA (ORZ0.18 for survival, P!0.02) and in SurA (P!0.04). Conclusions P254 1-AVP is involved in protecting survival in the early stage after CA, Ald plays important role in mechanisms responsible for survival in further stages after CA. Increased serum AGEs is a distinct finding in lean women with PCOS 1 2 3 2-High concentration of AVP just after CA and markedly elevated concentration Evanthia Diamanti-Kandarakis , Ilias Katsikis , Christina Piperi , of Ald in the 3rd day after CA are markers of bad prognosis. Eleni Kandaraki3, Athanasia Piouka2, Athanasios Papavassiliou3 & Dimitrios Panidis2 1Endocrine Section, First Department of Medicine, Laiko Hospital, Medical School, University of Athens, Athens, Greece; 2Division of Endocrinology and Human Reproduction, Second Department of Obstetrics and Gynae- cology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, P256 Greece; 3Laboratory of Biological Chemistry, University of Athens Medical Concentration of interleukins as prognostic factor in patients after School, Athens, Greece. cardiac arrest Anna Samborska-Sablik1, Zbigniew Sablik2, Wojciech Gaszynski3 & Dariusz Piotrowski1 In insulin resistant, young women with PCOS elevated serum AGEs and their 1Department of Emergency Medicine and Disaster Medicine of Medical receptor RAGE have been reported. The present study (approved by the local University of Lodz, Lodz, Poland; 2I Department of Cardiology and Cardiac ethical committee) was undertaken to determine whether increased levels of Surgery of Medical University of Lodz, Lodz, Poland; 3Chair of serum AGEs in PCOS is a distinct finding compared with age- and BMI-matched Anesthesiology and Intensive Therapy of Medical University of Lodz, Lodz, women, presenting the isolated components of the syndrome and whether serum Poland. AGE levels were different among PCOS phenotypes. A total of 193 lean non- insulin resistant women were studied. 100 women diagnosed as PCOS (Rotterdam criteria), and further divided to quartiles of well-defined phenotypes. 68 women The aim of the research was to assess whether concentrations of inflammatory matched for age and BMI with the isolated components of the PCOS phenotype markers in blood of patients after cardiac arrest (CA) are related to clinical state (HYPERZbiochemical hyperandrogenemia only, nZ25; ANOVZanovulation and survival. only, nZ21 and PCOZUS-PCO morphology only, nZ22) were also studied Material and methods along with 25 women, who served as controls. Serum AGE levels as well as the Forty-six patients after CA, 21 after out-of-hospital and 25 after in-hospital CA, in metabolic, hormonal profiles and intravaginal ultrasound were determined in all the age 63G12 years, were enrolled. Clinical state of them was evaluated by subjects. PCOS population phenotypes and controls did not differ in BMI means of Glasgow Coma Scale (GCS) and Acute Physiology and Chronic Health (PZ0.152), waist-to-hip ratio (WHR; PZ0.495), fasting insulin concentration Evaluation II (APACHE II). In the day next to the day of CA (day-1) and in the (PZ0.655) and glucose-to-insulin ratio (GIR; PZ0.320). Total PCOS women following day (day-2) were measured blood concentrations of high specific (exhibited statistically higher AGEs levels (7.96G1.87 U/ml, P!0.001) C-reactive protein (hs-CRP), tumor necrosis factor TNF-alfa, interleukin10 compared with women with isolated hyperandrogenemia (5.61G0.61 U/ml), (Ile-10) and interleukin-6 (Ile-6). 25 patients survived after CA and were anovulation (5.53G1.06 U/ml) and US-PCO (5.26G0.25 U/ml) as well as with discharged from hospital (CA-S), 21 died during hospitalization (CA-D). the controls (5.86G0.89 U/ml). The present study shows, for the first time, that Results women with PCOS had statistically significant elevated serum AGE levels In CA-D patients, compared with CA-S, we found significantly higher compared with women with isolated hyperandrogenia, anovulation and US-PCO. concentrations of hs-CRP (in day-1 19G5vs15G4, in day-2 21G3vs No difference was detected in AGEs levels among the different PCOS 16G5 mg/l, P!0,001) and Ile-6 (in day-1 24.9G19.8 vs 9.2G11.3, in day-2
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
24.2G19.7 vs 6.9G6.8 IU/ml, P!0,001). Concentrations of TNF-alfa were Hypoglycaemia continues to be a difficult condition to treat especially in infants greater in CA-D than in CA-S in day-1 (0.42G0.75 vs 0.18G0.21 IU/ml, and young children who cannot administer treatment themselves. Administering P!0.04). the correct dose of sugar is difficult for several reasons: the child may not want to Concentrations of hs-CRP and Ile-6 were correlated with values of GCS and intake food and it may be difficult to force the child to chew or swallow, it is APACHE II. Using logistic regression analysis significant relation of difficult to identify the quantity of sugar necessary to reach optimal glucose concentrations of hs-CRP and Ile-6 in day-1 and in day-2 with survival after levels. If too much sugar is administered, high levels of blood glucose may result CA was proven. from liver glycogenolysis and, to reduce hyperglycaemia, the patient needs more Conclusion insulin. However if more insulin is administered the child will need more food. Early strong immunoinflammatory reaction, expressed in higher concentrations of This situation produces a ‘vicious circle’ and an alternative therapy is needed. Ile-6, hs-CRP or TNF-alfa, is correlated not only with worse clinical state of The aim of the study was to evaluate the effect of administering small amounts of patients after CA but with diminished survival of them, as well. glucose through the glucose RapidSpraye (GRS) during hypoglycaemia to prevent hyperglycaemic rebound in children with type 1 diabetes (T1D) and to study the efficacy of RGS so as to improve the metabolic control. We designed an open randomized trial in children with T1D aged 1–5 years. Forty-eight patients with T1D, age-group 1–5 years, were randomly allocated into P257 2 groups: (A) RGS in the treatment of early warning signs of hypoglycaemia (10–20 puffs of RGS, 0.5–1 g glucose) during episodes of early symptoms of Cytokines secretion in long-standing diabetes mellitus type 1 and 2: hypoglycaemia; (B) traditional treatment of hypoglycaemia episodes. associations with low-grae systemic inflammation 1 1 2 Parameters of efficacy were: (1) HbA1c at time 0, at 3 months follow-up and at the Krystallenia I Alexandraki , Christina Piperi , Panayiotis D Ziakas , end of the study, (2) features of hypoglycaemia episodes, (3) quality of life. Nikolaos V Apostolopoulos4, Konstantinos Makrilakis5, Vassiliki Syriou2, 3 2 At present 17 patients have been introduced in the study. No adverse effects were Evanthia Diamanti-Kandarakis , Gregory A Kaltsas & observed and treatment with RGS was easily accepted by children and mothers. Anastasios Kalofoutis1 1 Quality of life under the unpleasant circumstances of hypoglycaemia can be Laboratory of Biological Chemistry, School of Medicine, National and improved by the use of RGS. Kapodistrian University of Athens, Athens, Greece; 2Division of Endo- crinology, Department of Pathophysiology, Laiko University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; 3Division of Endocrinology, First Department of Medicine, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; 4Department of Obstretics and Gynaecology, Homerton P259 University Hospital, London, UK; 5Diabetologic Center, First Department Obestatin inhibits high glucose-induced reactive oxygen species of Propaedeutic Medicine, Laiko University Hospital, School of Medicine, production and apoptosis in bovine aortic endothelial cells National and Kapodistrian University of Athens, Athens, Greece. E Arnoletti1, R Granata2, G Alloatti3, E Ghigo2 & G Muccioli1 1Department of Anatomy, Pharmacology and Forensic Medicine, University of Turin, Turin, Italy; 2Department of Internal Medicine, University of Background Turin, Turin, Italy; 3Department of Animal an Human Biology, University Low-grade systemic chronic inflammation has been recognized in diabetes. The of Turin, Turin, Italy. purpose of this study was the assessment of proinflammatory cytokines secretion profile in long-standing diabetes along with the presence of systemic inflammation. Endothelial dysfunction is thought to be a major cause of vascular complications Methods in diabetes. Our research shows that obestatin, a 23-aminoacid amidated peptide Twenty patients with type 1 (T1DM: 7 women, age (GS.E.M.): 30.90G1.93 years, recently identified as a product of the ghrelin gene, inhibited high glucose- duration of disease: 142.47G28.34 months) and 21 patients with type 2 diabetes induced apoptosis in cultured bovine aortic endothelial cells (BAEC). Exposure to mellitus T2DM: 11 women, age: 58.67G3.01 years, duration of disease: 68.32G high glucose concentration (30 mM) for 72 h caused a significant increase in 17.36 months) were studied along with 34 healthy subjects (17 women, age: apoptosis, as evaluated by Hoechst staining, but co-treatment of rat obestatin 53.61G2.48 years). Metabolic parameters were assessed. Serum levels of high (from 10K11 to 10K7 nM) eliminated in a dose–dependent manner high glucose- sensitivity C-reactive protein, interleukin-1b, interleukin-6 and tumor necrosis induced apoptosis in BAEC. Obestatin also protected endothelial cells from high factor-a were determined by ELISA. The number of cytokine-secreting glucose by reducing reactive oxygen species (ROS) production. Blockade of peripheral blood mononuclear cells before and after mitogenic stimulation was adenylyl cyclase and cAMP-dependent protein kinase A signalling prevented the determined by the Enzyme-Linked-Immuno-spot assay. inhibitory effect of obestatin on ROS production. Obestatin also activated Results phosphatidyl inositol 3-kinase (PI3K/Akt) and ERK1/2 pathway, whereas PI3K Patients with T2DM had an adverse metabolic profile compared to patients with and ERK inhibitors counteracted the obestatin anti-apoptotic effect. Finally, T1DM and controls. There was a difference in hsCRP, sIL-6 and TNF-a level saturation binding studies with radioiodinated [125I]-obestatin recognized high- between groups, with higher levels being observed in T2DM and lower levels in affinity (KdZ0.5 nM) specific binding sites in the BAEC cell line, suggesting that controls. T2DM patients were characterized by higher count of cytokine-secreting these sites may be involved in the cytoprotective effect of the peptide. In PBMCs compared to patients with T1DM and controls. Patients with T1DM conclusion, the results of our study demonstrate, for the first time, that obestatin showed a higher count of IL-1b-secreting PBMCs compared to controls. After inhibits both high glucose-induced apoptosis and ROS production in endothelial stimulation with PMA, an increased number of all cytokine-secreting PBMCs cells and suggest that this peptide may have potential in preventing vascular were observed in the studied groups, but this rise was higher in the control group complications in diabetic patients. compared to diabetic groups. Conclusion The present study revealed increased levels of several circulating markers of chronic inflammation in diabetic groups compared to healthy subjects, but the grade of inflammation was higher in T2DM. Furthermore, both groups presented a defect in P260 cytokines production by the PBMCs after stimulation compared to healthy subjects. The presence of low grade inflammation and the abnormal PBMCs function in The high prevalence of testosterone deficiency syndrome and erectile diabetic patients may result in the long-term sequelae of diabetes such as the dysfunctions in the aging men with diabetes mellitus type 2 accelerated atherosclerotic process and the susceptibility to infections. Michal Rabijewski & Wojciech Zgliczynski Department of Enocrinology, Medical Centre for Postgraduate Education, Warsaw, Poland.
Objective P258 The aim of the study was to determine the prevalence of subclinical late-onset Rapid glucose spraye for the management of hypoglycaemia in hypogonadism (SLOH) and erectile dysfunctions in the elderly men with diabetes children with type 1 diabetes type 2. Ekaterina Pronina1, Helen Petraikina1, Michail Antsiferov1, Material and methods Olga Duchareva1, Chiara Guglielmi2, Manon Yeganeh Merola2 & We investigated 51 men mean aged 68.3 years with diabetes type 2 according Paolo Pozzilli2 ADA recommendations. Androgens concentrations, BMI, HbA1C were 1Morozovskaya Children City Hospital of Moscow, Moscow, Russian measured. All of men were treated with oral antidiabetic drugs or insulin. LOH Federation; 2University Campus Bio Medico, Rome, Italy. was expected on the basis of low testosterone concentration (%3.5 mg/l) and the
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 index T/LH%1, while erectile dysfunctions were expected according IIEF score. study was to evaluate the acute effects of atrazine on testicular antioxidant Results systems and on some spermatological parameters in rats. The mean duration of diabetes was 18.4 years. The mean testosterone Atrazine was administered to wistar rats at a dose equivalent to 120 mg/kg or concentration was 4.09G1.4 ng/ml and the mean T/LH index was 0.82G0.29. 200 mg/kg b. wt daily for seven days. The results indicate a decrease in the Seventy-five percent of men presented the criteria of SLOH according the T/LH terminal body weight and food consumption in both treated groups. Testicular and index but only 44% had testosterone levels below 3.5 ng/ml. About 65% patients epididymal sperm number, spermatozoa viability and motility in atrazine treated had IIEF score below 16 points. There was inverted correlation between the T/LH animals decreased significantly. Therefore atrazine treatment provoked a index and duration of diabetes, BMI and age (P!0.02). The mean DHEA-S significant decrease in daily spermatozoal production. The induction of abnormal levels also negative correlated with duration of diabetes and age (P!0.05), but sperms was increased by atrazine. These effects were seen in a dose dependent not with BMI. There was also inverted correlations between testosterone levels manner. While there were no significant effects on lipid peroxidation, superoxide and T/LH index and IIEF score (P!0.005 and P!0.002 respectively). dismutase (SOD) and catalase (CAT) activities and H2O2-generation in the Conclusions atrazine groups, glutathione (GSH) and glutathione-S-transferase (GST) activities In elderly men with diabetes mellitus 2 the prevalence of SLOH is about 75%, in the testis after the last day of treatment showed a significant increase vs control. while ED is about 65% and were more common than in population of elderly men The epithelium of the seminiferous tubules showed normal histology. without diabetes. The T/LH index was more sensitive in these men as the criteria Possibly the dose and duration of exposure was inadequate to induce tissue of diagnosis of SLOH and ED than total testosterone concentrations. In all the pathology or that atrazine have a direct effect on spermatozoa. Our study patients with diabetes mellitus the possibility of SLOH and ED should be has added the information that oral atrazine exposure attributes to alterations investigated. In the other hand, elderly men with SLOH also must be screening to in spermatological parameters without significant effects on the parameters of exclude the symptoms of diabetes and erectile dysfucntions. testicular oxidative stress. This appears not to be mediated by the seminiferous tubules epithelium and may be secondarily related to the restricted food intake and growth rate. Furthermore, our data implicates the GSH/GST status as sensitive markers for atrazine testicular toxicity during short-term exposure. P261 The influence of testosteone replacement therapy on erectile dysfunctions in aging men with testosterone deficiency and diabetes mellitus type 2 Michal Rabijewski & Wojciech Zgliczynski Department of Endocrinology, Medical Centre for Postgraduate Education, Warsaw, Poland. P263 Objective Endocrine disruption in lower vertebrates: Xenobiotic exposure affects The role of testosterone in the anatomy and physiology of erection is becoming testicular structure and biochemical composition of semen in a male clear. Erectile dysfunctions (ED) are very common observed in men with diabetes teleost mellitus type 2 (DM2). The aim of the study was to determine the efficacy of Bodil Korsgaard & Tina Rasmussen testosterone adminisartions in elderly men with ED and DM2. University of Southern Denmark, Institute of Biology, 5230 Odense M, Material and methods Denmark. We investigated 41 men mean aged 65.4 years with late onset hypogonadism according Polish Endocrine Society recommendations and DM2 according ADA Natural and synthetic chemicals such as estrogenic and androgenic compounds recommendations, who had not been treated with PDE5 inhibitors. All men have been observed to contribute to the pool of endocrine disruptors in the effluent received testosterone enanthate in dose of 200 mg. i.m. every second week. water from sewage treatment works and may interfere with the endogenous Durations of treatment was mean 12 weeks. Efficacy of treatment was measured hormonal system regulating reproduction in aquatic organisms. The teleost by the IIEF domain before and after 4 and 12 weeks of treatment. All of men were Zoarces viviparus is a recognized model used in aquatic toxicology due to the treated with oral antidiabetic drugs or insulin. Hypogonadism was expected on the existence of a maternal-fetal trophic relationship with embryos/larvae developing basis of low testosterone concentration (%3.5 mg/l) and the index T/LH%1. in the ovary during a period of approx. 5 months. Results In the present work Z. viviparus males were exposed in a flow through seawater After 4 weeks of treatment 21/41 patients showed improvement in erections. At system to different xenoestrogens and the effect on testicular structure, seminal the and of 4 month 32/41 patients showed improvement in the score on IIEF (from fluid volume, spermatocrit and Sertoli cells was studied. 7.9G3.2 to 12.3G3.4; P!0.05). There were inverted correlations between The xenoestrogenic exposure was observed to severely affect gonadosomatic testosterone levels and efficacy of testosterone treatment and also between index. and testis histology. The testes appeared degenerated with cellular duration of DM2 and IIEF score. abnormalities, increased fibrosis in the interstitium between the seminiferous Conclusions lobules and with abnormal Sertoli cells phagocytising spermatozoa and In elderly men with hypogonadism related to aging (late-onset hypogonadism) spermatids. The normal composition of semen was also affected as observed by and diabetes mellitus 2 after 1 month of testosterone replacement therapy there a decrease in seminal fluid volume and amino acids and a concomitant increase in was a small number of patients in whom treatment results in erectile spermatocrit, Ca, K, and Mg ions. improvement, but many more patients benefit after 3 months of therapy. Testosterone therapy is time-dependent and combination with PDE5 inhibitors should start only after at least 3-months of monotherapy with testosterone.
P264 Investigating the effects of Liquorice consumption on Salivary Steroid hormones profile and blood pressure in healthy volunteers 1 1 2 2 Endocrine disruptors Emad A S Al-Dujaili , Claire Macdonald , Chris J Kenyon & Moira Nicol 1Queen Margaret University, Edinburgh, Scotland, UK; 2University of P262 Edinburgh, Edinburgh, UK. Lipid peroxidation, antioxidant enzymes activities in testis and spermatotoxicity of rats during short-term exposure to atrazine Sunny O Abarikwu3, Adebukola C Adesiyan1, Titilola O Oyejola1, Mathew Glycyrrhetinic acid (GA) has diverse in vitro effects as an inhibitor of 11beta O Oyeyemi2 & Olatunde O Farombi1 hydroxysteroid dehydrogenase (11HSD), 5alpha reductase and hormone receptor 1Drug Toxicology Research Laboratories, Faculty of Basic Medical binding. However, in vivo GA studies have focussed on the hypertensive effects Sciences, University of Ibadan, Ibadan, Nigeria; 2Department of Veterinary associated with the syndrome of apparent mineralocorticoid excess (SAME) in Surgery and Reproduction,Faculty of Verterinary Medicine, University of which 11HSD inhibition allows glucocorticoid hormones to bind inappropriately Ibadan, Ibadan, Nigeria; 3Division of Biochemistry, College of Natural to MR and subsequent decreased aldosterone synthesis. Here we consider whether Sciences, Redeemer’s University, Redemption City, Nigeria. GA’s other in vitro effects are reflected in altered steroid hormone profiles in vivo. The effect of liquorice (containing GA) has been assessed by measuring steroid hormone levels in healthy individuals. Ten men and 10 women (18–30 years) Atrazine is a chloro-s-triazine herbicide that has been in used worldwide for over were given 100 g liquorice sweets (3% liquorice extract) or non-liquorice 4 decades now. Its endocrine disrupting effects have been shown in mammals but containing confectionary for 7 days in a crossover study. Saliva was collected the specific mechanism or mechanisms of action remain unknown. The aim of this 30 min after waking, at 1100–1300 h and at 1800–2100 h for cortisol, cortisone,
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 aldosterone (Aldo), deoxycorticosterone (DOC), DHEA and testosterone The mean levels of CRP in groups with metabolic syndrome were 2.5G measurements by in-house, sensitive and specific ELISA methods. Systolic 2.12 mg/dl, in healthy women 1.64G1.56 mg/dl (P!0.05). blood pressure measured at the end of the two periods of treatment showed non- There was a positive correlation (P!0.05) between TNFa: with FAI (rZ0.233, significant increases (PZ0.127) in response to liquorice consumption. Cortisol P!0.05, NZ69), with the percentage of free testosterone (rZ0.328, P!0.05, was significantly higher (PZ0.003) and cortisone and aldo were reduced by NZ69), with percentage of bioavailable testosterone (rZ0.329, P!0.05) and liquorice (P!0.001) consistent with the SAME. DHEA, testosterone and DOC negative correlation with SHBG(rZK0.236, NZ69). were increased (P!0.001) possibly because of reduced hepatic clearance. There was asignificantly positive correlation of TIMP1: with BMI (rZ0.308, However, these steroids are not 11HSD type 2 substrates indicating liquorice P!0.05, NZ63), with waistline (rZ0.372, P!0.01, NZ63), with WHI might also have inhibited hepatic 5alpha reductase. Recent studies also implicate (rZ0.288, P!0.05, NZ63). the bi-directional 11HSD type1 enzyme in DHEA metabolism. GA is equipotent There was a significantly positive correlation of MMP9: with fasting plasma as an inhibitor of 11HSD type 1 and type 2 oxidase activity. 7-Hydroxy-DHEA, a glucose (rZ0.264, P!0.05, NZ77). major metabolite of DHEA is inter-converted with 7-keto-DHEA by 11HSD type During the climacteric period in women the indexes of endothelium functioning 1 and could, therefore, secondarily interfere with DHEA metabolism. We (MMPs-9, TIMP-1, TNFa and CRP) decreased with the intensification of conclude that in addition to cortisol, other biologically active steroid hormones symptoms of metabolic syndrome: obesity, levels of fasting plasma glucose and are affected by liquorice. Increased salivary levels of DHEA and testosterone levels of free testosterone index. suggest that liquorice modulates their bioavailability.
P267 New hepatic autoantigens in mice with APS-1 like disease Matthias Hardtke-Wolenski1, Katja Fischer1, Mark Anderson2, P265 Michael P Manns1 & Elmar Jaeckel1 1Hannover Medical School, Hannover, Germany; 2University of California Clinical and laboratory symptoms of metabolic syndrome in women in San Francisco, San Francisco, California, USA. climacteric period Jolanta Mieczkowska, Wojciech Barud & Grazyna Orlicz-Szczesna Medical University, Lublin, Poland. The AIRE gene (autoimmune regulator) has been identified as an important mediator of central tolerance against ectopically expressed peripheral antigens. Mutatations of AIRE are responsible for autoimmune polyendocrinopathy The aim of the study was the analysis of dependencies between sex hormones and syndrome type I (APSI) in human characterized by a multiorgan autoimmune metabolic syndrome. disease. Autoimmune hepatitis (AIH) is part of the clinical spectrum in humans Forty-five women with metabolic syndrome and 49 healthy women were and mice. 19% of patients with AIRE mutations develop an autoimmune hepatitis examined. which is characterized by autoantibodies against cytochrome P450 2A6 and 1A2. The diagnostic criteria of metabolic syndrome: waistline R80 cm, waistline/hips We investigated AIH in mouse models with various AIRE mutations on different index WHIR0.85 and also having 1 or 2 cardiovascular risk factors: genetic backgrounds. Initially we characterized the immunohistochemical glucoseR100 mg%, RRR130/80, HDL! 50mg% and TGR150 mg%. staining pattern of sera from AIREK/K mice on rat liver, kidney and stomach The levels of estradiol (E ), testosterone (T), dehydroepiandrosterone sulphate 2 sections and on HepG2 cells. In parallel, sera analysis has been done on western- (DHEA-S), sex hormone binding globulin (SHBG) were measured. Free blots loaded with whole liver lysate. We could demonstrate that the strength and testosterone index (FTI), free estradiol index (FE I) and free testosterone (FT) 2 broadness of the humoral immune response correlates well with disease activity were determined by means of a calculation method. of the AIH in AIRE deficient mice. We could show that AIH development is A significant difference between the group with metabolic syndrome (FTI-5.13G dependent on the genetic background used. Furthermore within the Balb/c 3.72, FE I-517.28G539.69, SHBG-48.49G32.18 nmol/l) and the control group 2 background AIH development is dependent on the underlying AIRE mutation. (FTI-3.04G1.65, FE I-281.72G313.6, CRP-1.49G1.38 mg/dl, SHBG-61.28G 2 Humoral immune responses in AIRE deficient mice are not directed against the 30.89 nmol/l) concerned FTI(P!0.01), FE I(P!0.05), SHBG (P!0.05). 2 antigens described for human AIH. We therefore set out to characterize the target There was a significant correlation of waistline with SHBG (rZK0.274), with antigens of the adaptive immune response in mice with AIH to study the defects in FTI (rZ0.324) and with FE I(rZ0.248) and WHI with SHBG (rZK0.239), 2 their immune tolerance. We therefore developed a column retention assay of for with FTI (rZ0.302), with FE I(rZ0.210) in women with metabolic syndrome. 2 non-denatured liver antigens followed by a proteomics analysis with mass The pathogenesis of metabolic syndrome in menopausal women is connected spectroscopy. With this approach we identified several potential new autoantigens with bioavailability of sex hormones and binding proteins. of the humoral immune response.
P268 P266 Thyroid gland hormonal disturbances after iodine excess among Functioning of endothelium in metabolic syndrome in the climacteric children period of women Jolanta Zdanowska, Grazyna Orlicz-Szczesna, Jolanta Mieczkowska Jolanta Mieczkowska, Wojciech Barud & Grazyna Orlicz-Szczesna & Andrzej Bilan Medical University, Lublin, Poland. Medical University, Lublin, Poland.
The aim of the work was the analysis of dependencies between sex hormones and Aim of the study was to evaluate influence of potassium iodide on hormonal functioning of endothelium in women in the climacteric period with metabolic thyroid function. syndrome. In medicine there are widely used medias with large, overphysiologic doses of Fifty-three women with metabolic syndrome and 45 healthy women were iodine for both treatment and diagnosis. We investigated influence of high examined. repeated iodine doses on hormonal thyroid balance in healthy children with no Lipidogram (LDL: cholesterol-LDL, HDL: cholesterol-HDL), triglycerides(TG) previous history of any thyroid diseases. and fasting glucose levels were determined. Body mass index BMI and Thirty eight children at age from 6 to12 years old with no personal and familiar waistline/hips index (WHI) were calculated. history of thyroid diseases, were treated with potassium iodide solution for a week The levels of testosterone (T) were measured using the RIA method. The level of as an oral pharynx disinfection. Indications were chronic pharynx infections. sex hormone binding globulin (SHBG) in blood was calculated using the IRMA Evaluated patients had no contact with iodine during last twelve months. Thyroid method and CRP using the turbidymetric method. The levels of matrix hormone levels, antythyroid peroxidase antibodies and thyroid gland in metalloproteinases (MMPs-9), tissue inhibitors of metalloproteinases (MMP-1) ultrasound examination with 10 MHz sound were in normal range before larynx and human tumor necrosis factor alpha (TNFa) were measured using treatment. In all patients we measured levels of TSH and FT4 before disinfection immunoassay method. in the same day and after 4 and 12 weeks. Written informed consent was collected Free testosterone index (FTI) and free testosterone (FT) were determined by and study was approved by the Ethics committee. The collected results were means of a calculation method. Fasting plasma glucose level was determined by submitted to a statistical study. Repeated measures ANOVA and posthoc analysis enzymatic method with glucose oxidase. with LSD test were performed. P!0.05 was considered to indicate a statistically
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 significant difference. Statistical computations were executed with Statistica, differences were discovered in serum levels of TTR in children, in adults this commercially available Software (StatSoft USA). difference was non-significant. In serum concentrations of RBP in children there The mean TSH and FT4 levels of analyzed group stayed in laboratory normal were no statistically significant differences found, in adults this difference was range but changes were statistically significant. In ten out of thirty eight children significant. We assessed also the ratio RBP/TTR and estimated reserve of retinol we observed hypothyroidism after 1 month and they needed thyroxin treatment. in liver. In both cases we discovered significant differences in children as well as Results of our study demonstrate that use of iodine at low risk thyroid disease in adults. children is not safe and makes serious complications. Potassium iodide in excess Conclusion amounts should not be used among children. When applied, careful PCB belong among the most significant disruptors of the environment. RBP endocrinological and thyroid hormones control should be performed. together with the ratio RBP/TTR can be suggested as a biomarker of chronic pollution of the environment by PCB.
P269 The UV absorber 4-methylbenzylidene-camphor (4-MBC) causes effects comparable to primary hypothyroidism Inka Gotthardt1, Cornelia Schmutzler1, Kirschmeyer Petra2, Endocrine tumours Wuttke Wolfgang2, Jarry Hubertus2 &Ko¨hrle Josef1 P271 1 2 Charite´-Universita¨tsmedzin Berlin, Berlin, Germany; Universita¨tsmedizin The comparison of serum VEGF levels between patients with metastatic Go¨ttingen Georg-August-Universita¨t, Go¨ttingen, Germany. and non-metastatic thyroid cancer, and patients with non-toxic multinodular goiter The endocrine active compound 4-methylbenzylidene-camphor (4-MBC) is Joanna Klubo-Gwiezdzinska & Roman Junik frequently used as an UV absorber in sunscreens and various skin care products. Department of Endocrinology and Diabetology, Collegium Medicum in Though 4-MBC is weakly estrogenic in the reproductive system of fishes and Bydgoszcz, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland. rodents it shows strong anti-osteoporotic effects. Furthermore, different studies show percutanous absorption of 4-MBC after dermal administration resulting in One of the important proangiogenic factors involved in the growth of normal and identical biotransformation in humans and rats. Female Sprague-Dawley rats neoplastic tissues is vascular endothelial growth factor VEGF. received five concentrations of 4-MBC (10–600 mg/kg per b.w. days) via gavage Therefore we hypothesized, that serum VEGF concentration would differ between over a period of five days on a background of a soy-free diet. As controls for the patients with metastatic and non-metastatic thyroid cancer, with multinodular thyroid axis served T4 and the antithyroidal drug methimazole (MMI), while E2 goiter and healthy subjects. We also hypothesized that endogenous TSH was used to evaluate estrogenic effects. TSH, total T4 and T3 were measured by stimulation would effect serum VEGF level. The study protocol was approved RIA. Transcript levels of genes involved in the feedback control in the pituitary 0 by the Ethical Committee of the Collegium Medicum in Bydgoszcz, Nicolaus (aGSu, Tshb,5-deiodinases (Dio1, Dio2)) as well as gene expression of TSH Copernicus University, Poland. All patients gave informed consent. receptor (Tshr), sodium-iodide symporter (Nis) and thyroid peroxidase (Tpo) in The study group consisted of 71 patients (62 females, 9 men), aged 44. 9G12.3 the thyroid gland were detected by Real-time RT-PCR. TSH serum levels were R year, with differentiated thyroid cancer, (50 papillary, 17 follicular and 4 significantly elevated at concentrations 33 mg 4 MBC/kg while T4 serum levels oxyphilic), treated in our department in the years 2003–2006. All patients had were slightly decreased, and T3 levels remained almost unchanged, which is undergone total or near total thyroidectomy and radioactive iodine treatment, that typical for the initial phase of hypothyroidism when the peripheral organs still had resulted in remission in 59 patients and persistent/recurrent disease in 12 maintain T3 serum levels. In the pituitary aGSu and Tshb were markedly O patients. The study included two control groups – 30 patients with non-toxic increased at concentrations 33 mg/kg. Dio1 gene expression was down- multinodular goiter and 30 healthy subjects. regulated while Dio2 transcript levels were increased depending on the 4-MBC Serum VEGF concentration was significantly higher in patients with distant concentration applied. Moreover, the animals exhibited remarkably increased metastases than in patients with remission or healthy. (423.4 vs 217.6 vs thyroid gland weights at concentrations exceeding 33 mg/kg. The data on 235.55 pg/ml, P!0. 05). This was not observed in patients with increased gene expression of Tshr, Nis and Tpo in the thyroid gland were locoregional metastases. During endogenous TSH stimulation, VEGF supported by immunohistochemistry. These data are consistent with decreased significantly decreased (215.3 vs 169.6 pg/ml, P!0.05). Patients with Dio1 activity in the liver, indicating that 4-MBC is a potent inhibitor of the multinodular goiter showed significantly lower VEGF concentrations than pituitary–thyroid–axis. the remaining study groups. Serum VEGF concentration might be used as an additional marker of thyroid cancer with distant metasases, but it’s interpretation should be undertaken very cautiously. Endogenous TSH stimulation decreases VEGF levels in patients either with and without thyroid tissue, suggesting its P270 regulatory effects through receptors located outside the thyrocytes. Serum level of vitamin A, transthyretine and retinol binding protein in a region polluted by polychlorinated biphenyls in a long term Zuzana Semanova´1,Ma´ria Tajta´kova´2, Darina Petra´sˇova´3 & Jaroslav Rosenberger4 11st Private Hospital, Kosˇice-Sˇaca, Slovakia; 21st Internal clinic FNLP, Kosˇice, Slovakia; 3Institute of experimental medicine, Kosˇice, Slovakia; 4 KISH, Kosˇice, Slovakia. P272 Special multiple endocrine neoplasia (MEN) Vitamin A (retinol) plays a non-substitutable role in a process of growth and Piedad Santiago1, Cesar Ramirez2, Isabel Ruiz3, Pilar Martinez1, differentiation of tissues. Deficit of retinol can be encountered at its long-term diet Jose Antonio Lopez1, Carolina Sanchez1 & Alberto Moreno1 deprivation (primary deficit), but it can occur also as a consequence of 1Endocrinologia, Jaen, Spain; 2Anatomia Patologica, Jaen, Spain; 3Cirugia, metabolism disorders on various levels (secondary deficit). Secondary deficit of Jaen, Spain. retinol can occur also in people exposed to chemical substances in the long term or people living in an environment polluted by chemicals for a long time. One of the most significant environmental pollutants is polychlorinated biphenyls (PCB). The ‘Multiple Endocrine Neoplasia’ predominantly affect the pituitary gland, Region of the Eastern Slovak Lowland belongs to regions with high exposure of parathyroids, thyroids, adrenal glands and pancreas. We present the case of a inhabitants to PCB. patient with three different functioning endocrine gland tumours, but who cannot Material and methodology be included in any of these groups. Serum level of retinol, transthyretine (TTR) and retinol binding protein (RBP) Case report was examined in 24 adults and 43 children from Stra´zˇske (PCB). Control group Sixty-five-years-old female with recurrent episodes of nephritic colic and (KON) was comprised of 19 adults from the village Zˇ danˇa and 40 children from hypertension for 2 years; non-specific gastrointestinal complaints, hirsutism, Bardejov. hypertrichosis on the limbs, frontoparietal alopecia and increased libido. Results Examination In adults there was no significant difference in serum levels of retinol found. BMI: 32 kg/m2, androgenetic alopecia, facial hirsutism, hypertrichosis on the Serum level of TTR was within a normal range. Statistically significant limbs, increased pilification midline; increased size of thyroid gland with nodule
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 on midline, 2 cm in diameter and of an elastic consistency that moves on Purpose swallowing. Vitiligo on hands. 111In-octreotide scinti aphy may be useful in patients with insulinoma during Complementary pre-surgical localization of the tumor and octreotide is effective in inhibiting Calcium 10.6 mg/dl, phosphorus: 2.21 mg/dl. Calciuria: 394 mg/24 h; RTP: insulin secretion and reducing the hypoglycemic events. The aim of the study was 74.8%, PTH: 95.6 pg/ml. FSH: 15.7 IU/l, LH: 7.42 IU/l, testosterone: 2.54 ng/ml, to evaluate 111in-octreotide scintigraphy in localizing primary and metastatic FAI: 19.63. SESTAMIBI gammagraphy: pathological deposit in upper right insulinomas and predicting the response to octreotide administration. parathyroid projection area. Thyroid ultrasound: 2.4!2!1.5 cm diameter nodule Patients and methods on isthmus. Transvaginal ultrasound and abdominal CT: normal. Diagnosis of insulinoma was made in 17 subjects (M/F 9/8; aged 41.8G15.3 Total thyroidectomy and a parathyroidectomy for parathyroid adenoma were years) based on hyperinsulinemic hypoglycemia (mean IRI/BG ratio 0.91G0.23) therefore performed, because a suspected malignant thyroid nodule was found, during a 72-h fasting test and confirmed by surgical procedure (mean tumor which was diagnosed as papillary thyroid carcinoma. diameter 1.3G0.4 cm). One patient had a malignant insulinoma. All patients had Post-surgical examination, clinical manifestations of hyperandrogenism persisted Octreoscan. Blood glucose and serum insulin were measured fasting and at 20, 40, with testosterone of 3.52 ng/dl, FSH: 21.9 IU/l, LH: 11.7 IU/l; It was decided 60, 80, 100, 120, 140, 160, 180 minutes during intravenous infusion of octreotide bilateral oopherectomy: the anatomopathological diagnosis was a steroid cell at a rate of 100 mg/hour for three hours (Intravenous Octreotide Suppression Test); tumour in the right ovary (NOS), and the left ovary: hyperthecosis and cystic response was considered: ‘good’ when mean insulin secretion during the test was follicles. suppressed over 50% of basal value, ‘fair’ when it was suppressed between 20 and Following the oopherectomy the patient clearly improving in terms of hirsutism 49%, and ‘absent’ when suppression did not reach the 20% of basal value. and presenting a regrowth of hair. Testosterone: 0.12 ng/ml, FSH: 33.35 IU/l, LH: Results 11.36 IU/l. Octreotide inhibited insulin secretion in 14 on 17 patients (overall results: mean Conclusion basal insulin 36.8G31.2 mUI/ml, mean insulin during the test 13.5G7.6 mUI/ml – This patient presented with: primary hyperparathyroidism, papillary thyroid P!0.05). Fifteen on 17 (88%) pancreatic insulinomas and 1 liver metastasis were carcinoma and functioning ovarian tumour. Although she cannot be included localized with Octreoscan, among these patients 12 (80%) were responders within any of the MEN groups that have been defined to date, this is an atypical (3 good responses and 9 fair responses) and 3 (20%) were non responders. clinical profile of multiple endocrine neoplasia. Malignant insulinoma had a good response. The rate of suppression ranged from 0% to 84.1% (mean rate 34.7G25.2%). Conclusions According to the study 80% of insulinomas detected by 111In-octreotide scintigraphy may respond to octreotide administration with a very variable rate of inhibition of insulin secretion.
P273 The early results of the treatment of well differentiated thyroid cancer and its dependence on chosen factors P275 Joanna Klubo-Gwiezdzinska & Roman Junik Nerve vagus schwannoma Department of Endocrinology and Diabetology, Collegium Medicum in Adem Karatas1, Mete Duren1, Kagan Karabulut1, Husrev Hatemi2, Bydgoszcz, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland. Guler Turkes Ates¸2 & Serdar Giray2 1Istanbul University Cerrahpasa Medical Faculty, Istanbul, Turkey; 2Universal Hospitals Group Das Deutsche Krankenhaus, Istanbul, Turkey. The aim of the study was to estimate the influence of a thyroid remnants’ volume, postsurgical concentration of thyroglobulin and radioiodine dose on the early treatment efficacy of well differentiated thyroid cancer. Introduction Material and methods Schwannomas are benign, encapsulated, solitary, slow-growing tumors which We retrospectively analyzed 91 patients (76 females, 15 men) with well originate from nerve sheath cells in cranial, periferic, symphathetic nerve system. differentiated thyroid cancer. Aproximately, 25–45% of schwannomas are in head and neck region. N. Vagus Results Schwannoma are seen relatively, rarely. The patients frequently apply with a Histological classification revealed 68.1% (62/91) papillary thyroid cancers, slow-growing, painless servical mass. Malign transformation is unusual. 25.3% (23/91) follicular thyroid cancers, and 6.6% (6/91) oxyphilic thyroid Case report cancers. Among the group, 74 (81.3%) patients reached the remission criteria and The patient 37 years old applied to our clinic because of mass on his the remaining 17 patients (18.7%) showed biochemical and morphological neck.In his history, it was applied lymphadenopathy excision when he was evidence of metastatic disease. The remission was obtained in 100% of patients 11 years old and it was applied servical radiotherapy because his pathology in stage I of the disease, 68.4% – in stage II, 78.6% – in stage III and 33.3% in result showed Hodgkin lymphoma. The thyroid function tests were normal. stage IV. The total radioiodine dose used in patients with remission, did not differ It was found a colloidal nodul 4 cm in the right thyroid lobe and a 2 cm from the dose used in patients without remission. We did not observe the lymphadenopathy lateral to the right lobe in the neck ultrasonography. influence of remnant’s volume on treatment efficacy, however larger remants The result of fine needle biopsy that was applied from right thyroid lobe required higher dose of radioiodine to obtain the remission. Patients with was evaluated as follicular neoplasm. It couldnot diagnose with fine needle remission had lower postsurgical thyroglobulin concentration, than patients biopsy from the mass that was in the right lateral neck. It was performed without remission. (22.2 vs 103.3 ng/ml, PZ0.00025). NPV of Tg level bilateral total thyroidectomy to the patient and It was performed excisional !5 ng/ml was 100% and PPV of Tg O15 ng/ml was 39.35%. biopsy from the mass because of the close relationship with nerve vagus in Conclusions the mass of right neck. At histopathologic examination it was found Early treatment results of well differentiated thyroid cancer depend on the clinical schwannoma in the nerve vagus and thyroid follicular adenoma. It wasnot stage, and postoperative serum thyroglobulin level, measured after endogenous attempt again because the mass was asemptomatic and had a close TSH stimulation. Early treatment results are not dependent on age, sex, relationship with nerve vagus. The patient who doesnot have any complaint histological type of thyroid cancer, the dose of radioiodine used in brackets of is still observed. 60–150 mCi and additional diseases. Total thyroidectomy is equally efficient as Discussion near total. It was found frequently in the vestibular nerve (acustic neuroma). The most of patients are between 20–50 years old. ıt was more common on women. Nerve Vagus Schwannomas are relatively less common.˙ It can be used fine needle biopsy and magnetic resonance imaging. The treatment is excision of the mass by protecting the nerve vagus. Nerve continuity can protect by mycrosurgical technique which was described by Fujino et al. In patients that underwent P274 incomplete resection or have surgical contraindication the alternative cure methods are radiotherapy and sterotactic radio-surgery. The risk of malign Variability in rensponse to octreotide in patients with insulinoma transformation is extremely rare. The patient with Von Recklinghausen disease detected by 111In-octreotide scintigraphy (Octreoscan) develop a malignant schwannoma in 3–13% of case but never before 10–20 year Fabrizio Diacono & Guido Tamburrano latent period. So the patients should be observed. University Sapienza, Rome, Italy.
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d:g2 \dA ) !2 rBs g_ j 10th European Congress of Endocrinology, Berlin, Germany, 2008
P295 P297 Melatonin restores the basal level of lipid peroxidation in rat tissues The Relaxin peptide is a novel regulator of S100A4 (metastasin) in under conditions of exposure to potassium bromate thyroid carcinoma cells Magdalena Stasiak3, Andrzej Lewinski2 & Malgorzata Karbownik- Yvonne Radestock1, Cuong Hoang-Vu1 & Sabine Hombach-Klonisch2 Lewinska1 1Clinics of General, Visceral and Vascular Surgery, Halle, Sachsen-Anhalt, 1Department of Oncological Endocrinology, Medical University of Lodz, Germany; 2Department of Human Anatomy and Cell Science, Faculty of Lodz, Poland; 2Department of Endocrinology and Metabolic Diseases, Medicine, University of Manitoba, Winnipeg, Manitoba, Canada. Medical University of Lodz, Lodz, Poland; 3Department of Endocrinology and Metabolic Diseases, Research Institute, Polish Mother’s Memorial Hospital, Lodz, Poland. The peptide growth factor relaxin (RLN) is expressed in human thyroid carcinoma cell lines and tissues. We have previously established thyroid carcinoma cell transfectants with over-expression of relaxin and demonstrated Potassium bromate (KBrO3) is a known prooxidant and carcinogen. that relaxin increases cellular motility and in-vitro invasiveness in these Melatonin is a highly effective antioxidant. Indole-3-propionic acid (IPA) transfectants. This increase in motility and migration is relaxin receptor – an indole substance, and propylothiouracil (PTU) – an antithyroid drug, (LGR7)-dependent. S100A4 (metastasin), a member of the S100 family of also reveal some antioxidative effects. The aim of the study was to evaluate calcium binding proteins, is known to confer invasiveness in breast cancer cells KBrO3-induced lipid peroxidation in vitro in tissues collected from either and its expression in carcinoma tissues correlated with advanced stages of the control or melatonin-treated rats, and to compare potential preventive effects disease. S100A4 is considered a molecular marker for the metastatic potential for of melatonin, IPA and PTU. carcinoma with high prognostic significance. We have shown that S100A4 is Kidney, liver and lung homogenates from either the control or the increased in thyroid adenoma, in papillary, follicular and anaplastic thyroid melatonin-treated rats (0.0645 mmol/kg b.w., i.p., twice daily, for 10 days) carcinoma tissues as compared to goiter tissues and S100A4 protein is localized in were incubated in the presence of KBrO3 (0.1, 0.5, 1.0, 2.5, 5.0, 10.0 mM). the cytoplasm of tumor cells. Highest intra-tumor levels of S100A4 expression As prooxidative effect of KBrO3 was observed only in the control lung were detected in papillary thyroid carcinoma with nodal metastasis. We show homogenates, they were then incubated in the presence of KBrO3 (10.0 mM) here that the relaxin/LGR7 ligand-receptor system is a novel transcriptional plus melatonin (0.01, 0.1, 0.5, 1.0, 5.0, 7.5 mM), or IPA or PTU (0.01, 0.1, regulator of S100A4 expression in thyroid carcinoma cell line FTC133. The 0.5, 1.0, 5.0, 7.5, 10.0 mM). The level of lipid peroxidation products – relaxin-mediated increase in motility is mediated by an increased expression of malondialdehyde C4-hydroxyalkenals (MDAC4-HDA) – was measured S100A4 mRNA and protein. Furthermore, S100A4 siRNA knock-down spectrophotometrically. prevented the relaxin-induced increase in cellular motility of the cell line FTC- KBrO3 treatment increased lipid peroxidation in the control lung 133. Thus, relaxin expression is a novel regulator of S100A4 in thyroid carcinoma homogenates, but not in the lung from the melatonin-treated rats. Melatonin, cells and S100A4 may mediate the relaxin-induced increase in cancer cell IPAandPTUreducedKBrO3-induced lipid peroxidation. Unexpectedly, invasiveness. KBrO3 caused a concentration-dependent decrease in lipid peroxidation in liver and kidney homogenates from the control rats, whereas such an effect was less pronounced in tissues from the melatonin-treated rats. In conclusion, KBrO3-induced lipid peroxidation in rat lung suggests that it may be the target organ for this carcinogen. An exposure of an organism to P298 melatonin decreases tissue sensitivity to KBrO -induced damage, possibly 3 Cyclic Cushing disease: clinical case by restoring the oxidative balance. Thus, melatonin could be recommended 1 1 1 2 for its possible cancer prevention effects. Jacinta Santos , Carla Baptista , Isabel Paiva , Manuel Rito & Manuela Carvalheiro1 1Endocrinology, Diabetes and Metabolism Department HUC, Coimbra, Portugal; 2Neurosurgery Department HUC, Coimbra, Portugal.
Cyclic Cushing’s disease is a rare situation due to episodic hypersecretion of ACTH. Suspicion is raised when strong clinical stigmata occur, with normal basal values of cortisol and normal responses to dynamic tests. After performing several tests, particularly during phases without symptoms (well-being), the probability of successful diagnosis increases. We describe the case of a 33 years old female patient with full-blown clinical P296 picture (weight excess, hirsutism, hypertension, muscular weakness, moon facies, Relaxin and S100A4 alter the invasive potential in estrogen- buffalo hump and supraclavicular fat pads) since about a year. Repeated FUC independent human MDA-MB-231 breast cancer cells showed fluctuating values – 112, 200 and 68 mg/24 h (N: 10–80). Plasma cortisol Yvonne Radestock1, Cuong Hoang-Vu1 & Sabine Hombach-Klonisch2 values at 8 am and 11 pm were respectively 11 mg/dl and 13 mg/dl. ACTH was 1Clinics of General, Visceral and Vascular Surgery, Halle, Sachsen-Anhalt, 26 pg/ml at 8 am and 34 pg/ml at 11 pm. Low dose DXM suppression test Germany; 2Department of Human Anatomy and Cell Science, Faculty of suppressed plasma cortisol to 1.1 mg/dl. Pituitary MRI suggested a ‘pars Medicine, University of Manitoba, Winnipeg, Manitoba, Canada. intermedia cyst’. An Inferior petrosal sinus sampling study (IPSS) was performed in an asymptomatic phase: ACTH reached 703 pg/ml in the right side and 541 pg/ml in the left side. Patient was submitted to transsphenoidal surgery The heterodimeric peptide hormone relaxin is involved in extracellular (pathology: corticotrophinoma). After surgery, blood pressure normalized, matrix turnover during development and lactational differentiation of the hirsutism and body weight decreased. Six weeks after surgery, hormonal study breast. Relaxin expression is increased in human breast cancer and serum showed: ACTH 10 pg/ml (8 am) and 7.4 pg/ml (11 pm); cortisol 7.4 mg/dl (8 am) relaxin levels in breast cancer patients were reported to correlate with and !1 mg/dl (11 pm); Cortisol after overnight 1 mg dexamethasone suppression metastatic disease. We have established relaxin over-expressing transfectants test !1.0 mg/d;. There were no other pituitary hormonal disturbances. Three of the highly invasive estrogen receptor-negative human breast cancer cell months later, MRI was repeated, with no evidence of relapse or tumoral residue. lineMDA-MB-231(MDA/RLN)toinvestigatetheroleofrelaxinin Conclusions estrogen-independent breast cancer cells. MDA/RLN revealed decreased The strong suspicion of Cushing syndrome justified keeping on with imagiologic cellular motility and migration through extracellular matrices when and hormonal studies, in spite of normal DXM suppression test and slightly compared to MDA/EGFP control transfectants. S100A4 (metastasin) elevated FUC at the beginning. The hypercortisolism alternating with normal increased cell motility in different cell models and has been associated hormonal secretion suggests that we are facing a cyclic Cushing syndrome. with tumor invasiveness. In the present study, we showed that the calcium binding protein S100A4 is down-regulated in stable MDA/RLN transfectants and in paternal MDA-MB-231 breast cancer cells after exposure to human recombinant relaxin. Furthermore, tumor growth in nude mice was studied following subcutaneous injection of MDA/RLN and MDA/EGFP clones and P299 revealed reduced tumor growth of the MDA/RLN xenografts. MDA/RLN xenografts also revealed a down-regulation of S100A4 transcripts and Adrenal ganglioneuroma: a new cause of increased serum calcitonin protein. S100A4 siRNA knock-down revealed reduced cell motility Theodosia Bakola, Anastasios Gkountouvas, Anastasia Aggelopoulou, suggesting S100A4 to be a downstream target of relaxin/ relaxin receptor Athanasia Tertipi, Anastasios Pappas, Ioanna Iakovidou, signaling. (Supported by Wilhelm-Roux-Program, FKZ 15/09) Athanasios Nisiotis & Philippos Kaldrimidis Metaxa Memorial Hospital, Piraeus, Greece.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Introduction P301 Ganglioneuromas are rare, benign tumors of mature ganglion cells, arising from Genetic testing of RET protooncogene in multiple endocrine neoplasie the sympathetic ganglia and 20% are located in the adrenal medulla, representing type 2 and medullary thyroid carcinoma 1–4% of adrenal incidentalomas. About 1/3 secrete catecholamines but Ute S Groß, Hjo¨rdis H S Drexler, Sandra Fleischer & Heinrich M Schulte hypertension and other adrenergic symptoms are rare. About 60% are depicted Endokrinologikum Hamburg, Hamburg, Germany. with 131I- MIBG. Case report A 72-year-old man was admitted for a left adrenal tumor 9!8 cm, incidentally Introduction found in abdominal CT scan for investigation of haematuria. The patient was Multiple endocrine neoplasia type 2 (MEN2) and medullary thyroid carcinoma normotensive and diabetic type II. Basic and dynamic tests for cortisol and (MTC) are autosomal-dominant inherited diseases caused by germline mutations aldosterone hypersecretion were normal, 24 h urinary normetanephrine (2070 mg within the RET protooncogene. Until now, genetic testing for mutations of exon (105–354)), norepinephrine (422 mg (20–100)) and dopamine (425 mg (80–350)) 10, 11, 13, 14, 15 and 16 was recommended for these patients (familial and were elevated (normetanephrine was 7 times the upper normal limit). Urinary sporadic cases) to identify disease-causing mutations. Because of a strong epinephrine and metanephrine were normal. 131I- MIBG whole body scan showed genotype–phenotype correlation in these diseases, early genetic testing of an intense uptake by the mass. Serum CgA was increased (334 ng/ml (!98)). relatives of the affected gene carrier is important to detect asymptomatic gene Serum calcitonin (121 pg/ml (!15)) was increased without ultrasound apparent carriers to plan thyroid management e.g. total thyroidectomy. thyroid nodules. The tumor was diagnosed as a pheochromocytoma and a left According to ‘Consensus Guidelines for Diagnosis and Therapy of MEN1 Type 1 adrenalectomy was performed with no perioperative complications. Histology and Type 2’ we started to expand genetic testing for RET mutations within the revealed a gaglioneuroma with mature ganglion cells and abundant Schwann remaining 15 exons of the RET protooncogene in 100 unrelated apparently cells. Immunohistochemical staining for calcitonin was positive. Six months sporadic index cases tested negative for exon 10, 11, 13, 14, 15 and 16. Thus, we postoperatively, urinary catecholamines and normetanephrines were normal, want to get knowledge about the frequency and localisation of mutations within abdominal CT scan showed a normal right adrenal, 131I- MIBG scan was negative other regions of the gene to improve genetic testing strategy if necessary. and serum CgA decreased to almost normal levels (102 ng/ml). Calcitonin also Methods decreased to normal (4.6 pg/ml). Genomic DNA was extracted from peripheral blood leukocytes, followed by PCR Conclusion amplification and direct sequencing of exons including corresponding exon– Untill now only pheochromocytomas and composite pheochromocytomas – intron boundaries. tumors containig both chromafine and ganglion cells – are reported to secrete Results calcitonin. To our knowledge this is the first reported ganglioneuroma secreting Until now additional analysis of six exons revealed two novel heterozygous calcitonin. germline mutations in exon 8: p.Ala513Gly and p.Arg552Gln. In addition, we detected a RET mutation p.Thr338Ile known from a study of Hirschsprung’s disease. Conclusion So far, we detected three RET mutations in three out of 100 apparently sporadic patients tested negative for exon 10, 11, 13, 14, 15 and 16. Our data indicate by now that genetic counseling and genetic testing for RET mutations should include rare mutations and be done in familial and apparently sporadic MTC/MEN2 index cases to confirm the diagnosis and define asymptomatic gene carriers for early therapy.
P300 Proteomic profile of GH-secreting versus non-functioning pituitary tumors 1 2 3 3 Chiara Verpelli , Giovanna Mantovani , Marco Locatelli , Lorenzo Bello , P302 Paolo Beck Peccoz2, Anna Spada2, Claudio Sala1 & Andrea Lania2 1CNR Institute of Neuroscience and Department of Pharmacology, Impact of the use of recombinant TSH stimulated thyroglobulin University of Milan, Milano, Italy; 2Endocrine Unit, Department of Medical measurement on health related quality of life in patients in follow-up for Sciences, University of Milan, Fondazione IRCCS Ospedale Maggiore differentiated thyroid carcinoma (DTC) Policlinico, Milano, Italy; 3Neurosurgery, Department of Neurological ACM Persoon1, WJ Sluiter1, PL Jager2, AV Ranchor3, BHR Wolffenbuttel1 Sciences, University of Milano, Fondazione IRCCS Ospedale Maggiore & TP Links1 Policlinico, Milano, Italy. 1Department of Endocrinology, University Medical Center Groningen, Groningen, The Netherlands; 2Department of Nuclear Medicine, McMaster University Medical Center Site, Hamilton, Canada; 3Northern Centre for GH-secreting and non-functioning pituitary tumors are clinically distinct, Healthcare Research, University Medical Center Groningen, University of usually benign but potentially locally aggressive lesions originating from the Groningen, Groningen, The Netherlands. replication of a single mutated pituitary cell. As for the underlying genetic and epigenetic alterations, also the patterns of activation of specific signaling pathways as well as the prognostic molecular factors leading to Introduction local invasiveness are, to date, largely unknown. In this study, we used two- Thyroglobulin (Tg) measurement is the cornerstone in the follow-up of DTC. dimensional electrophoresis and mass spectrometry to directly analyze Sensitivity can be optimised by measuring recombinant TSH stimulated Tg protein profiles changes between GH-secreting (GH-omas) and non- (rhTSH-Tg). Higher sensitivity results in more Tg positive patients who need functioning (NFPAs) pituitary tumors. In particular we analyzed 10 NFPA imaging and considerable patient burden. We assessed the impact of rhTSH-Tg and 10 GH-omas surgically removed from patients not previously treated measurement on health related quality of life (HRQOL). either by radiotherapy or somatostatin analogues. Proteins analysis has been Methods performed by comparing ten gels obtained from each group of surgically In 121 patients in follow-up for DTC, Tg during thyroid hormone suppression eradicated tumors. Forty-two significant spots have been analyzed by mass therapy (Tg-on) and rhTSH-Tg were measured with a sensitive Tg assay. Patients spectrometry, resulting in the identification of eleven proteins significantly with rhTSH -TgR1.0 ng/ml (TgC patients) underwent imaging. Anxiety items of down-regulated and twenty-five proteins significantly up-regulated in non- the Hospital Anxiety and Depression scale, the General Health Questionnaire functioning pituitary tumors in comparison to GH-secreting tumors. In (psychological distress) and cancer worries (CW) were completed at baseline and particular, non-functioning pituitary tumors are characterized by a significant after being informed about rhTSH-Tg result. Additionally, TgC patients increase in Insulin-like growth factor-binding protein 2, Ubiquinol- completed these questionnaires after being informed about imaging results and cytochrome-c reductase complex core protein 1 and GTP-binding nuclear disease status. Non-parametric statistic tests were used. protein Ran expression. Interestingly, these proteins, whose function has not Results been yet investigated in human pituitary, are typically associated with a RhTSH-Tg measurement resulted in 101 TgK and20TgC patients. Imaging more aggressive tumor phenotype. These preliminary data to be further showed recurrence in 3/19 TgC patients. Two of these three patients could have investigated, seem to suggest a more aggressive phenotype of non- been identified solely by Tg-on. In 16/19, TgC patients imaging was negative. functioning pituitary tumors compared with GH-secreting pituitary tumors. For TgC patients, anxiety, psychological distress and CW significantly increased Experiments comparing the normal pituitary protein expression pattern with after being informed about Tg result. Only CW remained increased after being secreting and nonsecreting pituitary tumors are in progress. informed about disease status. For TgK patients, anxiety decreased after being informed about rhTSH-Tg result, no other changes were found.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Conclusion pathway was unaffected. We also detected inhibitory effect of sorafenib on Notification of positive rhTSH-Tg has a negative effect on HRQOL and increment receptor tyrosine kinases like PDGF receptor alpha and beta and VEGF receptors, of CW persists despite of negative imaging. The limited clinical benefit and while EGF receptors and other erbB receptors were not affected. After 4 to 8 h of adverse effects on HRQOL of rhTSH-Tg measurement questions the use of this sorafenib treatment, cells showed apoptosis induction. Cell cycle analyses test in the follow-up of DTC. Tg-on measurement with a sensitive Tg assay may revealed a sorafenib-dependent arrest mainly in the S phase of the cell cycle in the represent a useful diagnostic tool, preventing needless patient burden. remaining living cells, while the G0/G1 peak was diminished. Conclusion The BRAF- and multi-targeted kinase inhibitor sorafenib showed various inhibitory effects on intracellular signaling pathways in thyroid carcinoma cells and caused cell cycle arrest and apoptosis induction. Since sorafenib was effective in all thyroid carcinoma cell lines independently of the presence of an activating BRAF-mutation, this drug may be a new therapeutic option for dedifferentiated thyroid cancer. P303 Cushings’ syndrome due to ectopic ACTH secretion: four cases Sema Yarman, Meral Mert, Serpil Salman, Refik Tanakol, Harika Boztepe & Faruk Alagol Istanbul University, Istanbul, Turkey.
Ectopic ACTH syndrome (EAS) occurs in around 10% of all cases with ACTH- P305 dependent hypercortisolism. The mean age of clinical presentation varies from 45 A rare case of hiperandrogenism bilateral Leydig cell tumor of the to 50 years, and most of them caused by intrathoracic neoplasm, and recognition ovary of the disorder may be delay. Subsequently, it may be difficult to locate the ACTH Mafalda Marcelino, Ema Lacerda Nobre, Joa˜o Conceic¸a˜o, source and manage the patients’ hypercortisolism. We present our patients with Arlindo Carvalho, Ana Paula Horta & Joa˜oJa´come de Castro EAS from 2000 to 2007. Four patients, aged 15–43 years, two females and two Hospital Militar Principal, Lisboa, Portugal. males included in the study. Symptoms duration lasted from 5 months to 4 years. All patients presented clinical signs of hypercortisolism with intense weakness due to proximal myopathy, 3 presented arterial hypertension, 1 presented poor Background controlled diabetes mellitus for 8 months, none of them presented hyperpigmenta- The androgen-secreting tumors constitute fewer than 1% of ovarian tumors. tion, and two patients presented a mild psycotic picture. Hypokalemia was present Leydig cell tumor is one of the most common of this type of lesion and it is in 2 cases (!3 mEq/l), all of them presented absence of cortisol circadian rhythm. usually benign, small and unilateral. Considering the upper limit of normal values for the assay, plasma ACTH levels Case report were within normal range in 3 and slightly high in one. Three had osteoporosis A 67-year-old women was referred to the Endocrine clinic due to hirsutism (score and fracture. None of them did respond to 8-mg 2-d high-dose dexamethasone 22 Ferriman–Gallwey) and male type alopecia with 3 years of evolution and suppression test. Chest X-ray and CT localized the ACTH-secreting tumor in only progressive worsening. Biochemically she had high levels of serum testosterone – one patient, and diagnosis proved by biyopsy. All imaging modalities (CT/MRI/ 662 ng/dl (N!62 ng/dl). Transvaginal ultrassonography, and abdomen–pelvic octreotide scintigraphy) were negative in the others. Two patients did not respond CT scan didn’t show any signs of adrenal or ovarian tumors. Bilateral to CRH, and whereas one of these patients and another one did not showed a oophorectomy was performed and histopathologic exam revealed bilateral central-to-peripheral ACTH gradient on IPSS. Tumor markers, such as calcitonin, Leydig cell tumors, measuring 1 cm each. Four months after surgery, the patient gastrin, CEA, and 5-HIAA were also negative in all patients. One patient had had a marked improvement of the signs (score 3 Ferriman–Gallwey) and curative surgery, and three patients underwent bilateral adrenalectomy for control normalized testosterone levels (35.9 ng/dl). hypercortisolism. Subsequent imaging with CT/MRI. Discussion Octreotide scintigraphy finally pointed to the presence of these tumors Androgen-secreting tumors are rare, but they should be excluded in cases of rapid (2 pulmonary ACTH-secreting tumor, and one pancreatic neuroendocrine onset of virilization and elevated androgen levels. Tumors are frequently tumor) from 4 months up to 7 year later. One out of three are alive. Although undetectable by imaging techniques because of their small dimensions. initial failed localization is common, survival is good among the patients with Exploratory surgery by a skilled team is frequently necessary and is often the pulmonary ACTH-secreting tumors. best treatment for the majority of these cases. We present a rare case of bilateral Leydig cell tumor. Only five cases have been reported in the literature. The clinical history and the elevated levels of testosterone had suggested the presence of an androgen-producing tumor. Attempting to the fact that our patient was in a post-menopausal stage, we decided that the appropriate treatment would be P304 bilateral oophorectomy. The histopathologic disclosed the diagnosis and allowed the patient’s cure. Inhibition of intracellular signaling pathways and induction of cell cycle arrest by the multi-kinase inhibitor sorafenib in thyroid carcinoma cells Martina Broecker-Preuss, Anja Redmann, Martin Britten & Klaus Mann Division of Clinical Chemistry, Department of Endocrinology, University Hospital Essen, Essen, Germany.
Objective Therapeutic options for patients with dedifferentiated thyroid carcinoma are rare and alternative treatment strategies are needed. Among the most promising new P306 agents for these patients are protein kinase inhibitors like the BRAF- and multi- Distinct catecholamine phenotypes in hereditary pheochromocytoma targeted kinase inhibitor sorafenib. We have already shown that sorafenib inhibits Graeme Eisenhofer1, Jacques WM Lenders2, Massimo M Mannelli3, Stefan growth of dedifferentiated thyroid carcinoma cell lines with and without BRAF R Bornstein1 & Karel Pacak4 mutation. The purpose of this study was to analyze the molecular effects of 1University of Dresden, Dresden, Germany; 2St Radboud University sorafenib on cell signalling and cell cycle. Hospital, Nijmegen, The Netherlands; 3University of Florence, Florence, Methods Italy; 4National Institutes of Health, Bethesda, Maryland, USA. In thyroid carcinoma cell lines (anaplastic, dedifferentiated follicular and papillary), we analyzed inhibition of signaling molecules of the MAP kinase pathways and of members of the receptor tyrosine kinases after sorafenib This study examined whether different forms of hereditary pheochromocytoma treatment by means of phospho-specific antibodies. Flow cytometric cell cycle are characterized by different catecholamine phenotypes and whether this is analyses were performed to investigate cellular effects of sorafenib. Sorafenib reflected by differences in plasma concentrations of normetanephrine, was kindly provided by Bayer HealthCare. metanephrine and methoxytyramine – the respective O-methylated metabolites Results of norepinephrine, epinephrine and dopamine. Subjects included 154 patients After sorafenib treatment, a rapid inhibition of members of the Map-kinase family with hereditary pheochromocytoma, 72 with tumors associated with von Hippel– including MEK1 and MEK2, Erk1 and Erk2 and p38 Map-kinases was achieved. Lindau (VHL) syndrome, 39 with multiple endocrine neoplasia type 2 (MEN 2), Additionally, members of the Jnk kinase family were inhibited, while the Akt 4 with neurofibromatosis type 1 (NF1), 34 with mutations of the succinate
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 dehydrogenase type B (SDHB) gene and 5 of the succinate dehydrogenase type D 1Endocrine and Diabetes Unit, Department of Medicine I, University of (SDHD) gene. Plasma and urinary catecholamines and metabolites, and tumor Wuerzburg, Wuerzburg, Germany; 2Institute of Pathology; University of tissue catecholamines in a subset of patients, were measured by HPLC. Relative Wuerzburg, Wuerzburg, Germany; 3Endocrine Unit, Department of Medical proportions of norepinephrine, epinephrine and dopamine in tumor tissue were Sciences, Fondazione IRCCS Ospedale Maggiore Policlinico and closely matched by relative increases of plasma O-methylated metabolites, but University of Milan, Milan, Italy; 4Department of Endocrinology, not by those of the parent catecholamines. Patients with tumors due to MEN 2 or University of Duesseldorf, Duesseldorf, Germany. NF1 had increases in both plasma metanephrine and normetanephrine, whereas those with mutations of VHL, SDHD and SDHB genes showed increases mainly in plasma normetanephrine. Plasma levels of methoxytyramine were increased in Adrenocortical carcinoma (ACC) is a malignant tumor with poor prognosis and 65% of patients with tumors due to mutations of the SDHB gene, but were no established therapy in advanced stage. Cisplatin is the most frequently used otherwise generally normal. The study establishes that differences in tumor cytotoxic drug, but even combined with doxorubicin and etoposid, the response ! catecholamine phenotypes can be accurately assessed using measurements of rate is 50%. Recently, it has been demonstrated that the excision repair cross plasma O-methylated metabolites and that these phenotypes differ markedly complementing group 1 (ERCC1) plays a relevant role in the DNA repairing among patients with different hereditary forms of pheochromocytoma. This process, particularly in the correction of platinum-induced DNA adducts. information may be useful in determining relative likelihoods of different disease- Accordingly, ERCC1 expression predicted prognosis in patients with different causing mutations in patients who otherwise have no clinical stigmata or family types of cancers when treated with platinum-compounds. In this study, we history consistent with a hereditary syndrome. evaluated the expression of ERCC1 by immunohistochemistry in ACC and correlated it with clinical outcome. We evaluated 170 adrenal tumor samples spotted on three tissue microarrays, comprising 15 benign tumors (5 inactive, 5 cortisol producing and 5 aldosterone producing adenomas) and 155 ACCs. ERCC1 protein was highly expressed in 14 benign tumors (93%) and only in 71 ACCs (46%, P!0.005). No differences in baseline clinical or histological parameters were found between ACC patients with high and low ERCC1 staining. No impact of ERCC1 expression on overall or disease-free survival was observed in patients who did not receive platinum-based chemotherapy. However, ERCC1 expression was associated with clinical outcome in patients treated with platinum- P307 based regimens (nZ36). Two of 17 ‘positive’ patients had a partial response to treatment, while 4 of the 19 ‘negative’ patients experienced a partial (nZ3) or a VDR gene polymorphisms in patients with differentiated thyroid cancer Z Marissa Penna-Martinez1, Julienne Stern1, Heinrich Kahles1, complete response (n 1). In univariate analysis, ERCC1 expression was the only Ju¨rgen Reusch1, Nora Hinsch2, Martin-Leo Hansmann2, Ivan Selkinski3, significant predictor of survival after first platinum administration (median 3 4 5 survival: 7 months in ‘positive’ versus 17 months in ‘negative’ patients, HR: 2.1, Frank Gru¨nwald , Robert Wahl , Katharina Holzer , Elizabeth Ramos- ! Lopez1 & Klaus Badenhoop1 95% CI: 1.1–5.5, P 0.05). In conclusion, ERCC1 expression may be a novel 1Division of Endocrinology, Department of Internal Medicine I, Diabetes prognostic factor for predicting survival in ACC patients treated with platinum- and Metabolism, University Frankfurt, Frankfurt, Germany; 2Senckenberg based chemotherapy and may provide critical information for individualized Institute for Pathology, University of Frankfurt, Frankfurt, Germany; treatment. 3Department of Nuclear Medicine, University of Frankfurt, Frankfurt, Germany; 4Department of Surgery, Bu¨rgerhospital Frankfurt, Frankfurt, Germany; 5Department of Surgery, University of Frankfurt, Frankfurt, Germany.
Background/aim Vitamin D receptor (VDR) expression has been shown to be upregulated in several tumors and is thought to represent an important endogenous response to tumor progression. Therefore, in order to evaluate the role of VDR-gene and of P309 the 25(OH)-Vitamin D3 in thyroid cancer we analysed four polymorphisms in patients with thyroid cancer and healthy controls. Leptin exerts apoptotic effects and regulates androgen receptors in Patients and methods human prostate cancer cells Patients (nZ136; 84 females and 52 males) with differentiated thyroid cancer Sigal Samuel, Esther Weiss-Messer & Ronnie J Barkey (follicular or papillary) and healthy controls (nZ210; 99 females and 111 males) Department of Pharmacology, Bruce Rappaport Faculty of Medicine and were genotyped for the ApaI (rs7975232), BsmI (rs154410), TaqI (rs731236) and Rappaport Family Institute of Research in Medical Sciences, Technion- Fok I (rs10735820) polymorphisms within the VDR-gene in the German Israel Institute of Technology, Haifa, Israel. population by the PCR-RFLP method. In addition, the 25(OH)-Vitamin D3 serum levels in patients were measured using RIA. Introduction Results Prostate cancer (PCa) progression is known to depend on various hormones The genotype aa of the ApaI polymorphism was significantly less frequent (5.1 vs ! and growth factors, but their role and underlying molecular mechanisms 18.6%; P 0.0003) while heterozygosity was more frequent in patients than in remain poorly understood. We recently presented preliminary findings controls (62.5 vs 45.2%). No association between BsmI, TaqI and Fok I and indicating that leptin causes a greater level of activation of the JAK2/STAT3 thyroid cancer was observed. Furthermore, 74% of the patients showed low serum ! and MAPK (ERK1/2) pathways, as well as transactivation of HER2, in levels of 25(OH)-Vitamin D3 ( 20 ng/ml). androgen-sensitive LNCaP cells than in androgen-insensitive PC3 and DU145 Conclusion human PCa cell lines. We and others were previously unable to demonstrate Both genotypes (Apa I polymorphism) within the VDR-gene and low serum proliferative effects of leptin in LNCaP cells. We now studied the effects of levels of 25(OH)-Vitamin D3 appear to be associated with differentiated thyroid leptin on LNCaP cell apoptotic proteins stimulated by starvation medium- cancer Germans. Nevertheless, additional work is necessary to define the induced stress via the intrinsic pathway, as well as on androgen receptor (AR) extended genotype of VDR and other loci of the vitamin D system and their protein expression. impact on the 25(OH)-Vitamin D3 levels as well as their possible clinical Results applications. Leptin (0.1–10 ng/ml; 6–72 h) caused clear apoptotic effects, seen as an increase in the downstream apoptotic effector caspase 3 protein expression (%2.3-fold; av.GS.E.M.: 1.86G0.09) and in cleaved (inactivated) poly-(ADP-ribose)- polymerase (cPARP89), an enzyme normally responsible for DNA repair and a downstream substrate of caspase 3 (%2.1-fold; av.GS.E.M.: 1.60G0.26). Leptin also caused increased expression of AR protein (%2.6-fold; av.GS.E.M.: 1.96G 0.34). All of these leptin effects were mostly maximal at 0.1–1.0 ng/ml and already at 6 h and generally still maintained at 10 ng/ml and for up to 72 h or P308 gradually reduced (caspase 3) from 24 to 72 h. With view to understanding the ERCC1 expression in adrenocortical carcinoma: relationship with mechanism of these leptin effects, we studied the effects of the JAK2 inhibitor baseline characteristics and response to platinum-based chemotherapy AG490 on leptin-induced signalling and apoptotic and AR proteins. In a Cristina L Ronchi3, Silviu Sbiera1, Patrick Adams2, Luthgard Kraus1, preliminary experiment, leptin-induced pJAK2 and pAKT (10 min) were clearly Heidi Linss1, Sebastian Wortmann1, Holger Willenberg4, Bruno Allolio1 inhibited by AG490, while the inhibitor had lesser effects on leptin-induced & Martin Fassnacth1 apoptotic and AR proteins (6 h).
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Conclusions 90% of ACC, and in 10% of ACA. There was a positive correlation between Clearly, further studies with other kinase inhibitors will be needed to delineate the the usual pronostic factors (tumors size and weight, MacFarlane stages, Weiss mechanism of leptin-induced apoptosis in human PCa and its relationship with the Score), and steroid hormone production. Tissue-specific PTHrP protein effects of leptin on AR. These studies are expected to provide new insights into processing was shown by western blotting. Immunohistochemical staining the possible role of leptin, presumably together with other hormones and growth revealed numerous, dense foci of PTHrP-containing cells in ACC, but few factors, in the progression of human PCa or its delay, and may provide a basis for positive cells in ACA or normal tissue. PTHrP stimulated the growth of discovery of new drugs for therapy of PCa. H295R cells, while specific anti-PTHrP antibody and PTHrP-R1 antagonist both enhanced their apoptosis. PTHrP did indeed activate the cell cycle in H295R cells and released the G1/S checkpoint, resulting in a redistribution of cells in the S and G2/M phases. PTHrP activated both adenylate cyclase/protein kinase A and the intracellular calcium /protein kinase C pathways via PTHrP-R1. The active synthesis of PTHrP is linked to a poor prognosis in ACC, where it may act as an autocrine/paracrinre factor in tumor growth and malignancy. P310 Long-term survival after surgical treatment in patients of adreno- cortical carcinoma Timur Britvin, Oleg Bogatyrev, Denis Pirogov, Alexander Gadzyra & P312 Arian Kalinin M.F. Vladimirsky Moscow Regional Clinical Research Institute, Moscow, Prognostic factors in localized adrenocortical carcinoma (ACC) after Russian Federation. complete resection Jens Obracay1, Martin Fassnacht1, Wolfgang Saeger2, Sarah Johanssen1, Quinkler Marcus3, Tobias Linden4, Koschker Ann-Kathrin1, Adrenocortical carcinoma is a rare tumor characterized aggressive growth and Wortmann Sebastian1, Michael Morcos5, Holger Willenberg6, poor prognosis. This tumor requires the complex way of treatment, where basic Peter Langer7, Matthias Behrend8, Silke Klose9, Nicole Reisch10, method is surgery. Michael Brauckhoff11, Stephan Petersenn12, Peter Bucsky4, The aim of this study was to evaluate the long-term outcome and role of surgery in Wolfgang Oelkers3, Uwe Maeder13, Stefanie Hahner1 & Bruno Allolio14 patients with adrenocortical carcinoma. 1Department of Medicine I, University Hospital, Wuerzburg, Germany; Methods 2Marienkrankenhaus, Hamburg, Germany; 3Charite, Berlin, Germany; From 1998 to 2007, 44 patients were operated for adrenocortical carcinoma 4Coordinating Center for the GPOH-MET 97 Study, Lu¨beck, Germany; (14 cortisol-secreting tumors, 1 virilizing tumor and 29 nonfunctioning tumors). 5University Hospital, Heidelberg, Germany; 6University Hospital, There were 28 women and 16 men, with a medium age 56.3 years (range, 21–72). Duesseldorf, Germany; 7University Hospital, Marburg, Germany; 8Hospital, The mean tumor diameter was 8.4 cm (range, 3–21), weight – 301.2 g (range, Deggendorf, Germany; 9University Hospital, Magdeburg, Germany; 21–2000). The pathological tumor’s stage was I (4 patients), II (8 patients), III 10University Hospital, Muenchen, Germany; 11University Hospital, Halle, (23 patients) and IV (9 patients). Germany; 12University Hospital, Essen, Germany; 13University Hospital, Results Tumor Center, Wuerzburg, Germany; 14University Hospital Wuerzburg, on Complete resection was performed in 41 patients. Among them, three patients Behalf of the German Adrenal Network GANIMED, Wuerzburg, Germany. had combined resection en bloc with the adjacent organs (kidney, spleen and pancreas). Three patients underwent liver segmentectomy and one patient lung resection. Incomplete tumor’s resection was performed in 3 patients. The Even after complete resection, patients with ACC have a high risk of relapse, and mean follow-up was 48.2 months (range, 2–96). Twenty-six patients are still adjuvant treatment with mitotane is frequently recommended. Although mitotane alive and 18 were died. The 5-year overall survival, calculated by the has significant efficacy in this setting, it is associated with a wide range of side Kaplan–Meier method, was 58.5%. The 5-year overall survival rate for effects. As survival is highly variable, prognostic factors are of great interest to patients at stage I, II, III and IV was 98.7, 82.3, 56.7 and 0%, respectively. better guide adjuvant therapy after radical resection. We analyzed clinical and histopathological data of patients without distant Local recurrence or metastases were observed in 13 patients. The mean Z disease-free survival was 26.4 months (range, 6–42). The 3-year disease-free metastases registered with the German ACC registry (n 291). As patients with histologically confirmed complete resection (R0; nZ162) have a significant survival was 40.5%. No significant differences in 3-year disease-free survival Z rates and tumor’s stage were revealed. better 5-year survival than patients with R1 resection (n 14)(68% (95%-CI: 59–78%) vs 36% (13–58); P!0.01) or with uncertain resection status (Rx; Conclusion Z Z Radical surgery with a complete resection of the primary tumor, adjacent organs n 72)(51% (37–65%); P 0.06), we only included patients with R0 resection in and, when feasible, solitary metastases offer the best prospects for long-term the detailed analysis. survival. In univariate analysis, the following factors were indicators of poor prognosis for disease-free and overall survival (DFS/OS): tumor size O8 cm, positive lymph nodes, tumor(thrombus) in v.cava, Ki67 O10%, absence of atypical nuclei or atypical mitoses, mitoses O5/50 HPF, spongiocytic tumor cells !25%, vascular invasion. Multivariate analysis demonstrated improved or impaired DFS (P!0.05) for the following factors: atypical nuclei (hazard ratio 0.39 (95% CI: P311 0.27–0.55)), atypical mitosis (HR 0.43 (0.31–0.59)), mitoses O5/50HPF (HR 2.3 (1.6–3.2)), advanced age (HR 1.02 (1.01–1.02)), positive lymph nodes (HR 3.2 Parathyroid-hormone related- Peptide and PTHrP receptor type 1 (1.9–5.1)), and vascular invasion (HR 1.8 (1.3–2.4)). Furthermore, spongiocytic are expressed in human adrenocortical carcinoma and regulate cell tumor cells !25% (HR 6.9 (2.6–18.1)), tumor (thrombus) in the v.cava (HR 2.8 proliferation and apoptosis in H295R an adrenocortical-derived (1.9–4.0)), and positive lymph nodes (HR 3.5 (2.3–5.3)) were associated with cell line decreased overall survival. Using these factors, it is possible to calculate ´ Marthe Rizk-Rabin, Guillaume Assie, Fernande Fernande, prognostic indices. A patient without any of these adverse risk factors has a 5-year ´ Karine Perlemoine, Hinda Hamzaoui, Frederique Tissier, disease-free survival rate of O90%. ´ ˆ Michele Lieberherr, Xavier Bertagna, Jeroome Bertherat & Zhor Bouizar In conclusion, we have identified important prognostic factors in ACC patients ´ Institut Cochin, Universite Paris Descartes, CNRS (UMR 8104), Paris, with R0 resection based on clinical and histological parameters. These factors France. may help to guide adjuvant therapy in ACC.
Adrenocortical tumor (ACT) is a rare, heterogeneous malignancy whose pathogenesis is unclear. The oncoprotein PTHrP, found in many common tumors, can regulate their growth in an autocrine/paracrine fashion through the receptor PTH-R1. Little is known about the role of PTHrP in ACT. We monitored the synthesis of PTHrP and PTH-R1 in a series of 25 ACT: 12 adrenocortical carcinoma (ACC), 13 adrenocortical adenoma (ACA), and P313 investigated the effects of PTHrP (1–34) on H295R cells derived from Multi-center, observational study on Sandostatin LAR treatment adrenocortical carcinoma. PTH-R1 mRNA and proteins were detected by patients with acromegaly in Poland: preliminary report RT-PCR and western blotting in all the ACT samples and in H295R cells. Wojciech Zgliczyn´ski1, Piotr Zdunowski1, Jerzy Sowin´ski2, Beata There was no significant difference between their concentrations in the ACT. Kos-Kudła5, Marek Bolanowski3, Graz˙yna Bednarek-Tupikowska3, PTHrP mRNA was assayed by quantitative real-time PCR. It was detected in Jolanta Kunert-Radek4 & Sławomir Mucha4
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
1Medical Center of Postgraduate Education, Warsaw, Poland; 2University of P315 Medical Sciences, Poznan´, Poland; 3Wrocław Medical University, 4 5 Epidemiology of pituitary tumours in Iceland 1955–2007: a Nationwide Wrocław, Poland; Medical University of Ło´dz´,Ło´dz´, Poland; Medical Study University of Silesia, Zabrze, Poland. Tinna Baldvinsdottir1, Jon G Jonasson4, Arni V Thorsson3, Asta Bragadottir1, Gunnar Sigurdsson2 & Rafn Benediktsson2 1Faculty of Medicine, University of Iceland, Reykjavik, Iceland; Aim 2 The aim of multi-center, observational study was to assess the outcome of the Department of Endocrinology and Diabetes, Landspitali University Hospital, Reykjavik, Iceland; 3Children’s Medical Centre, Landspitali treatment with somatostatin analogue octreotide-LAR (O-LAR) patients with 4 acromegaly. University Hospital, Reykjavik, Iceland; Icelandic Cancer Registry, Material Reykjavik, Iceland. Material consisted of 360 patients (60% women) aged 18–84 years (mean 45.5; G S.D. 12.9) with active acromegaly. Prior to the inclusion 172 patients underwent Pituitary tumours may be more prevalent than previously appreciated. Although unsuccessful neurosurgery. this is thought to relate mostly to greater utilisation of imaging techniques in Methods recent years, evidence suggests that the increased prevalence also applies to Observation was planned for 1 year. O-LAR monthly dose was adjusted to 10– clinically important tumours. 30 mg accordingly to IGF-1 levels. Assessments of clinical symptoms and We have created a nationwide registry of pituitary tumours occurring in Iceland GH/IGF-1 was performed quarterly. Visual field and pituitary MR was performed for the last 55 years. We have examined medical, surgical, pathology and imaging initially, and after 12 months. records at all hospitals as well as private practices in Iceland. We also scrutinized Results records of out of hospital imaging facilities and the Icelandic Cancer Registry. Observation completed 330 patients from 29 centers in Poland, mainly from A total of 312 individuals have been identified during this period, 119 men and Warsaw (84), Poznan´ (51) and Silesian region (45). Mean period of symptomatic 193 women (P!0.03). Overall, the median age at diagnosis was 41.9 years (range G disease prior to diagnosis was 8.8 years (1–24 S.D. 4.9). Concomitant diseases 3–88 years) being 35.2 years for women and 53.3 years for men. The most was hypertension (64.2%), diabetes mellitus (20.3%) and heart failure (8.3%). common tumour types were prolactinomas in 35% and non-functioning adenomas Goiter was present in 59.2% and hyperthyroidism in 8.6% cases. Prior to O-LAR in 26%. The overall age standardized incidence was 2.9/100.000 population for treatment pituitary macroadenoma was shown in 62%. Initially, mean GH women and 1.8/100.000 for men while the prevalence in December 2006 was G concentration was 19.5 mg/l (S.D. 35; 1.0–449 mg/l) and decreased significantly 82/100.000 population. For women the incidence increased from 0.1/100.000 to G during treatment to 8.4 mg/l (S.D. 11.5) after 3 months, and finally to 5.6 mg/l 6.3/100.000 comparing the first and last quarter of the study period while G ! (S.D. 7.9), P 0.0001. Parallelly, mean IGF-1 concentration was 894.5 mg/l comparable figures for men were 0.4/100.000 and 3.6/100.000. The increase in G G ! (S.D. 350; 209–2461 mg/l) and decreased to 573.5 mg/l (S.D. 311) (P 0.001), incidence observed was clearly associated with the introduction of modern G ! and finally to 457 mg/l (S.D. 262) (P 0.001). IGF-1 normalization was achieved imaging technology to Iceland. However, 84% of the individuals did have O in 61.6% patients. Pituitary tumor volume decreased significantly ( 25%) in symptoms or signs attributable to the tumour at diagnosis. 57% of patients. Treatment led to significant reduction of acromegaly symptoms: The increased incidence and current prevalence of pituitary tumours in Iceland is soft tissues edema was present initially in 95%, after treatment – in 47%, comparable to recent studies from elsewhere. The observation that the majority of hyperhydrosis in 90 and 42%, respectively, headaches 80–49%, arthralgia the patients had symptoms or signs attributable to the tumour highlights the 85–55%, weakness 69–43%, carpal tunnel syndrome 18–4%, paresthesiae importance of general physicians being aware of this condition. 43–39%, sleep apnoea 19–8%, galactorrhoea 6–1%. Adverse effects were mild and mainly affected gastrointestinal system (diarrhea in 15% and during treatment fell to 5%, abdominal pain 8% fell to 4%, and nausea affected 8% and fell to 5%. No therapy discontinuation occurred. This is the largest observational study to assess O-LAR efficacy in acromegaly reported. Results proves, high efficacy of medical therapy with somatostatin analogue in terms of clinical and biochemical improvement. Therapy is safe and well-tolerated. P316 Effects of pasireotide on bronchial carcinoids in primary culture Maria Chiara Zatelli1, Federico Tagliati1, Andrea Luchin1, Marta Bondanelli1, Federico Rea2 & Ettore degli Uberti1 1Section of Endocrinology, Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, Ferrara, Italy; 2Department of P314 Thoracic Surgery, University of Padova, Padova, Italy. A study on investigations for localizing insulinoma Mazhar Ul-Haq & Jiten P Vora Royal Liverpool University Hospital, Liverpool, UK. Bronchopulmonary endocrine tumors represent 25–30% of lung neoplasms. Surgery provides good survival for differentiated tumors (typical and atypical carcinoids), but is not useful for aggressive poorly differentiated We studied the practice of investigations for diagnosing and localising insulinoma forms. Somatostatin (SRIF) analogs can be used as medical therapy, in our hospital. We looked at the number of investigations performed before exact prolonging patient survival. However, the compounds employed so far did localisation of insulinoma. not display antiproliferative effects. Recently, a new stable SRIF analog, We identified 5 cases that were confirmed on clinical, biochemical or pasireotide (SOM230), which activates SSTR1, 2, 3, and 5, has been histopathological bases and were recorded on the histopathology and IT database developed. Our study aimed at clarifying whether SOM230 might affect cell as ‘insulinoma’ from 1986 to 2004. We looked retrospectively at the case notes of viability of bronchial carcinoids in vitro. We assessed SRIF receptor these cases. expression pattern, both at mRNA and protein level, as well as the in vitro All 5 cases had blood tests for insulin and c-peptide during a 72 h fast. Three out effects of SOM230 on cell viability. Sixteen brochial carcinoids (13 typical of 5 had abdominal ultrasound and this was normal in 2 and inconclusive in 1. All and 3 atypical carcinoids) were examined by RT-PCR and by microscopy had abdominal CT scan and was normal in 3. One CT scan was normal 8 years immunofluorescence for expression of Chromogranin A (CgA) and SSTRs. after symptoms onset and a repeat CT, after 15 years of symptoms, localized a In addition, primary cultures were tested with SOM230 in vitro. All samples mass. One CT localized the lesion quite close to the exact location as found on expressed CgA, while SSTR1 was expressed in 14 samples, SSTR2 and surgery. Angiogram, portal venous sampling and gut hormone profile were SSTR4 in 12, SSTR3 in 5, and SSTR5 in 7 samples. Treatment with performed in 2 patients. One patient had endoscopic ultrasound which localized SOM230 did not significantly modify cell viability, but was capable of insulinoma accurately. Two patients had pancreatic MRI which were blocking the proliferative effects of Forskolin, a potent stimulator of cyclic inconclusive. Four patients had surgical exploration and all of these had intra AMP (cAMP) pathway. This effect was apparent in primary cultures from operative ultrasound (IOUS). IOUS localized lesions only in 1 of 4 patients. carcinoid tumors expressing SSTR1 or SSTR2, as well as in tumors not Octreotide scan was done in 2 and both were normal. expressing SSTR3 or SSTR5. Our data demonstrate that cAMP pathway These findings suggest that none of the tests performed were able to localize activation up-regulates bronchial carcinoid cell proliferation, which can be insulinoma accurately all the time. We do not seem to have any consensus on any inhibited by SOM230 in selected cases. Indeed, our data suggest that this protocol for specific investigations to localize these disabling tumours and we effect is mediated by SSTR1 or SSTR2, and not by SSTR3 or SSTR5. Since performed a number of different imaging techniques. There is a need for drawing SSTR1 and 2 are the most represented among bronchial carcinoids, our data joint guidelines by physicians and surgeons for localizing these tumours support a possible role for SOM230 as a new tool for medical therapy of accurately. these tumors.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P317 We conclude that the hyperplasias that cause Cushing’s syndrome more The prognostic factors in adrenocortical carcinoma frequently than was tought, and they are associated with other diseases, Elwira Przybylik-Mazurek, Alicja Hubalewska-Dydejczyk, including CNC. Genetics defects of phophodiesterases might be a frequent Sylwia Kuzniarz, Katarzyna Lubaszewska & Bohdan Huszno cause of adrenal and other tumours. Collegium Medicum Jagiellonian University in Krakow, Krakow, Poland.
Adrenocortical carcinoma (ACC) is a rare neoplasm with poor prognosis. Patients present signs of hormone excess: virilisation, Cushing’s syndrome or only P319 enlarged abdominal mass. Incidentally ACC can be also detected in the ultrasonography. Some of ‘non-hypersecretory’ ACCs can produce non-bioactive Self-observations of total life situation in patients with Acromegalia hormones steroid precursors or not very big amount of them and sometimes Jonna Gintberg Jensen patients present subclinical Cushing’s symptoms. Surgery and adjuvant radio- Aarhus University Hospital, Aarhus, Denmark. therapy and chemotherapy with Mitotane is the treatment of choice. Aim Background The aim of the study was to analyse clinical features, hormonal test results and Acromegalia is an infrequent chronic disease requiring lifelong control. A total of prognosis in patients with secreting and non- secreting adrenal cancers. about 350 Danish patients have acromegalia. It is difficult for this patient group to Patients find information on coping strategies in fellow patients. The course of disease of 22 patients: 6 men and 16 women median age 45.5 year There are numerous international quantitative studies on the symptoms in was analysed. Clinical examination, the imaging studies and hormonal assays acromegalia patients; no qualitative studies on self-observations as a way to were performed. Seventeen patients underwent surgical treatment. Mitotane was exchange experiences and optimize nursing in connection with hospitalisations. administered in 16 patients. The purpose was to clarify patients’ self-observations on: Results † What it was like to live with a disease for many years before it was diagnosed Virilization was diagnosed in 3 patients, overt or subclinical Cushing’s and treated. syndrome in 12 patients. Fourteen patients were classified as the I-st or II-nd † Nursing is in connection with hospitalisations. stage, 8 as the III rd or IV th stage. The total and the asymptomatic survival † Patients’ outlook/perception of the future. time was longer in non-secreting patients than in secreting (53.86 vs 32.6 and Method 53.42 vs 13.9 months respectively). The secretory tumours were bigger than The theoretical approach was the operative constructivism by Niklas Luhmann. non-secretory (10.34 vs 6.15 cm). Due to ACC progress 10 patients died The qualitative interviews were based on the method of Steiner Kvale. From April among which only one had non-secretory tumour. The mean time of to December 2007, 37 patients were interviewed in connection with observation was 13.7 months. Three patients with advanced disease and 9 hospitalisations at Aarhus University Hospital, Denmark. The semi-structured patients with complete remission are still alive. In all patients with long-term interview guide was based on Katie Eriksson’s theories about disease, nursing and remission, the mean diameter of tumour was 5.7 cm, and the mean time of life suffering. The method of analysis was meaning condensation. Analyses will observation is 76.6 months. be made in January 2008. Conclusion Preliminary results The poor prognostic factors in ACC are: size of tumour, presence of local and Some patients see themselves as healthy, but most patients experience discomfort: distant metastases and hormonal activity. Chemotherapy with mitotane prolong † They are unfit for work life of patients, but is less effective in advanced disease with excessive steroid † They have problems structuring everyday life hormone secretion. † They have social problems † They worry about the future Anticipated conclusion: The results can be used for † Patient information † Optimization of nursing † Patient education to enable patients to manage complications at an early stage. P318 Cushing’s syndrome due to a pigmented nodular adrenocortical disease and a acromegaly corresponding to a Carney complex (CNC) Concha Sanabria, Natalia Perez-Ferre & Jose Angel Diaz Department of Endocrinology and Nutrition, Hospital Clinico San Carlos, Madrid, Spain. P320 Mitotane induces a concentration-dependent impairment of platelet aggregation in patients with adrenocortical carcinoma The CNC is a dominantly syndrome, characterized by spotty skin pigmentation, Stefanie Hahner 1, Martin Eigenthaler2, Theodoros Savvoukidis1, endocrine overactivity and myxomas (Carney & Young 1992), associated with Sarah Johanssen1, Sebastian Wortmann1, Ann-Cathrin Koschker1, lentigines and blue naevi; the disease links to 17q22-24, and its mutations have Bruno Allolio1 & Martin Fassnacht1 been identified in the genes PRKAR1a. The most common endocrine 1Endocrinology and Diabetes Unit, Department of Medicine I, University of manifestations affect two o more endocrine glands, including acromegaly, Wuerzburg, Wuerzburg, Germany; 2Institute for Clinical Biochemistry and thyroid and testicular tumours and ACTH-independent Cushing’s syndrome due Pathobiochemistry, University of Wuerzburg, Wuerzburg, Germany. to primary pigmented nodular adrenocortical disease (PPNAD). There are around 160 cases reported. We describe the case of a 52-year-old menopausal woman who complained for Standard treatment of adrenocortical carcinoma (ACC) comprises adrenolytic pain in the right flank, but the anamnesis reflected symptoms of mild therapy with mitotane. Prolongation of bleeding time has previously been hypercortisolism (hypertension, troncular over weight, asthenia, strengthless.) observed based on a series of 7 patients (Haak et al. 1991). As patients with ACC and a spotty skin; a Cushing’s syndrome was confirmed: lost of the circadian frequently undergo surgery for local recurrence or metastases, we have studied rhythm of cortisol (26.3 mcgr/dl pm 24.5 mcgr/dl), high free urine cortisol the effect of mitotane on coagulation in 44 patients with ACC before and/or (135 mcgr/24 h), and no suppression of the cortisol levels after 1 (259 mcgr/dl) during treatment with mitotane (total sample size nZ62). and 8 mg (285 mcgr/dl) of Dexametasone. A 2.6 cm lesion in the left adrenal Platelet aggregation was performed with standard light transmission aggrego- was described in the abdominal scanner and also a 8.5 cm mass in the left metry using platelet rich plasma. Major components of the extrinsic and intrinsic kidney. She was operated and the histopathology reported a pigmented nodular coagulation cascade pathways were determined by routine coagulation testing hyperplasia of the adrenal and an angiomiolipoma. The follow-up verified a using the Dade Behring BCS analyzer system or manual ELISA testing. In vitro cortisol deficiency; although there was and improvement of the symptoms, she bleeding time was detected as PFA-100 measurement. still complained about asthenia and malaise with pain in the joints. Acromegaly During mitotane therapy, a successive decrease in platelet aggregation occurred was diagnosed after the pituitary study, with confirmation of elevated IGF-1 that was closely correlated with mitotane levels. This effect was most pronounced levels (482 ng/dl) and no suppression of the GH levels after OGTT (peak of for ADP-induced platelet aggregation (Pearson rZ0.77; P!0.001) and induction GH 7 ng/dl) and an image of global growth of the pituitary in the MRI. The with collagen (rZ0.47; PZ0.002), but less so for challenge with epinephrine (rZ response to the treatment with somatostatin analogs (Sandostatin 20 mg/28 - 0.25; PZ0.1), and ristocetin (rZ0.18; PZ0.2). Platelet counts, in vitro bleeding days) was good, clinically and the analysis. Breast tumour, cardiac myxoma, time, global plasmatic coagulation and von Willebrand parameters remained thyroid disease and colonic cancer were ruled out, after the images studies. The unaffected. With mitotane levels above 10 mg/l, 18 out of 19 patients had genetic study of mutations in the PRKAR1a was request. pathologic ADP-induced platelet aggregation.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
In conclusion, in a large series of patients with ACC we show impaired agonist- declining thereafter. Conversely, in EGb 761-treated patients, a slight not induced platelet aggregation strongly dependent on plasma mitotane levels. significant increase of MN without a peak was observed. Therefore, mean MN Routine in vitro bleeding time is not suitable to detect this platelet defect and to increment was significantly higher in placebo- than in EGb 761-treated patients assess bleeding risk. ADP-induced platelet aggregometry testing prior to surgery (P!0.01). Moreover, an early (7th day, P!0.005) and sustained (P!0.01, is recommended to determine mitotane-induced bleeding risk. Further studies ANOVA for repeated measures) MN increase induced by CFs was observed in the should investigate the potential role of prophylactic administration of DDAVP to placebo group while, in EGb 761-treated patients it never reached the statistical improve platelet function. significance. Again, mean MN increase induced by CFs was significantly higher in placebo- than in EGb 761-treated patients (P!0.05). Thyroid remnant resulted ablated in all the patients. Conclusions Although 131I therapy is essentially safe, our data encourage for the use of Ginkgo P321 biloba extract to prevent possible harmful genetic effects, particularly in patients One hundred minimally invasive parathyroidectomies without intra- with metastasis who require repeated radioiodine treatments. operative localisation and PTH monitoring Muhammad Suleman Farooq & Mrinal Saharay Queen’s Hospital, Romford, Essex, UK. P323 Background Neuroendocrine tumours (NETs): one centre experience Minimally invasive parathyroidectomy (MIP) for primary hyperparathyroidism is 1 1 routinely performed in many centres. Various preoperative and intraoperative Alicja Hubalewska-Dydejczyk , Malgorzata Trofimiuk , Anna Sowa- Staszczak1, Piotr Szybinski2, Jan Kulig2, Dorota Pach1, Aleksandra Gilis- localisation techniques are used along with intraoperative PTH monitoring 1 1 (IOPTH). Januszewska & Bohdan Huszno 1Chair and Department of Endocrinology, Medical College, Jagiellonian Results 2 We report the results of 110 consecutive patients presenting to our unit with a University, Krakow, Poland; The Gastrointestinal and General Surgery diagnosis of primary hyperparathyroidism from January 2004 until November Department, Medical College, Jagiellonian University, Krakow, Poland. 2007. All patients had sestamibi scintigraphy (MIBI) as the primary investigation for preoperative localisation. One hundred patients had a positive scan showing a Background single gland and underwent MIP by a single surgeon without any further pre or NETs are rare tumours arising from dispersed neuroendocrine system. Never- intraoperative localisation studies and without IOPTH monitoring. The remaining theless, their estimated prevalence increased lately, mostly due to progress in 10 patients underwent further localisation studies and bilateral conventional neck imaging, biochemical and histopathological diagnostics. exploration and were not included in the study. In 95 patients, a single abnormal The aim of the study was to present the characteristics of the NETs patient gland concordant with the localisation scan was identified and excised. In 5 surveyed in our Endocrinology Department since 2000. patients, no obvious abnormal gland was identified; they were converted to Material and methods bilateral neck explorations. In one among these, an abnormal gland was found on One hundred and fifty-eight patients (males – 42.4%, females – 57.6%) aged 1⁄ the opposite side to the scan report and was excised. In remaining 4, 3 2 glands 18–82 years were included in the analysis. Medullary thyroid cancer, small cell were excised. Primary outcome measure of normocalcaemia at 6 months was lung cancer and pheochromocytoma patients were excluded. achieved in 95/100 (95%). Of the 5 patients who remained hypercalcaemic, a Results second abnormal gland was identified on repeat MIBI scan in 1 patient and According to WHO NETs classification patient in stage Ia constituted 2.5%, successfully removed by further uncomplicated surgery. Two of the 4 remaining Ib-38.6%, II-57%, III-1.3%, IV-0.6% of the analyzed group. The most common patients were subsequently diagnosed as suffering with familial hypocalciuric localization of the primary tumour was pancreas (34.2%). About 18.4% of studied hypercalcaemia and 2 with parathyroid hyperplasia and treated conservatively. NETs arose from foregut, 25.3% from midgut (including 5% tumours from Conclusion appendix) and 17.1% from hingut. Five percent of disseminated NETs had unknown In the majority of patients with primary hyperparathyroidism and a positive MIBI primary origin. Among the NETs there were such rare as epiglottis and gallbladder scan, MIP can be safely undertaken without any further pre or intraoperative carcinoids. Distant metastases were found in 29% of the patients, which may be localisation and without IOPTH monitoring. attributed tothe relatively high proportionof indolentgastric NETs, insulinomas, and early diagnosed rectal carcinoids. Functioning NETs constituted 41.1% of the group. About 77.2% of the patients were treated surgically, 9.5% received systemic chemotherapy, 19.6% – radioactive peptide therapy. About 5.1% of the study group died – most often due to complications of ectopic Cushing’s syndrome. Conclusions P322 Modern and widely accessible diagnostic procedures (particularly endoscopy and Effect of Ginkgo biloba extract supplementation on genotoxic damage endoscopic surgery) result in increased number of early recognized NETs. It after thyroid remnant ablation by 131I implies the possibility of radical surgical treatment, although due to indolent Angela Dardano1, Michela Ballardin1, Claudio Traino3, Nadia Caraccio1, behavior of NETs all patient should be periodically screen for distant metastases. Chiara Colato2, Roberto Barale1, Giuliano Mariani1, Marco Ferdeghini2 Relatively low mortality among NETs patient, even with disseminated disease, may & Fabio Monzani1 be attributed not only to the tumour biology, but also to the new methods of 1University of Pisa, Pisa, Italy; 2University of Verona, Verona, Italy; treatment (particularly radiopeptide therapy), which are able to stabilize the disease 3S. Chiara Hospital, Pisa, Italy. and offer control of its symptoms.
Background Radioiodine (131I) therapy is performed in patients with differentiated thyroid cancer (DTC), either for thyroid remnant ablation or treating distant metastasis. P324 131 Although I therapy is generally considered safe, a genotoxic damage has been Abnormalities in glucose tolerance in acromegalic patients demonstrated both in vivo and in vitro. Maria Stelmachowska-Banas´, Piotr Zdunowski & Wojciech Zgliczyn´ski Aim Medical Center of Postgraduate Education, Warsaw, Poland. To evaluate the possible effect of Ginkgo biloba extract (EGb 761) supplementation on the time-course (up to 120 days) of clastogenic factors (CFs) and micronuclei (MN) appearance in lymphocytes from patients with DTC Background after thyroid remnant ablation, in a double-blind, placebo controlled study. Acromegaly is characterized by disabling symptoms and relevant comorbidities. Methods Insulin resistance, leading to glucose intolerance is one of the most important Nineteen patients with DTC (12 F, aged 30–68 years; administered 131I activity: contributory factor to the cardiovascular mortality in acromegaly. 2.96–5.50 GBq) were randomly assigned to EGb 761, 120 mg/day for 1 month Aim (nZ9, 6 F) or placebo (nZ10, 6 F). Blood was taken at various intervals after 131I To assess the impairments of glucose homeostasis in acromegalic patients and therapy (from 7 to 120 days), for the evaluation of the time-course of CFs and MN find association between activity of the disease and the severity of glucose appearance in peripheral lymphocytes. intolerance. Results Patients and methods In the placebo group, MN significantly increased after 131I therapy (P!0.001, In this retrospective study, we analyzed records of 220 patients (138 females – ANOVA for repeated measures), peaking at 7th day (P!0.005) and slowly 62.27% and 83 males – 37.73%) with untreated acromegaly diagnosed at our
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Department in the years 1994–2006. Diagnosis of active acromegaly was Introduction established on the basis of elevated plasma GH above 1 ug/l during the 75 g Transsphenoidal adenomectomy is the treatment of choice in secreting pituitary OGTT and elevated plasma IGF-1 above normal range for age and gender. The adenomas with the symptoms of Cushing’s disease, acromegaly as well as few patients with overt diabetes mellitus did not undergone the test. The abnormalities cases of Prolactinoma, which – due to resistance to pharmacological treatment – in plasma glucose concentrations were categorized according to WHO criteria. require surgery. The efficacy of selective adenomectomy ranges from 60 to 95%. Results It is the highest in patients with well-visualized by MRI microadenomas, lower in In the studied group, the mean age at the moment of diagnosis was 46.28G13.82 macroadenomas and the lowest when the surgery was performed without any years. The duration of the disease since the onset of the first symptoms was 7.50G changes in imaging techniques. 4.97 years. Due to complicated diagnostic procedures and the necessity of prolonged Normoglycemia existed in 45.52% of acromegalic patients. Among glucose postoperative observation it is necessary to prove which hormonal laboratory tolerance abnormalities we found impaired fasting glucose (IFG) in 20%, findings drawn shortly after pituitary surgery could foresee the lasting remission. impaired glucose tolerance (IGT) in 5.52%, both IFG and IGT in 6.90% and overt The early identification of a high risk of recurrence would allow to perform an diabetes mellitus in 22.07%. There was no statistically significant difference in immediate re-operation that increases the chance of cure during the same hospital basal plasma GH and IGF-1 concentrations between normoglycemic patients and stay. with impairments in glucose tolerance. The groups statistically significantly We have examined 40 patients with secreting pituitary adenomas being prepared differed when the age of diagnosis was concerned (PZ0.038). There was no at our site to surgical treatment and followed up for the next 12 months. All significant correlation between fasting plasma glucose and GH, IGF-1 patients were operated by the same neurosurgeon performing over 100 concentrations. transsphenoidal surgeries per year. Conclusions All patients had blood draws for serum cortisol, GH or PRL performed on the first The frequency of diabetes was four times higher in acromegalics than in general postoperative day and additionally FSH, LH, TSH. The same laboratory tests Polish population which should urge clinicians to treat this disease not only to were taken after 6, 12, 24 weeks and 12 months after surgery. reduce growth factors, but also to maintain the favorable effects on metabolism The results of our study indicate that subnormal (!2.0 ng/ml) serum cortisol and metabolism-related mortality. levels in the first postoperative day in CD can foresee lasting remission. In case of acromegaly, the low levels (!1.0 ng/ml) of serum GH can predict long-term remission. In patients suffering from Prolactinoma, we perform surgery only in tumors resistant to pharmacological treatment. The early results seem to be promising. Conclusion P325 The early results show a correlation between low serum cortisol, GH and PRL Mutations in the ret proto-oncogene in Romanian patients with multiple levels in the 1st day after surgery and long term remission. It simplifies endocrine neoplasia type 2 postoperative diagnostic procedures. In case of CD, we expect that the cut off Diana Paun1,2, Carmen Duta1,2, Maria Mohora1,2, Cristian Dogaru1,2 & point will be lower than 5 ng/ml – previously obtained in other studies. In Constantin Dumitrache1,2 addition, the early postoperative cortisol assessment allows to predict post- 1C.I.Parhon Institute of Endocrinology, Bucharest, Romania; 2UMF Carol operative function of the pituitary–adrenal axis. Davila, Bucharest, Romania.
Multiple endocrine neoplasia (MEN) is characterized by the occurrence of tumors involving two or more endocrine glands; MEN 2 is defined by medullary thyroid carcinoma in association with phaeochromocytoma and appears in several clinical variants, which may be inherited as autosomal dominant syndromes. P327 Mutational analysis of RET protooncogene has been use in the diagnosis and management of patients and families with MEN 2 variants. Prognostic value of 100 mcg s.c. octreotide test (SHort Octreotide Test – Aim SHOT) for prediction of medical treatment outcome in patients with In this study, we retrospectively analyzed 20 patients with MEN 2 from 14 acromegaly different families for relevance of specific mutations in the RET proto-oncogene. Piotr Zdunowski & Wojciech Zgliczyn´ski Materials and methods Medical Center of Postgraduate Education, Warsaw, Poland. Genomic DNA was extracted from peripheral leukocytes using a Promega blood minikit and two fragments covering the exons 10 and 11 of the RET gene were Background amplified by polymerase chain reaction using specific oligonucleotide primers Neurosurgery is treatment of choice in patients with GH-secreting pituitary (exon 10: 50-GCCTATGCTTGCGACACCAGTTG-30, exon 11: 50-CATGAGG- 0 adenoma. However, in about 50% of cases surgery is ineffective or contra- CAGAGCATACGCA-3 ) and the following protocol; 95CX 10 min followed by indicated. Long-acting somatostatin analogues are possible, although expensive 30 cycles 95CX 1 min, 64CX 1 min, 62CX 30 s and a final extension at 72C for therapeutic alternative. Generally, 60–70% of patients with active disease 7 min. The resulting fragments were sequenced directly with the Big Dye R responds to such medical treatment. Terminator v 3.1 cycle sequencing kit using a ABI Prism 310 Genetic Analyser. Aim Results Aim of this study was to identify factors influencing medical treatment outcome In 13 of 20 examined MEN 2 cases, missense mutation of codon 634 from exon 11 and to determine if testing injection of 100 mcg octreotide s.c. (SHort Octreotide of the RET proto-oncogene were detected. Nine of the MEN 2 samples proved to Test – SHOT) may be used as predictive tool. have an identical base sequence change TGC-TGG resulting in the substitution of Material Cys with Trp, two of the samples have the change TGC-GGC resulting in the Material consisted of 137 patients (88 F and 49 M) aged 17–83 years (mean 49.6) substitution of Cys with Gly and other two samples have the change TGC-CGC with active acromegaly, treated 2001–2005 in one center. Neurosurgery was resulting in the substitution of Cys with Arg. We cannot detect mutations in exon primary therapy in 48 cases. 10 or 11 of RET protooncogenes in 7 patients with specific tumors associations. Methods Conclusion SHOT: GH assessed in 30 min intervals during 2 h acute 100 mcg octreotide s.c. We conclude that, in all families with MEN 2, mutational analysis of the RET test. Treatment initiation: GH and IGF-1 concentrations were determined at 1, 3, proto-oncogene should be performed both to identify specific mutations and to 7, 14 and the 28 day following test dose 20 mg of OCT-LAR i.m. Prolonged prove gene carrier status for MEN 2. treatment: GH and IGF-1 assessments were performed quarterly during 2–5 years of medical treatment. Imaging (MR) was performed yearly and KNOSP scale was assessed. Results Significant reduction of GH concentration (by more than 75%) was achieved in 48 out of 137 cases (35%) SHOT suppressed GH below 2 ng/ml, but in 93 (68%) GH P326 reduction by more than 75% was achieved. Administration of the first OCT-LAR Is the early postoperative hormonal assessment a helpful predictor dose suppressed GH below 2 ng/ml in 44 patients (32%) and in 93 (68%) by more of the long term remission in secreting pituitary adenomas after than 75%, whereas the IGF-1 levels dropped to age–sex reference range in 39 transsphenoidal adenomectomy? cases (28%). Most pronounced reduction of GH level (mean drop from 26.2 to Przemysław Witek1, Wojciech Zgliczyn´ski1, Piotr Zdunowski1, 10.8 ng/ml) was registered at the 14th day following the OCT-LAR. During Maria Stelmachowska-Banas´1 & Grzegorz Zielin´ski2 prolonged treatment, GH and IGF-1 levels decreased slowly during first year, and 1 2 Medical Center of Postgraduate Education, Warsaw, Poland; Military then remained stable (mean 8.3 ng/ml S.D. 5.7 and 497 ng/ml S.D. 312 for GH Institute of the Health Services, Warsaw, Poland. and IGF-1, respectively). IGF-1 normalization were achieved in 76 (55%).
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Reduction of GH levels in SHOT tightly correlated with the GH level during long- Vit D was in the low-normal range 40 nM. SestaMIBI scintigraphy and cervical term treatment (RZ0.68, P!0.001). Assessment of GH and IGF-1 during first ultrasonography were normal. Eight months later PTH was very high 419 ng/l month of therapy has no additional value. Reduction of GH below 2 ng/ml defines with hypercalcemia 3.3 mM and low phosphorus levels 0.52. An 18 Fluoro-FDG cohort of most probable IGF-1 normalization (sensitivity (sen.) 96% and PET scan was normal with no fixation on bones or lungs. Creatinine clearance specificity (spe.) 95.5%), whereas by O75% precisely predicts good outcome of was 54 ml/min. After bisphosphonate and hydration without major effect long term therapy (sen. 97% and spe. 70%). Other, independent factors of good (calcemia 2.88 mM), cinacalcet was begun with titration: 30 mg BID one week, outcome is symptoms duration !10 years (sen. 72% spe. 65% and KNOSP grade 60 mg BID three weeks. Calcium levels were slightly decreased at 3 mM with low !3 sen. 63% spe. 48%). phosphorus levels: 0.38; 0.45; 0.61 mM. Cinacalcet dosage is now increased to Conclusions 90 mg BID and is presently well tolerated (no nausea or vomiting noticed). SHOT is effective in identification of cohort with favourable prognosis of Treatment titration is still going on; a new sestaMIBI scintigraphy is planned. pharmacological treatment efficacy. Though emergent, Cinacalcet seems promising to control hypercalcemia in parathyroid carcinoma. Actualization of our data will be given with genetic results of HRPT2.
P328 Cushing syndrome with an atypical evolution P330 Pierre Lecomte1, Peggy Pierre1, Marie Castric1, Christine Chabrolle1, Ovarian serous and mucinous tumors of low malignant potential: Loı¨c de Calan2 & Serge Guye´tant3 patterns of stromal invasion 1Endocrine Unit, University Hospital, Universite´ F. Rabelais, 37044 Tours Simona Costi, Alis Dema, Ioana Golu, Marioara Cornianu, Sorina Taban, Cedex 9, France; 2Endocrine Surgery, Universitary Hospital, Universite´ Anca Muresan & Elena Lazar F. Rabelais, 37044 Tours Cedex 9, France; 3Pathology Unit, University University of Medicine and Pharmacy, Timisoara, Romania. Hospital, Universite´ F. Rabelais, 37044 Tours Cedex 9, France.
Purpose A 72-year-old depressed woman complained about fatigue, weight gain The purpose of this study was to evaluate the histologic spectrum of stromal– (20 kilos/2 years), severe and recent hypertension, easy bruises, and venous epithelial patterns of invasion in ovarian serous and mucinous tumors of low insufficiency. Whereas she was treated with six antihypertensive drugs, she had malignant potential. hypokaliemia (2.6 mM). Cardiac ultrasounds showed myocardial hypertrophy. Materials and methods A Cushing syndrome was suspected. UFC was increased (400 mM/d), cortisol We retrospectively analyzed 31 cases of borderline ovarian serous and mucinous cycle disrupted and a standard DXM test showed no cortisol suppression tumors diagnosed of the Pathology Department of County Hospital Timisoara in a (775 nM/l). ACTH levels were consistently low. A 4 cm round mass with period of 5 years, between 2003 and 2007. Epithelial architecture, the patterns of calcifications, discovered by CT scan in the left adrenal gland, was removed by stromal invasion, number of invasive foci, size of individual invasive foci, and the laparoscopy. Pathological summary was 5 cm benign adrenal tumour (Weiss extent of the nondestructive foci were reviewed. score 2). The patient was treated with 15 mg hydrocortisone. Nine months later, Results she had gained 3 more kilos with biological signs favouring osteoporosis. UFC Five patterns of invasion were identified: (1) cell clusters and individual, detached was 1280 nM/d without DXM suppression (cortisol 604 nM/l) and kaliemia 3.2. eosinophilic cell (27/31, 87%), (2) simple individual papillae and simple A new CT scan visualized a polylobular mass in the same surgical area and branching papillae (8/31, 25.8%), (3) cribriform pattern (6/31, 19.35%), several ‘nodules’ near pancreas cauda, spleen and around spleen vein. After a (4) complex branching micropapillae (2/31, 6.45%), (5) inverted macropapillae ketoconazole short treatment, about twenty small nodules from 1 mm to 2.5 cm (5/31, 16.12%). Most cases contained a mixture of stromal–epithelial patterns. were surgically removed in the epiploon, near the pancreas cauda and the spleen, Conclusions similar to the main tumour (extemporaneous examination), apparently. The distinction between ovarian serous and mucinous tumors of low malignant Pathological results indicated that nodules limited by fibrosis were mostly potential and low-grade serous and mucinous carcinoma can be quite difficult agglomerates of large cells with 9 mitoses/50 large power fields and necrosis. because former type present a variety of stromal–epithelial alteration. The most Some foci were different with apoptosis, necrosis and oncocytes: 8 mitoses/10 hpf common stromal–epithelial pattern of invasion on this study was the individual (Ki 67 score 10–15%). There was no vascular invasion. Pathological diagnosis intra-stromal eosinophilic cell and cell cluster pattern. was adrenocortical carcinoma. The previous report was reviewed and noticed a 3 Weiss score (tumour of uncertain malignancy). The patient is treated with mitotane, hydrocortisone and fludrocortisone. Her condition is currently stable with some side effects of mitotane. This observation underlines the remaining difficulties of pathological exam of endocrine tumours even when they are performed by skilled pathologists. P331 Novel MEN1 germline mutations and clinical features in Greek patients with multiple endocrine neoplasia type 1 Melpomeni Peppa1, Vasilios Pikounis1, Smaragda Kamakari2, George Peros3, Theofanis Economopoulos1, Sotirios A Raptis1,4 & P329 Dimitrios Hadjidakis1 Parathyroid carcinoma treated with cinacalcet: a preliminary report 1Endocrine Unit, Second Department of Internal Medicine-Propaedeutic, Marie Castric1, Peggy Pierre1, Julie Magnant2, Christine Chabrolle1, Athens University Medical School, Research Institute and Diabetes Center, Caroline Mor3, Isabelle Orain4 & Pierre Lecomte1 ‘Attikon’ University Hospital, Athens, Greece; 2BioGenomica, Center for 1Endocrine Unit, University Hospital, Universite´ F. Rabelais, 37044 Tours Genetic Research and Analysis, Athens, Greece; 3Fourth Department of Cedex 9, France; 2Internal Medicine, University Hospital, Universite´ Surgery, Athens University Medical School, ‘Attikon’ University Hospital, F. Rabelais, 37044 Tours Cedex, France; 3Endocrine Surgery, University Athens, Greece; 4Hellenic National Diabetes Center, ‘Attikon’ University Hospital, Universite´ F. Rabelais, 37044 Tours Cedex 9, France; 4Pathology, Hospital, Athens, Greece. University Hospital, Universite´ F. Rabelais, 37044 Tours Cedex, France. Introduction A 61-year-old man was hospitalized for paresthesias and renal insufficiency Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant hereditary (creatinine clearance 24 ml/min) with proteinuria. Type 2 diabetes was diagnosed disorder, associated with mutations of the MEN1 gene, characterised by the in 2003 and hypertension in 2007. Hypercalcemia (4.6 mM) with normal combined occurrence of tumours of the parathyroid glands, the pancreatic islet phosphorus level 1.23 mM was discovered with very high PTH levels (863 ng/l; cells and the anterior pituitary. N!78). MIBI scintigraphy localized a right inferior parathyroid tumour. No Aim obvious sign favouring MEN1 was observed and no familial case was reported. To identify MEN1 gene mutations and characterize clinical manifestations in After a short pamidronate treatment and hydration, surgery allowed to remove the Greek patients with MEN1. tumour and a parathyroid carcinoma was diagnosed. Post surgery PTH levels Patients and methods decreased to about 100 ng/l. Two months later, a thyroid right lobectomy with We studied 4 unrelated index patients (one male and 3 females, age range 30–65 lymph nodes dissection was performed. No invasion was found. One month later, years). Twenty relatives, 8 affected (4 males and 4 females, age range 30–71 PTH was still high 191 ng/l with serum calcium concentration 2.18 mM and years) and 12 unaffected (7 males and 5 females, age range 22–74 years) and 100 phosphorus level 0.78 mM. No hungry bone syndrome was observed and 25-OH control subjects, were also studied. DNA extraction, polymerase chain reaction
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
(PCR) and sequencing the MEN1 exons 2–10 and exon/intron boundaries were 1University Hospital, Wuerzburg, Germany; 2University Hospital, Charite´ performed according to standard procedures. Campus Mitte, Berlin, Germany; 3Institute of Pathology, Marienkranken- Results haus, Hamburg, Germany; 4University Hospital, Heidelberg, Germany; We identified novel MEN1 gene mutations in 3 out of 4 index patients (75%) 5University Hospital, Du¨sseldorf, Germany; 6University Hospital, Marburg, and in 8 affected (100%) as well as in 2 unaffected (16.6%) relatives. Novel Germany; 7University Hospital, Magdeburg, Germany; 8University mutations included a frameshift mutation in exon 4 (c.794-795insG) at codon Hospital Innenstadt, Mu¨nchen, Germany; 9University Hospital, Halle, 229 resulting in the premature termination of menin synthesis at codon 231 Germany; 10University Hospital, Mainz, Germany; 11Tumour Centre, (Family 1); a missense mutation in exon 4 (c.886TOC) which substitutes leucine University Hospital, Wu¨rzburg, Germany; 12University Hospital, Charite´ with proline at codon 259 (L259P) (Family 2); a frameshift mutation in exon 8 Campus Benjamin Franklin, Berlin, Germany. (c.1270_1280dupAGGAGCGGCCG) involving codons 387–390, resulting in truncation of the menin protein at codon 447 (Family 3). We also found that all our 13 MEN1 carriers (100%) had clinical symptoms and/or biochemical Adrenocortical carcinoma (ACC) is a rare disease with poor prognosis. abnormalities. In the fourth index patient, only a common polymorphism Accordingly, in many cases, the attending doctors have no previous (D418D) was detected. experience with the disease. The aim of our study was to evaluate the Conclusions quality of care in a large number of patients with ACC in Germany. Data These data indicate the high prevalence of novel MEN1 gene mutations among from 263 adult patients of the German ACC registry were analyzed with MEN1 patients and the absence of genotype/phenotype correlation. Mutational regard to the following parameters: time to diagnosis, hormonal assessment, analysis for MEN1 identifies healthy carriers who are at a high risk of developing imaging, histopathological documentation, follow-up. The time from first tumours and helps in the clinical management of the patients and their families. symptoms to diagnosis varied widely, e.g. in patients with Cushing’s syndrome from several weeks to 36 months (median 8.5 months). Preoperative diagnostic work up was frequently insufficient: In the majority of patients no (16%) or only incomplete (46%) hormonal investigations were performed, putting the patient at unnecessary risk and impairing future P332 follow-up. Furthermore, in 47% no thoracic CT was performed. Histopatho- logical assessment by the respective local pathologists proved frequently not Ghrelin and its receptor are present in an ectopic ACTH lung reliable: during the last two years, the diagnosis of ACC was revised by the neuroendocrine tumour causing Cushing’s syndrome: potential patho- reference pathologist of the registry in 7 cases. In addition, resection status physiological implications was not given in the histopathological report in 15.4% of patients, although Ana Quintero1, Antonio J Martı´nez-Fuentes1, Manuel D Gahete1, this information is of key importance for treatment and prognosis. We Rafael Va´zquez-Martı´nez1, Carmen Gutie´rrez-Alcantara2, Luis Jime´nez- detected deficits also in follow-up: due to the high rate of recurrence in ACC, Reina3, Pedro Benito-Lo´pez2, Marı´a M Malago´n1 & Justo P Castan˜o1 regular restaging every 3 months is recommended. However, in a third of 1Department of Cell Biology, Physiology and Immunology, Instituto de patients a first postoperative follow-up was performed only after more than 6 Salud Carlos III, University of Co´rdoba and CIBER Fisiopatologia months. In conclusion, we have identified significant deficits in the care of Obesidad y Nutricion (CB06/03), Cordoba, Spain; 2Department of patients with ACC in Germany. Based on recommendations of the European Endocrinology and Nutrition, Reina Sofia Hospital, Cordoba, Spain; adrenal network ENSAT only 33% of the patients underwent sufficient 3Department of Morphological Sciences, University of Cordoba, Corrdoba, hormonal assessment, staging, and postoperative follow-up. Close and early Spain. interaction of physicians with specialized centres will be of key importance to improve the care of patients with this rare disease. Ghrelin is a 28-aa peptide originally isolated from stomach but present also in many tissues, including hypothalamus and pituitary, where it stimulates growth hormone (GH) release through the ghrelin/GH secretagogue receptor (GHS-R). Ghrelin also increases food intake and adiposity and could play a key integrative role in the endocrine–metabolic interface. Although its primary pituitary cell P334 target are somatotropes, ghrelin also modulates other pituitary cell types, The cAMP analog 8CL-cAMP enhances PKA RIIb, triggers apoptosis specially in certain pathologies. Indeed, we recently showed that human pituitary and blocks cells at S and G2 cell cycle phases after 4 days of treatment in adenomas causing Cushing’s disease express both ghrelin and GHS-R. Moreover, the human adrenocortical cells H295R. ghrelin was co-stored within ACTH secretory granules, and increased free 2 3 1 2C Zhor Bouizar , Jeroˆme Berterat & Marthe Rizk-Rabin cytosolic calcium ([Ca ] ) and presumably ACTH release via GHS-R. These i 1Institut Cochin, Universite´ Descartes, CNRS UMR8104, Paris 75014, results provided a cellular basis for the exaggerated ACTH response to ghrelin in France; 2INSERM U567, Paris 75014, France; 3Poˆle Endocrinologie- Cushing’s disease and suggested an association of the ghrelin/GHS-R system with Diabe´tologie Adultes-Enfants, Groupe Hospitalier Cochin St Vincent de the pathophysiology of corticotropinomas. Because Cushing’s syndrome is Paul, 27 Rue du FG St Jacques Paris 75014, France. frequently caused by ectopic ACTH secretion from non-pituitary neuroendocrine tumours, specially lung carcinoids, we explored the possible presence of ghrelin/GHS-R system in these tumours. Specifically, a 70-year-old woman Various alterations of the cyclic AMP (cAMP) signalling cascade has been was diagnosed of a lung carcinoid tumour with ectopic ACTH secretion. Freshly observed in adrenocortical tumors. Changes of the PKA regulatory subunits isolated tumour lung pieces were processed for: (a) immunomicroscopy; (b) expression in tumors may positively or negatively regulate proliferation. 8CL- 2C measurement of ghrelin-induced changes in [Ca ]i and secretory activity in cAMP, a site selective cAMP analogue, induces growth inhibition in a variety of single living cells; and (c) RT-PCR expression analysis. As expected, 97% cells human cancer cell lines. The aim of the study was to determine if 8CL-cAMP acts from the ectopic lung carcinoid tumour showed ACTH immunofluorescence. on adrenocortical carcinoma H295R cell growth. RT-PCR confirmed ACTH (POMC) expression and further revealed that the lung We have determined the involvement of PKA, PKA R subunits in this activity and carcinoid tissue also express ghrelin and GHS-R1a. Moreover, ghrelin (1 mM) studied the mechanisms of action on cell cycle molecule targets and cell cycle 2C Z K4 stimulated [Ca ]i in 80% of cells (n 20), and increased the rate of distribution. Cells were incubated for 96 h or 7days with 8CL-cAMP (10 M). incorporation of the fluorescent dye FM-5-95, suggesting increased hormone Cell viability and proliferation was evaluated by MTT assay and BrdU release. Taken together, our results demonstrate that, as in pituitary cortico- incorporation. Apoptosis was investigated by annexin FITC assay. Western tropinomas, ghrelin and GHS-R1a are functionally present in an ectopic blotting was performed, for PKA subunits, cyclin and cyclin dependent kinase corticotropinoma causing Cushing’s syndrome, and could therefore provide an protein expression. Cell cycle distribution was analysed by flow cytometry. autocrine mechanisms involved in the pathophysiology of these tumours. 8CL-cAMP induces PKA activation, modulates the expression of PKA regulatory subunits by increasing the type II isozymes. The cAMP analogue reduces cell proliferation and enhances apoptosis in the H295R cells. These effects were associated with the accumulation of cells at S and G2 phases. This is consistent with the accumulation of cyclin A in the nucleus and cyclin B both in the cytosol P333 and the nucleus. Cells blocked from progression through M phase by nocodazole Deficits in the clinical management of patients with adrenocortical (1 mM, 18 h) or G1/S phase by aphidicollin (2.5 mM, 24 h), revealed that addition carcinoma in Germany of 8CL-cAMP resulted in a delay in S/G2 transition and a blockage in G2/M Sarah Johanssen1, Ann-Cathrin Koschker1, Stefanie Hahner1, chekpoint. Marcus Quinkler2, Wolfgang Saeger3, Michael Morcos4, These results imply that cAMP/PKA RIIb pathway regulates S and G2/M phase Holger Willenberg5, Peter Langer6, Silke Klose7, Nicole Reisch8, progression in H295R. Activation of PKA RIIb holoenzyme may be responsible Felix Beuschlein8, Michael Brauckhoff 9, Christian Fottner10, for the growth arrest, by altering the cell cycle regulator pattern and the induction Sebastian Wortmann1, Wolfgang Oelkers12, Uwe Maeder11, of apoptosis. Martin Fassnacht1 & Bruno Allolio1
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P335 Aim Hyperprolactinaemia: different clinical expression in childhood To ascertain the prevalence of PA and the characteristics of the patients diagnosed Ljiljana Saranac, Gordana Kostic, Hristina Stamenkovic, with them in a large population of inhabitants. Snezana Zivanovic & Maja Slavkovic-Jovanovic Methods Pediatric Clinic, Nis, Serbia. A survey on the GP surgeries of Banbury (Oxfordshire, UK) covering 89 334 inhabitants was carried out following approval from the Local Research Ethics Committee. Finally, 14 out of 16 approached GP Surgeries agreed to participate Hyperprolactinaemia is the most common disturbance in the pituitary gland allowing the inclusion of 81 149 inhabitants. Patients were initially identified function. Different physiological and patological conditions could influnce through IT search at the Surgeries using relevant search terms. The notes of the prolactin (PRL) secretion. Prolactin secreting tumors (micro and macroprolacti- selected subjects were scrutinized to confirm the diagnosis. nomas) are rare in children and adolescents (estimated incidence is 1 per milion). Results Functional diversity of prolactin action is responsable for different initial clinical We found 64 cases (43 females; median age at diagnosis (MAG) 37 years (range expression of hyperprolactinaemia. 16–74)), and the prevalence was 78.87 cases/100 000 inhabitants. The series We investigated causes of hyperprolactinaemia in 11 children and comprised 36 prolactinomas (56%), 7 patients with acromegaly (11%), 11 non- adolescents (6 females and 5 males), aged from 1.5 to 17.5 years with functioning adenomas (NFA) (17%), 1 Cushing’s disease (1.6%) and 9 pituitary different clinical expression at admission. Children with primary hypothy- masses of unknown functional status (UF) (14%). The median symptomatic roidism, jatrogenic hyperprolactinamia and PCOs adolescents were excluded. period before diagnosis in non-apoplectic PA was 1.7 years (48 patients, range Four patients had short stature or growth deceleration, the same number was 0.5–15 years). MAG and sex distribution were: prolactinoma (89% female, MAG clinicaly obese, two adolescent girls had secondary amenorrhoea, two girls 32 years), NFA (18% female, MAG 54 years), acromegaly (43% female, 47 had premature thelarche and gynaecomastia and hypogonadism were years), Cushing’s disease (0% female, MAG 57 years), UF (66% female, MAG indication for endocrinologic examination of two adolescent boys. Vasculitis 39 years). and obesity and recidivant herpes viral infections and obesity were present Conclusions in two school children. Hyperprolactinaemia was found also in the youngest This is the first cross-sectional, community study on the epidemiology of PA girl with multiple ovarial cysts. performed in a large population of the United Kingdom. Our prevalence is three We documented very high PRL level in PRL profile in all patients (mean times higher than previous estimates, and prolonged symptomatic periods before 2100 mU/l). MRI of pituitary was indicated and revealed 4 microprolacti- diagnosis were common. PA affects patients at a young, economically active nomas, 1 congenital hypophyseal cyst and 1 tumor of the hypothalamus. population. Prolactinomas are far more common in females, while acromegaly and Children with hyperprolactinaemia expressed a wide variety of initial NFA are more common in males. Increased awareness of these treatable conditions is clinical presentations. The most common were growth and puberty disorders important to reduce diagnostic delay. and obesity. PRL determination should be included in investigation protocols of obese and short children as prolactinoma, although rare, is nevertheless a likely disease, even in childhood.
P336
G12/13-dependent growth of small cell lung cancer cells in vitro and in vivo Thomas Bu¨ch, Marius Grzelinski, Olaf Pinkenburg, Maike Gold, P338 Achim Aigner & Thomas Gudermann Gastric NETs: new diagnostic and therapeutic approach Philipps University, Marburg, Germany. A Hubalewska-Dydejczyk1, A Gilis-Januszewska1, P Szybinski2, A Sowa-Staszczak1, S Klek2, B Huszno1 & J Kulig2 1Chair and Department of Endocrinology, Jagiellonian University, Krakow, The malignant phenotype of small cell lung cancer (SCLC) cells critically Poland; 2Gastrointestinal and General Surgery Department, Medical relies on the autocrine stimulation of G12/13- and Gq/11-coupled neuropeptide College, Jagiellonian University, Krakow, Poland. receptors. By this means, G12/13-andGq/11-dependent signalling pathways are constitutively activated in these cells. While Gq/11-dependent signalling has been shown to promote proliferation of SCLC cells, the role of The incidence of GNT appears to be increasing, what can be explained by the signalling pathways via G12/13 is still elusive. Thus, we employed shRNA- increased detection caused by the common use of the endoscopy and the mediated down-regulation of Ga12,Ga13, or both, in human SCLC cell pervasive use of acid suppressive therapy leading to enterochromatofine like cells lines. The use of a lentiviral expression system rather than non-viral proliferation. There are numerous new diagnostic/therapeutic GNT methods in transfection resulted in robust, specific, and stable knockdown of both target use like: EUS, SRS, somatostatin therapy and 90Y/177Lu-DOTA-TATE proteins. This decrease in Ga12 or Ga13 levels markedly reduced radiotherapy. proliferation in SCLC cell lines in normal culture medium as well as Materials and methods colony formation in semi-solid medium. However, double targeting of both In 1998–2007, 25 patients were diagnosed with the hist. path. confirmed GNT Ga12 and Ga13 did not exert a synergistic anti-proliferative effect in vitro. (mean age – 59G12; 19 F, 5 M). In all patients gastroscopy, CT/MRI, EUS 99Tc- In a subcutaneous tumor xenograft mouse model, the downregulation of EDDA/HYNIC-Octerotate scintigraphy, chromogranin A serum level, clinical Ga12 or Ga13 resulted in decreased tumor growth, which was due to reduced manifestation of the disease and type and efficacy of the therapy were assessed. tumor cell proliferation. More importantly, double knock-down of Ga12 and Results Ga13 completely abolished tumorigenicity in mice. Thus, intact G12/13 Among 25 GC patients, in 65% type I in 5% type II and in 30% type III was signalling is a prerequisite for proliferation of SCLC cells in vitro and diagnosed. During 4 years of the observation 6 patients with dissemination died tumorigenicity in vivo. (2 patients- type I, 1- type II and 3 -type III). The best detective value was found for the 99Tc-EDDA/HYNIC-Octerotate scintigraphy both for the primary and the metastatic lesions. In all patients, the increased level of chromogranin A was found (55.8G98 U/l; n: 2–18 U/l), maximum value in patients with dissemination (max. 295 U/l). In most cases partial/total gastric resection was performed. P337 However, in 3 patients with type I GNT treated only with the somatostatin a High prevalence of pituitary adenomas: a cross-sectional study in the complete endoscopic remission was observed in 1 case, and partial remission in 2 city of Banbury (Oxfordshire) cases. Alberto Fernandez, Niki Karavitaki & John AH Wass Conclusion Endocrinology Department, Oxford Centre for Diabetes, Endocrinology and As the number of GNT is increasing the extensive diagnostic and therapeutic Metabolism, Churchill Hospital, Oxford, Oxfordshire, UK. methods development are needed. However, the endoscopic or surgical gastric resection are still a basic treatment, the use of somatostatin in type 1, somatostatin and 90Y/177Lu-DOTA-TATE radiotherapy in nonoperative, disseminated cases Background seems to be very promising. Due to the different clinical course of the disease it Pituitary adenomas (PA) are considered very rare conditions, with an estimated seems that the treatment should be individually tailored to reach the best and prevalence of 25 cases/100 000 inhabitants. However, community-based studies optimal effect. on the prevalence of PA are currently scant.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P339 Full gene coding sequence of somatostatin receptor 5 and 2000 bp of upstream Fenotypes in patients with Y791F mutation of RET protooncogene region was estimated using direct sequencing in 28 patients with acromegaly and Tatjana Isailovic, Milan Petakov, Djuro Macut, Bojana Popovic, 97 controls. Total 19 polymorphisms were identified (SNP1-19) and possible Ivana Bozic, Sanja Ognjanovic & Svetozar Damjanovic haplotypes were reconstructed. From all polymorphisms found silent substitution School of Medicine, Institute of Endocrinology, Belgrade, Serbia. SNP15 was significantly associated with acromegaly as compared with control group (PZ0.005). Another substitution SNP17 involves the amino acid change from proline at position 335 to leucine that was less frequent in acromegalic Mutation Y791F of RET protooncogene is a well known mutation so far described patients compared to controls (PZ0.02). Moreover, two patients homozygous for in families with FMTC and familial pheochromocytoma in one family. It activates SNP15 were resistant to somatostatin analog sandostatin as characterized by the receptor in a monomeric form. Here we present eight unrelated families with elevated GH and IGF-I levels as well as recurrent surgical removal of adenomas. the same mutation but different fenotype expression. These data suggest the role of SSTR5 genetic variants in progression of Patients and methods acromegaly as well as possible identification of genetic marker of resistance to In last 20 years, we analyzed 216 patients with MTC (age range: 3–75 years, 45.0 somatostatin treatment. Present study has been approved by Latvian Central mean). Genetic testing for mutation in RET proto-oncogene was performed by Committee of Medical Ethics. direct double-strand sequencing of the PCR products obtained after amplification of genomic DNAs. Results Of 216 patients with MTC, in 48 (22.3%) familial form of disease was found. In 23 patients (34.3%) from 8 non-related families germ-line mutation was found P342 in c791 (Y791F). Only four had MTC and they were index cases in their families. The first two patients were diagnosed, operated and cured at the age of 33 and 42, Cushing syndrome: cycling around diagnosis respectively. Metastatic MTCs were diagnosed at the age of 53 in the third patient Filipe Mota, Catarina Matos, Miguel Afonso, Rui Almeida & and she died at the age of 62. The fourth patient was diagnosed with metastatic Olinda Marques MTC at the age of 62. No one had associated diseases. Nineteen patients were Hospital de Sa˜o Marcos, Braga, Portugal. carriers (age range: 10–68, mean 35.7) with no evidence of the diseases but 6 of them (31.6%) had kidney development malformations. One patient had kidney Introduction hypoplasia and PHPT. She was negative for MEN1 mutations. Cyclic Cushing syndrome (CCS) involves rhythmic fluctuations in ACTH Conclusion secretion resulting in a cyclic variation of adrenal steroid production. The frequency of inherited MTC in our population is in concordance with other Case presentation publications, but the frequency of c791 mutation is higher than in other studies. A 37-year-old woman was referred to our Pituitary Clinic in 1999, for evaluation Phenotype varies from no evidence of oncogenic activity to overt disease. While of galactorrhea and irregular menses that had started four months ago. She also more aggressive disease has been described in patients with coexistent L769L complained of depression, facial hirsutism, alopecia and progressive obesity. polymorphism, the occurrence of kidney malformations may reflect the Blood pressure was normal. Endocrinological evaluation revealed prolactin blood insufficient RET protein expression despite oncogenic mutation during the level elevated twice and a half the reference value, low gonadotrofins blood embryogenesis or the coexistence of other disease. values, and urinary free cortisol (UFC) of 166.1 mg/24 h (reference: 28.5–214). The cerebral magnetic resonance imaging suggested a non-functioning pituitary macroadenoma without optic quiasm compression. Two years later, tumor dimensions were unchanged and UFC remained normal (50.6) but without cortisol circadian rhythm. One year later, she was admitted with diabetic P340 ketoacidosis and 1 month later, insulin was suspended because of frequent Insulin sensitivity in a patient with gastric ghrelinoma hypoglycemias. Shortly thereafter, she was readmitted because of vomiting, Bojana Popovic, Ivana Bozic, Djuro Macut, Nebojsa Lalic, metabolic alkalosis and hypokalemia. Four months later, basal UFC was 387.8 Aleksandra Jotic, Srdjan Djuranovic, Tatjana Isailovic, Milan Petakov & and ACTH was 128 pg/ml (reference: !46), with a paradoxical response to the Svetozar Damjanovic high dose dexamethasone supression test. Despite medical advice, she left the Institute of Endocrinology, Diabetes and Metabolic Diseases, Belgrade, Serbia. country before pituitary surgery. Three years later, she returned to our Clinic and normal UFC and ACTH were observed. Surgery was performed in 2007 and immunochemistry revealed diffuse positive ACTH tumor staining. Ghrelin is a somatotrophic, orexigenic and adipogenic hormone that has an important Discussion homeostatic role by linking regulatory systems for growth and energy balance. One of the proposed explanations for the mechanism behind the CCS of pituitary Ghrelin- secreting neuroendocrine tumors are rare, but we had the opportunity to origin is the occurrence of spontaneous, episodic haemorrhage in the tumor with study a 71 years old female patient with a gastric ghrelinoma. The patient was temporary damage of the actively secreting cells. CCS should be strongly submitted to gastroenterological examination after having episodes of diarrhea, and suspected in patients with signs or symptoms of hypercortisolism but normal small subepithelial polyp (5 mm) was revealed on gastroscopy. Pathohystological cortisol levels and paradoxical responses to the dexamethasone test. analysis after endoscopic biopsy proved it to be a well-differentiated neuroendocrine tumor (Ki 67–1%) with immunostaining positive for general neuroendocrine markers (CgA and synaptophysin CCC) as well as for ghrelin (CCC). The patient was otherwise in good health condition, was slightly obese (BMI-27.4 kg/m2) and had no clinical signs of acromegaly. Serum ghrelin level was elevated. It has been previously shown in gastrectomized patients that short-term ghrelin administration P343 during hyperinsulinemic euglycemic clamp induces a transient increase in GH Raloxifene induces growth arrest and apoptosis in prostate cell lines levels, a decrease in IGF1 level, and a decrease in C-peptide level, thus having a expressing both ERa and b negative influence on insulin secretion and glucose consumption. Our patient had Giuseppe Bellastella1, Valentina Rossi1, Daniela Visconti1, normal IGF1 level for age and gender (155 ng/ml, ref. 64–188), but her basal GH Vincenzo Palumbo1, Paolo Chieffi2, Stefania Staibano3, Giuseppe Mascolo3, level was elevated (3.9 ng/ml), with no signs of GH-producing pituitary tumor. Her Domenico Preziosi4, Antonio Bellastella1 & Antonio Agostino Sinisi1 basal insulin level was normal (17.6 mmol/l), with marked increase during glucose 1Endocrinology, Second University of Napoli, Napoli, Italy; 2Experimental tolerance test ((300 mmol/). We performed a hyperinsulinemic euglycemic clamp Medicine, Second University of Napoli, Napoli, Italy; 3Pathology, Federico and found significantly reduced M value (2.83 mg/kg bw per min). We conclude that II University, Napoli, Italy; 4Urology, Federico II University, Napoli, Italy. chronic hyperghrelinemia may induce insulin and GH resistance.
Raloxifene (RAL) is a selective estrogen receptor (ER) modulator (SERM) proposed for chemoprevention of breast cancer and osteoporosis. SERMs exert agonist–antagonist effects depending on tissue or ERs expressed. RAL induces P341 apoptosis in both androgen-dependent and independent cell lines, suggesting a Association of genetic variants of somatostatin receptor 5 with selective activation of ERb and prevalent antagonist effect on ERa in prostate cells acromegaly (PC). In this study we evaluated effects of estradiol (E2) and RAL on epithelial Janis Klovins1, Ivo Kapa1, Inga Balcere1, Darja Ciganova1, Liene Nikitina- prostate cell growth, using two in vitro models: the androgen-dependent epithelial Zake1, Helgi Schioth3 & Valdis Pirags2 PC line EPN, that expresses both ERs, and a stabilized PC line derived from 1Latvian Biomedical Research and Study Center Ratsupites 1, Riga, Latvia; prostate cancer (PCaECS) that lacks both ERs. Semiconfluent starved cultures 2Paul Stradins Clinical Hospital, Pilsonu Street 13, Riga LV-1002, Latvia; were treated with E2 or RAL (10K9–10K6 M) or solvent. Cells were harvested 48 h 3Department of Neuroscience, Uppsala University, Uppsala, Sweden. after the treatment and stained with propidium iodide for flow cytometry analysis
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 by FACS calibre or analyzed by TUNEL assay for in situ DNA fragmentation, or signaling pathway and in maintaining tumor cell growth both in vitro and in an recovered for western-blot analysis. Activation of MAPK was also evaluated in in vivo xenograft mice model. short term experiments. An increase of apoptosis and of S and G2-M cell cycle Results phase inhibition with G0/G1 arrest was observed in EPN after E2 (10K9 M) or RAL We have found expression of the LRP5D receptor in 16 of 19 primary breast (10K6,8 M). Percent of apoptosis and cell growth inhibition were also significant carcinomas and in several breast cancer cell lines, including MCF-7. No when 10K9 M RAL was used (P!0.05 vs control). Bcl-2 protein levels in cell expression of LRP5D was observed in normal breast tissues. Experiments on extract were significantly reduced by E2 (10K9 M) and RAL (10K6 to 10K9 M); MCF-7 cells will be presented, strongly supporting a fundamental role of the PAR-4 levels increased in EPN after E2 or RAL. In PCaECS, there was no effect on LRP5D receptor in deregulated Wnt/ß-catenin signaling and tumor growth in cell growth control after E2 or RAL. RAL induced a rapid and transient transplanted SCID mice. phosphorylation of ERK in EPN and sustained effects on PCaECS. Conclusions Pharmacological concentrations of RAL that acts as a partial ERb agonist and ERa antagonist are able to inhibit cell growth in EPN, but result inefficient in PCaECS lacking both ERs. P346 p107Rbl1 is an haploinsufficient tumor suppressor in mouse pituitary Gloria Martinez1, Carmen Carneiro1, Miguel Estravis1, Nancy Yeh2, Andrew Koff2 & Anxo Vidal2 1Department of Fisioloxia, University of Santiago de Compostela, Santiago P344 de Compostela, Spain; 2Molecular Biology Program, Memorial Sloan- Pituitary adenomas: the reality of Braga Kettering Cancer Center, New York, New York, USA. Filipe Mota, Catarina Matos, Miguel Afonso, Rui Almeida & Olinda Marques Hospital de Sa˜o Marcos, Braga, Portugal. The pocket protein family members, pRb, p107 and p130, are negative regulators of the cell cycle. But, while the role of pRB as a tumor suppressor has been extensively established, genetic inactivation of p107 or p130 is uncommon in Introduction tumors. Previous studies have shown that p130 cooperates with the CDK inhibitor There are limited data on the incidence and prevalence of pituitary adenomas p27Kip1 restricting proliferation of mouse intermediate lobe pituitary cells. (PA). Although classically considered rare, systematic assessments from autopsy Accordingly double knockout mice show higher incidence of pituitary tumors than and radiological studies have shown a prevalence of 17% in the general single KO animals. Because of functional redundancy between p130 and p107, to population. study contributions of p107 as a tumor suppressor we have generated p107C/K; Objective p130K/K mice and combined them with p27 inactivation (5/6KO strain). We describe the epidemiologic of PA in Braga, the third most populous district of We found that reduction of p107 gene dosage caused a significative reduction in Portugal (860 000 inhabitants, 2673 km2), over the last 20 years. tumor-free survival time. As previously described, p27 deficient mice developed Methods adenomas almost exclusively in the pituitary and adrenal medulla, while p130 We reviewed the clinical files and the laboratorial, radiological and pathological mutation collaborated to increase the frequency of pituitary and adrenal tumors. data of all the patients with pituitary tumors diagnosed in our Pituitary Reference In this context, 5/6KO mice showed accelerated appearance of pituitary tumors, Center. The prevalence and incidence were expressed as number of cases/million while the pheocromocytomas, mostly unilateral in p27 null and DKO mice, where people and number of cases/million people per year, respectively. bilateral with almost complete penetrance. Strikingly, microscopic examination Results of pituitary tumors revealed that in the case of 5/6KO mice tumors were clearly A total of 160 patients (123 female (F) and 62 male (M)) with prolactinomas – invasive and showed features of aggressive carcinomas. PR-(59 F; 16 M), non-functioning PA – NFPA-(18 F; 25 M), GH-secreting (25 When we studied the expression of cell cycle regulators, we found than wildtype F; 8 M), or corticotrope adenoma – CA-(8 F and 1 M), were characterized. The intermediate lobe has undetectable amounts of p107. This finding was confirmed mean age at diagnosis was 41.7G17.3 years (range: 14–85 years) being for PR in extracts from p27 deficient adenomas. Nevertheless, p107 protein was detected 32.7 years, for NFPA 53.2 years, for GH 45.6 years, and for corticotrope adenoma in p130 null animals, suggesting a mechanism of compensatory expression. 49.3 years. The prevalence of PA was 186, being for prolactinomas 87.2, for Moreover, by both RT-PCR and immunoblot we found that p107 was still NFPA 50.0, for GH-secreting 38.4, and for CA 10.5. In the last 10 years, the mean expressed in tumors arising in the 5/6KO mice, indicating that p107 can act as a annual incidence of PA was 16.4, being for PA 7.1, for NFPA 4.5, for haploinsufficient tumor suppressor in mouse pituitary. GH-secreting 3.7, and for CA 1. We identified 66.3% of macroadenomas, which corresponded to 46.7% of prolactinomas, 100% of non-functioning PA, 67% of GH-secreting, and 55.6% of corticotrope adenoma. Conclusions The frequency of different PA types, the age of presentation and female predominance verified in our district are similar to literature. The growing P347 awareness and the diagnosis improvement may account for the apparent increase in PA incidence, over time. Immunohistochemical evaluation of ghrelin expression in somatotroph and non-functioning pituitary tumours Magdalena Jaskula1, Ryszard Wasko1, Malgorzata Kotwicka2, Wlodzimierz Liebert3 & Jerzy Sowinski1 1Department of Endocrinology, Internal Diseases and Metabolism, University of Medical Sciences in Poznan, Poznan, Poland; 2Department of Cell Biology, University of Medical Sciences in Poznan, Poznan, Poland; P345 3Department of Neurosurgery, University of Medical Sciences in Poznan, Deregulated Wnt/b-catenin signaling in breast cancer: the LRP5D Poznan, Poland. receptor Peyman Bjo¨rklund, Jessica Svedlund, Anna-Karin Olsson, Gunnar Westin &Go¨ran A˚ kerstro¨m Introduction Uppsala University, Uppsala, Sweden. Ghrelin is known to strongly stimulate growth hormone release from the pituitary. It was also found to be produced locally in hypothalamus and anterior pituitary and in different types of pituitary adenomas. It’s been suggested that ghrelin Background synthesized locally in hypothalamo–pituitary area or within pituitary tumours can Aberrant accumulation of cytoplasmic/nuclear b-catenin frequently occurs in be an important factor contributing to pituitary tumorogenesis. breast cancers and breast cancer cell lines. Deregulated expression of Wnt Aim ligands, sFRP1 and Dvl1, but no inactivating or activating mutations in Wnt The aim of the study was the immunohistochemical assessment of ghrelin signaling components have so far been reported. We have recently described an expression in somatotroph and non-functioning pituitary tumours and the internally truncated LRP5 receptor (LRP5D) in 91% of hyperparathyroid tumors, comparison of the presence of ghrelin in somatotropinomas treated and untreated and showed that LRP5D was strongly implicated in the aberrant accumulation of preoperatively with a long acting somatostatin analogue. active ß-catenin in these tumors (Bjo¨rklund et al. PLoS Med 2007). Materials and methods Objectives and methods The studied material consisted of somatotroph and non-functioning pituitary We have initially analyzed a small number of primary breast carcinomas (19) and tumours tissues obtained during neurosurgical removal of the tumour. There were several breast cancer cell lines, as well as normal breast tissue for expression of somatotropinomas obtained from patients treated with a somatostatin analogue LRP5D. Further, we have investigated function of LRP5D in the Wnt/b-catenin (octreotide LAR) before the surgery and not treated (paraffin sections collected in
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 the past when SS analogues were not routinely used in presurgical farm- 3Institute of Clinical Chemistry and Laboratory Medicine, Greifswald, acotherapy). As a control for immunohistochemical analysis, the mucous Germany; 4Pfizer Endocrine Care, Sollentuna, Sweden. membranes of the stomach (obtained during gastrectomy due to stomach neoplasms) as well as normal pituitary tissues (obtained during autopsy) were used. Tumour tissue samples were placed in formaline and then in paraffine. Objective Immunohistochemical study was done with the use of rabbit polyclonal Age- and gender-specific reference values for quality of life (QoL) measures are antibodies against human ghrelin 1:400 in TBS (Phoenix Pharmaceuticals, Inc). important to assess the impact of growth hormone deficiency (GHD). The objective Results of this study was to develop population-based data for the QoL-AGHDA instrument Immunohistochemical analysis confirmed that ghrelin is present in non- for Germany and to compare this data with corresponding Qol-AGHDA scores of the functioning pituitary tumours and somatotroph adenomas, even after the German KIMS cohort during growth hormone treatment, to investigate the treatment with octreotide LAR. Characteristic staining was observed in the association between the Qol-AGHDA score and the IGF-1 values in the German cytoplasm of cells, in some of them predominantly in perinuclear area. KIMS cohort as well as in the background population. The expression of ghrelin was also shown in normal pituitary, it was, however, Design restricted only to few cells. For the purpose of this study, a questionnaire was developed that contained the Conclusions QoL-AGHDA as well as questions recording an individual’s general situation and The results of the study confirmed the presence of ghrelin in non-functioning social functioning. The questionnaire was sent out to a sample of 3,925 individuals adenomas and somatotropinomas, also after farmacotherapy. Further studies drawn from a cross-sectional study in Germany. Corresponding data for 651 would allow a better understanding of pituitary tumours pathogenesis. patients were retrieved from the German KIMS cohort. Moreover, the association between the Qol-AGHDA score and the IGF-1 values in the KIMS cohort as well as in the background population were analysed. Results The mean QoL-AGHDA scores for the general population were 4.5 (4.6) for men Growth and development (women), respectively, compared with 8.8 (9.1) for KIMS patients before starting P348 growth hormone replacement. For both males and females differences in mean QoL-AGHDA scores between general population and patients were statistically Secular height changes in Greek conscripts significant for all age categories (P!0.05). In the general population, the mean Grigorios Fytanidis1, Anastasios Papadimitriou1, Dimitrios Papadimitriou1, QoL-AGHDA score for each category of self-assessed health status increased Iakovos Fytanidis2 & Polyxeni Nicolaidou1 progressively, indicating a poorer QoL as health status declined. 1Paediatric Endocrinology Unit, Third Department of Paediatrics, Attikon Conclusions University Hospital, University of Athens, Haidari, Attiki, Greece; 2Surgery This study reports QoL-AGHDA scores for a population-based sample of Germany Department, Rethymno General Hospital, Rethymno, Greece. and confirms the extent of QoL impairment in patients with GHD in comparison with the general population. Introduction In some developed countries, the acceleration of physical development has already reached a plateau. Objective P350 Aim of our study was to examine whether an improvement of the body height of A study of IGF-1 serum concentrations and kinetics of growth hormone adult men is still observed in Greece and to correlate the body height with socio- assays in stimulation tests used for diagnosing insufficient somatotrope economic and demographic factors. secretion Research methods and procedures Marie Monge The height of 3068 Greek conscripts, aged 18–26 years, was measured and analyzed Pasteur Cerba, Paris, France. according to their socio-demographic characteristics, level of education (according to the years of obligatory education) and type of residence (urban or rural). Our data were compared with those of similar studies performed in 1968 and 1990. Introduction Results The diagnosis of insufficient somatotrope secretion (growth hormone deficiency The mean height (GS.D.) of the recruit soldiers was 177.4 (G7.0) cm. Mean height or GHD) is important in children. according to the type of residence and educational level is shown in Table 1. In France, a child is considered to have a deficit if no serum GH concentrations greater than 20 mIU/l are recorded in 2 different stimulation tests. One of the tests Table 1 must be ‘coupled’, i.e. combining 2 pharmacological agents. However, this 20 mIU/l threshold does not take account of the type of test and Years of schooling Urban Rural large response variances that can be reported, depending on the product used. Nor G P Mean height ( S.D.) cm does it factor in the patient’s weight, age and pubertal development. Total 178.1 (7.1) 176.4 (6.7) !0.0001 The goal of this study was to evaluate the interpretation of these tests vis-a`-vis the * %9 174.4 (7.0) 174.6 (7.8) 174.2 (6.3) NS legalthreshold of 20 mIU/l depending on the product administered, and to compare it R10 177.9 (6.9) 178.3 (6.9) 176.8 (6.7) !0.0001 P !0.0001a !0.0001 !0.0001 to IGF-1 results obtained, according to the standard reference values given by the supplier according to age. * Non significant. Materials and methods Chemiluminescent assays of hGH were performed in our laboratory in 2007 using From 1990 to 2007 mean height increased from 175.7 (S.E.M. 0.15) cm to 177.4 Beckman Coulter’s DXI instrument and somatomedin C assays were conducted (S.E.M. 0.22) cm, corresponding to 1 cm per decade, P!0.0001. From 1968 to 1990 using the Immulite 2000 from DPC (Siemens). HGH assays were calibrated to the mean height increased from 167.9 to 175.7 cm, corresponding to 3.5 cm per international standard IS 98/574, as recommended. decade. Results Conclusions: Of the 430 dynamic tests and regardless of the product(s) used, only 50% showed a In the last 38 years a continuous significant increase of Greek men’s final height positive response, with a secretion peak above 20 mIU/l. This percentage varied was shown. However, in the last 16 years a deceleration of the rate of the according to the product used: improvement of the final stature was observed. The socio-economic status † ornithine (51.3%), insulin (22.8%), glucagon (42.8%), L-Dopa (50%) and the type of residence have a significant influence on body height. It appears that † clonidine–betaxolol (28.6%), glucagon–betaxolol (64.8%), glucagon– the male Greek population has still not exhausted its genetic potential. propanolol (69%), kerlone–glucagon (65.5%) In light of these results and because the highest GH concentrations are observed at very different times from one patient to the next, it is important to comply with the different protocol times to avoid overlooking an unrecorded peak. P349 Despite the relationship between GH and IGF-1, the percentage of low IGF- 1 concentrations in patients with a positive response to dynamic tests (15% Population-based data of quality of life assessment of growth hormone of the 73 tests with ornithine) does not differ considerably from that deficiency in adults (QoL-AGHDA) ! 1 2 1 3 observed in those presenting a response 20 mIU/l (19.7% of the 66 tests Joern Moock , Christin Albrecht , Henry Voelzke , Matthias Nauck , with ornithine). Therefore, IGF-1 assays cannot be used as a substitute for Maria Koltowska-Haggstro¨m4, Thomas Kohlmann1 & Henri Wallaschofski2 1 2 dynamic tests in diagnosing a GHD. Institute for Community Medicine, Greifswald, Germany; Department of Keywords: hGH, IGF1, dynamic tests, GHD Gastroenterology, Endocrinology and Nutrition, Greifswald, Germany;
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P351 to BT and T6 (P!0.03). HOMA-IR index at T1 was higher compared to BT and T6 (P!0.03). Insulin sensitivity index as ISI was lower at T1 compared to BT 45,X/46,XX mosaicism: clinical implications in adulthood ! Lionel Homer1, Marie-The´re`se Le Martelot1,Fre´de´ric Morel2,3, and T6 (P 0.01). Michel Collet1, Marc De Braekeleer2 &Ve´ronique Kerlan4 Conclusions 1Gyne´cologie Obste´trique et Me´decine de la Reproduction, CHU Brest, Insulin sensitivity decreased during rhGH therapy, even if without the onset of Brest, France; 2Cytoge´ne´tique, Cytologie et Biologie de la Reproduction, impaired glucose tolerance, and was restored after stopping treatment. It remains CHU Brest, Brest, France; 3Laboratoire d’Histologie, Embryologie et to be clarified if this variation of insulin sensitivity during and after rhGH Cytoge´ne´tique, Faculte´ de Me´decine et des Sciences de la Sante´, Universite´ treatment could be related to changes in body composition and pubertal de Bretagne Occidentale, Brest, France; 4Service d’Endocrinologie, CHU development or to rhGH treatment itself. Brest, Brest, France.
Introduction Turner syndrome is well known, but prognosis for 45,X/46,XX mosaicism under P353 30% of aneuploidy has not been established. We realised a retrospective study among women aged 21–43 years, to evaluate differences in clinical features and Impaired Se metabolism provokes gender-specific growth defects biological parameters between patients who had sex chromosome mosaicism in mice Kostja Renko1, Alexandra Chadt2, Marten Michaelis1, Ulrich Schweizer1, diagnosed incidentally and controls women. 2 1 1 Material and methods Hadi Al-Hasani , Josef Ko¨hrle & Lutz Schomburg 1Institut fu¨r Experimentelle Endokrinologie, Charite´ Universita¨tsmedizin Among infertile population, 71 women with sex chromosome mosaicism 2 (45,X/46,XX) range from 4 to 28% were compared to 72 controls (46,XX). We Berlin, Berlin, Germany; Deutsches Institut fu¨r Erna¨hrungsforschung evaluated clinical changes for menarche, menses, premature ovarian failure, (DIfE), Potsdam, Germany. height and body mass index. Assessments for early-follicular-phase blood values of FSH, LH, inhibin B, estradiol and TSH were measured at our laboratory. At Background last, we wondered if spontaneous fertility and pregnancy outcomes were Selenoproteins are involved in oxidative stress defence, cell signalling and influenced by such an aneuploidy. hormone metabolism. Accordingly, impairment of selenium (Se) metabolism or Results transport results in a complex phenotype as exemplified in selenoprotein P Eight percentage or more of aneuploidy was responsible for a lower height knockout mice (SePP-KO). This mouse model is characterized by a disrupted G G Z compared to controls (160 6 vs 165 6cm; P 0.01). Sex chromosome metabolism of Se resulting in neurological and growth defects. Hypothesis: Z aneuploidy was positively correlated to BMI (P 0.0001) and negatively Se impairs regular tissue development by modifying growth signal biosynthesis, Z correlated to menarche (P 0.045); moreover, menarche occured earlier when anabolic responses or oxidative stress levels within endocrine glands or target G G Z aneuploidy reached 10% or more (12.3 1.0 vs 13.5 1.3 years; P 0.01). There tissues. G G was no difference between the groups for FSH (8.41 2.6 UI/l versus 8.28 Methods Z G G Z 4.0 UI/l; P 0.85), LH, estradiol (50.6 23.7 vs 51.7 32.1 pg/ml; P 0.81), Male and female wild-type, heterozygous and SePP-KO mice were raised on G G Z G Inhibin B (55.5 36.5 vs 57.4 33.7 pg/ml; P 0.80) and TSH (1.74 0.8 vs regular chow with defined Se-content. The expression of growth-relevant genes G Z 1.83 1.1 micUI/ml; P 0.64). Premature ovarian failure incidence did not differ was studied in target tissues by qPCR and Northernblot analyses at 35 or 42 days between the two groups. Spontaneous abortions were more frequent in study of age. Serum markers like IGF-1 and IGF-BPs were determined by ELISA. G G Z group (2.0 0.9 vs 1.2 0.4; P 0.01) and recurrence was positively correlated Results Z to aneuploidy percentage (P 0.008). Male SePP-KO mice displayed progressively reduced body weight gain starting Conclusion two weeks after weaning. In contrast, female SePP-KO mice had a reduced Sex chromosome mosaicism is responsible for clinical changes since 8% of bodyweight right from the beginning, but body mass differences diverged not aneuploidy, corresponding to main phenotypic features of Turner syndrome. further during the observational period. Significant differences in mRNA levels (57% reduction versus wild-type, P!0.01) and IGF1 serum levels (23% reduction versus wild-type, P!0.05) were exclusively observed in males. These findings underline the importance of Se for regular growth and health status and highlight medically important gender-differences in Se metabolism. Conclusion Se metabolism, Se status and transport are involved in tissue growth and body P352 mass regulation. Our findings on the impact of gender on the SePP-KO phenotype Evaluation of insulin sensitivity in growth hormone (GH) deficient may help to understand sex-specific effects of Se-supplementation in the clinics children before and at the end of rhGH therapy during disease prevention programs and therapeutical trials. Silvia Savastio1, Simonetta Bellone1, Jaele Bellone1, Fiorella Zanetta1, Supported by Deutsche Krebshilfe (10-1792 SchoII) and DFG (SCHO 849/2-1). Giuseppina Di Dio1, Sara Giacoma1, Antonella Petri1, Flavia Prodam1, Ginevra Corneli1, Gianni Bona1 & Gianluca Aimaretti2 1Division of Pediatrics, University of Piemonte Orientale, Novara, Italy; 2Division of Endocrinology, Department of Clinical and Experimental Medicine, University of Piemonte Orientale, Novara, Italy. P354 Introduction Potential ageing effects in long-term cultured mouse neurospheres Therapy with recombinant GH (rhGH) allows GH-deficient children (GHD) to Vladimir Vukicevic, Linda Gebauer, Anna Jauch, Christian Ziegler, reach an adequate adult stature. Previous studies have reported a significant rise in Alexander Krug, Kuei-Fang Chung, Richard Funk, Stefan Bornstein, serum insulin levels during GH therapy. It has been demonstrated that insulin Albrecht Mueller & Monika Ehrhart-Bornstein resistance is a risk factor for the development of DMT2, atherosclerosis, Molekulare Endokrinologie, Medizinisch Theoretisches Zentrum, Univer- dyslipidemia and hypertension. sita¨tsklinikum Dresden, Dresden/Saxony, Germany. Subjects and methods Aim of our study was to evaluate changes in insulin sensitivity in a group of GHD children longitudinally followed during rhGH treatment. We measured fasting Neural cells are isolated from forebrain of 14.5 days old mouse embryos. glucose and insulin levels and after oral glucose tolerance test (OGTT) in 11 GHD In selective conditions these cells cluster forming sphere-like structures – children (seven males and four females) at three times: 1) before starting of GH neurospheres (NSCs). NSCs are heterogeneous structures containing only 2–5% therapy (BT); 2) during the last year of therapy (T1); 3) 6 months (T6) after of stem cells and progenitors being reportedly capable to transdifferentiate. stopped therapy. At BT children presented age of 9.2G0.7 years, height SDS Initially, aim of this study is to establish optimal culture conditions prior to K1.9G0.2, while during T1 age was 15.4G0.3 years, height SDS K1.2G0.2. investigation of transdifferentiation capacity of transplanted NSCs in kidney and GH treatment was administered subcutaneously at a mean dosage of adrenal glands. It was reported low reproducibility of such experiments but the 0.2–0.3 mg/kg per week. age of transplanted NSCs was not considered as significant issue. In fact, it is Results generally assumed that progenitors and stem cells remain intact in long-term No children showed impaired glucose tolerance or DMT2 during the therapy. culture and therefore convenient for potential transplantation. In spite, we Basal glucose levels were similar among the three times. Glucose levels in hypothesized that potential ageing effects of overall sphere certainly will impact response to OGTT were statistically higher at T1 compared to BT and T6 the fraction of stem cells and progenitors. This assumption was tested exploring (P!0.007). Fasting and during OGTT insulin levels were higher at T1 compared distinct aspects of ageing in long-term NSC culture. Potential alterations that
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 might occur due to ageing were monitored within 1–16 weeks of culturing. Material and methods Initially, tremendous structural and numerous chromosomal aberrations were Nocturnal GH peak during 2-h assessment (5 samples every 30’) was compared in observed upon 16 weeks of culturing. This was accompanied with p53 up the 2 groups of children, classified as: 1/ GHD – decreased both GH peak in 2 regulation. Moreover, p53 engagement may indicate higher apoptotic rate as self- stimulating tests (!10 ng/ml) and IGF-I secretion (IGF-I SDS !K1.5 for age defense mechanism in order to prevent further DNA burden. Telomere shortening and sex (nZ24), 2/ idiopathic short stature – normal both GH peak in stimulating was considered as senescence indication what may imply reduced number of cell tests and IGF-I secretion (nZ27). ROC analysis was performed in order to assess divisions from certain time point. Telomere length measurement revealed the sensitivity and specificity of nocturnal GH peak for different cut-off levels. decrease after 5 and 16 weeks. Although with jeopardized overall homeostasis, Results NSC unexpectedly displayed gradually elevated capacity to form spheres even in The best accuracy of 2-h nocturnal GH profile was found for the cut-off level seeded low cell density up to 16 weeks culturing. Increased capacity to form of GH peakZ16 ng/ml, with the sensitivity of 87.5% and specificity of 59.3%. spheres is accompanied with decreasing ability to differentiate into neural The sensitivity on the level of 95% (acceptable for screening procedures) lineages. Genetic instability and diminished differentiation capacity seem to be a required increasing the cut-off value up to 20 ng/ml. Using the same cut-off consequence of long term culturing implying potential transformation. levelZ10 ng/ml decreases the sensitivity of the examination to only 56.2%, with a slight increase of specificity – up to 74.1%. Conclusions Nocturnal 2-h profile of GH secretion may be a screening tool in diagnosing GHD, however with the cut-off level higher than for GH stimulating tests. There is no evidence for using the same cut-off values for GH peak in nocturnal profile as that established for stimulating tests.
P355 Health-related quality of life in constitutionally tall children and adolescents Galina Melnitchenko1, Dmitry Koloda1, Vyacheslav Pronin1 & Anatoly Tiulpakov2 1 I M Sechenov Moscow Medical Academy, Moscow, Russian Federation; P357 2Endocrinology Research Center of Federal Agency for Provision of High Technology Medical Aid, Moscow, Russian Federation.
. Objective To evaluate the health-related quality of life (HRQoL) in children and adolescents with constitutional tall stature (CTS). Abstract withdrawn Materials and methods Sixty-two patients (20 males and 42 females) with CTS aged 9.3–16.4 years (12.9G2.4 years, meanGS.D.) were enrolled in this study. Sixty-eight normal subjects (24 males and 44 females) aged 9.8–16.2 years (13.1G2.1 years) served as controls. The evaluation of the HRQoL was performed using validated Russian version of 23-item PedsQL 4.0 (pediatric quality of life inventory) generic core scales. Results P358 Mean total score (TS) and psychosocial health summary score (PHSS) were significantly lower in CTS females than in controls (mean TS: 69.4G3.4 vs Comparison between the results of 2-h and 6-h assessment of nocturnal 81.5G2.3; PZ0.02; mean PHSS: 65.2G3.1 vs 80.8G2.7; PZ0.012). Similar growth hormone (GH) secretion in short children - preliminary report results were observed in parent proxy-reports (mean TS: 63.2G2.2 vs 81.3G2.1, Maciej Hilczer, Joanna Smyczyn´ska, Renata Stawerska & Andrzej Lewin´ski PZ0.004; mean PHSS: 60.4G3.3 vs 79.8G2.2; PZ0.006). In contrast the Chair of Endocrinology and Metabolic Diseases, Research Institute, Polish physical functioning score was not significant different from that determined in Mother’s Memorial Hospital, Medical University of Lodz, Lodz, Poland. controls. Also there were no significant differences in HRQoL parameters between CTS males and control group. Background Conclusions Assessment of nocturnal GH secretion is useful tool in diagnosing GH deficiency Females with CTS rated their HRQoL considerably lower than healthy (GHD) in children. The time period of the evaluation, the number of blood controls, the domains of social and emotional functioning being particularly samples, as well as the choice of cut-off value for this examination – are still the affected. The parents’ ratings were considerably lower than those of the matter for discussion. patients. Aim The aim of the study was to compare the results of 2-h and 6-h assessment of nocturnal GH secretion in children with suspected neurosecretory dysfunction of GH secretion (NSD). Material and methods The analysis comprised the results of 2-h and 6-h assessment of nocturnal GH secretion in 33 short children with GH peak normal in stimulating tests (O10 ml) but decreased in 2-h nocturnal assessment (!16 ng/ml – i.e. the cut-off value with most accuracy in diagnosing GHD, according to ROC analysis) and decreased P356 IGF-I secretion. The 6-h nocturnal profile was performed after approximately 6 Utility of 2-h nocturnal assessment of growth hormone (GH) secretion months from the first evaluation. The blood samples for GH measurement were as a screening procedure in diagnosing GH deficiency in short children: obtained in both tests every 30 min. own observations Results G ! Joanna Smyczyn´ska, Maciej Hilczer, Renata Stawerska & Andrzej Lewin´ski GH peak in the first 2-h test was 8.5 4.5 ng/ml, being significantly (P 0.05) G G Chair of Endocrinology and Metabolic Diseases, Research Institute, Polish higher in the second test: 12.3 6.5 ng/ml during 2 h and 13.5 6.9 ng/ml during Mother’s Memorial Hospital, Medical University of Lodz, Lodz, Poland. 6 h of profile. The results of the second evaluation were consistent with those of the first test in 24 children, while in the remaining 9 cases nocturnal GH secretion in repeated assessment presented over the cut-off level. In the 6-h profile, the Background highest GH peak was observed during first 2 h in 26 patients, while later – only in Nocturnal profile of GH secretion is proposed to be a screening diagnostic 7 children. However, in just 1 case only, the earliest value that exceeded the cut- procedure for GH deficiency (GHD) in short children. Every screening procedure off level was obtained later than during first 2 h of the test. must be characterised by very high sensitivity and good specificity. The data Conclusions concerning the cut-off level between normal and subnormal nocturnal GH Repeated assessment of nocturnal GH secretion may prevent overdiagnosing secretion are scarce and non-consistent. NSD in children. It seems no necessary to assess 6-h nocturnal GH profile in such The aim of the study was to assess the clinical utility of 2-h nocturnal profile of cases. GH secretion in diagnosing GHD in children.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P359 P361 Lipid peroxidation as possible mechanism of apoptosis activation in low Changes in cortisol and insulin during pregnancy in relation to basal birth weight children metabolic rate (BMR) Ewa Barg, Kazimierz Gasiorowski, Beata Wikiera, Anna Skoczynska, Svetozar Damjanovic, Rada Stojic, Nebojasa Lalic, Milan Petakov, Barbara Turczyn, Elzbieta Wojcik & Marcin Grabowski Aleksandra Jotic, Tanja Isailovic, Bojana Popovic, Djuro Macut & Wroclaw Medical University, Wroclaw, Poland. Ivana Bozic Institute of Endocrinology, Diabetes and Metabolic Disease, Medical School of Belgrade University, Belgrade, Serbia. Children born with low birth weight (LBW, below 2500 g) exhibit slower development with deficit of height susceptibility to recurrent infections, especially of respiratory tract and, in adulthood, an increased risk of developing Cortisol rise during pregnancy is connected with fetal maturation. Together syndrome X. One possible explanation could be an enhanced elimination of cells with the increase of insulin resistance it might have a role in allocation of by apoptosis. nutrients between mother and fetus. Cortisol and insulin secretion during The aim of this study was evaluate of mechanism of lipid peroxidation and pregnancy seems to be induced by fluctuations in BMR. Here, we try to activity of caspase 3 in children with low birth weight. identify relationship between BMR and secretion of cortisol and insulin Subjects for study were 10 children with LBW and growth retardation during pregnancy. 2 (SDSHV!K1.8) and high frequency of apoptotic cells in cultures of In 25 healthy women (age range 20–39 years; meanGS.D., 28.6G4.4 kg/m ) lymphocytes and with the 50 kb domain on the DNA electrophoretic profiles, body weight (BW), body mass index (BMI), BMR, basal insulin, and aged 4–11. Control group was 30 children with birth weight above 2700 g, aged cortisol were measured in gestational weeks 12, 26 and 36. Homeostatic 4–11. model index (RHOMA) and individual differences (D) between values at 36 Plasma total cholesterol, HDL- cholesterol, HDL2-cholesterol, HDL3-cholesterol, and 12 week of gestation for each variable were calculated. We used a LDL- cholesterol, lipid peroxidase (LPO). Activity of caspase 3 was estimated in ventilated hood system (Deltatrac Metabolic Monitor; Datex Instrument- supernatant blood cells. arium Corp., Helsinki) to measure CO2 and oxygen consumption during The study protocol was approved by Ethics Committee of Wroclaw Medical 20 min period. Insulin and cortisol were measured by RIA method. In University. statistical assessment repeated – measures analysis of variance and Pearson Results product moment were used. The levels of HDL2-cholesterol, LPO and BCL2 were higher in LBW children Both BMI and BMR significantly rose with advancing of pregnancy than in the control group, so that activity of Caspase 3, the level of (P!0.001 for both). Cortisol increased from 396.9G173.2 nmol/l at HDL3-cholesterol was markedly lower, whereas total HDL and LDL concen- gestational week 12, to 775.1G354.1 nmol/l and 800.0G285.0 nmol/l at trations did not differ between LBW and the control group. gestational weeks 26 and 36, respectively (P!0.001, for both). Similarly, In children with LBW the concentration of LPO negatively correlated with HDL3 insulin secretion was augmented (from 7.9G3.0 mIU/l to 9.1G3.9 mIU/l cholesterol (rZK0.77, P!0.05). Activity of Caspase 3 positively correlated and 11.7G5.4 mIU/l; PZ0.001). RHOMA index rose, but this was less with HDL2-cholesterol concentration. (rZ0.91, P!0.05). No significant pronounced (PZ0.042). We also found close positive correlation between correlations were found in the control group. DBMR with DBMI (rZ0.47, PZ0.008), Dinsulin (rZ0.40, PZ0.038) and Conclusions Dcortisol (rZK0.42, PZ0.03). It is known that lipid peroxidation products activate apoptosis in human The rise of maternal serum cortisol and insulin suggest the activation of lymphocyte cultures through the direct stimulation of caspase 2 and caspase hypothalamo-pituitary–adrenal axis. Negative relationship between the 3. Enhanced lipid peroxidation in blood of LBW children could be deduced increase of cortisol and BMR reflects cortisol induced decrease of fetal from our data which showed the increase of LPO activity in those children, metabolic rate in late pregnancy. These may suggest brain involvement in accompanied with the decrease of HDL3-cholesterol level. Since HDL3 is control of energy homeostasis during pregnancy. efficient in prevention of LDL non-enzymatic, Haber-Weiss peroxidation, we suggested that both enzymatic and non-enzymatic lipid peroxidation could be elevated in LBW children. These results were in accord with increased frequency of apoptosis, found in cultures of lymphocytes obtained from venous blood of LBW children. Growth factors P362 Does IGF-BP3 assay contribute to the diagnosis of GHD in children? Simon Kayemba-Kay’s, Sophie Epstein, Antoine Burguet, Pierre Ingrand & Re´gis Hankard P360 Poitiers University Teaching Hospital, Poitiers, France. Study of dimer and oligomers of human growth hormone Riia Junnila, Zida Wu & Christian Strasburger Clinical Endocrinology, Berlin, Germany. Background Diagnosing GDH in children remains matter of debate due to variability in results obtained with pharmacological tests, one child may fail one test, but pass another. There is a high heterogeneity of human growth hormone (hGH), variation rising Spontaneous GH secretion assessment is costly, time consuming, and results may from the different genes in pituitary and placenta, alternative splicing, post- show poor correlations with those obtained with provocative tests. To add to translational modifications, oligomerization and binding to the growth hormone diagnosic power of provocative tests, testing IGF-I and IGF-PB3 have been binding protein (GHBP). Distinguishing between different variants remains suggested. In recent years, however, the contribution of IGF-PB3 assay to problematic and there is still quite little information about the proportion of these diagnosis of GHD has been questioned ( ). variants in circulation of both healthy individuals and of patients with growth Objective hormone disorders. Studying the abundance of dimer and oligomers in different To evaluate the contribution of IGF-PB3 assay to the diagnosis of GHD. physiological and pathological conditions is highly interesting since these forms Population and methods of hGH will have longer half lives in circulation. In this experiment, 22 kDa hGH Retrospective case study. Boys and girls aged 0–18 years who attended our was expressed by HEK 293 cells and the hGH secreted in supernatant was studied. Paediatric endocrinology clinic for short stature and/or follow-up post-irradiation, The western blot has shown, that in addition to monomer, hGH was also produced and had at least one provocation test for GH secretion assessment. We excluded as dimer and oligomer. The dimer and oligomers are partially reduced by the those with hypothyroidism, Laron syndrome, severe malnutrition, chronic renal reducing agent breaking down the disulfide bonds. Nevertheless, the dimer and failure and liver failure. oligomers can be detected even in reducing conditions, implicating that part of the Results dimer and oligomers are formed covalently otherwise than by disulfide bonding. Fifty-eight children were enrolled and grouped according to results as GHD (C) A non-denaturing method based on fractionation with FPLC followed by high- (19 cases) and GDH (K) (39 cases). IGF-I and IGF-BP3 assay was carried out in sensitivity time-resolved immunofluorometric assays has turned out promising for 88% and 62% respectively, both groups were comparable for age, sex, BMI, the study of dimer and oligomer. The peaks measured by the immunoassays for target height, pubertal stage and bone age. There was a difference in maximum monomeric versus dimeric and oligomeric hGH offered valuable information on GH peak obtained between GDH (C) and GHD (K) groups (41.8 mUI/lG21.7 the proportion of these forms. The function and structure of hGH dimer and versus 11.5G5.9 mUI/l, P!0.00001, respectively). No difference was found oligomers as well as their relationship to hGH monomer need to be distinguished between groups with regards to IGF-I Z-scores and IGF-BP3 Z-scores. There was, by further studies. however a positive correlation between IGF-I Z-scores and IGF-BP3 Z-scores (rZ0.50; P!0.0016).
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Conclusions 156 pg/ml IFN-b. Measurement of 6–16 mRNA by real-time RT-PCR and bDNA – IGF-BP3 assay contributes poorly to diagnosis of GHD, with 24% Sensitivity is readily adaptable for the detection and measurement of NAbs against IFN-b. and 92% Specificity respectively. Thus, sera from patients receiving IFN-b therapy (21 months) effectively – Due to lack reference values adjusted for age, sex, and pubertal stage, we do not neutralised IFN-b-stimulated 6–16 mRNA expression (100% neutralisation at a recommend its routine use. serum titre of 1:600; 50% neutralisation at a serum titre of approximately 1:4000), whilst pre-treatment serum from the same patients had no effect at the highest concentration tested. These data suggest mRNA-based assays could be used for bioactivity measurements of therapeutic products and also in a clinical setting for the monitoring of patients receiving IFNb treatment. P363 Does administration of octreotide acetate prevent development of diabetic nephropathy? an ultrastructural evaluation of the effects of octreotide acetate on kidney tisssue in Streptozotocin induced diabetic rats P365 Selen Bahc¸eci1, Yusuf Nergiz1, Mithat Bahceci2 & Murat Akkus1 Association between serum levels of insulin-like growth factor-I and 1Department of Histology and Embrylogy, Diyarbakir, Turkey; 2Depart- development of congestive heart failure: a prospective study in a normal ment of Endocrinology, Diyarbakir, Turkey. population Mikkel Andreassen1, Ilan Raymond2, Caroline Kistorp1, Per Hildebrandt3 & Jens Faber1 Background and aims 1Department of Endocrinology, Herlev Hospital University of Copenhagen, Growth hormone and insulin-like growth factors to be involved in the Copenhagen, Denmark; 2Department of Cardiology, Gentofte Hospital pathogenesis of diabetic kidney disease. The aim of this study was ultrastructural University of Copenhagen, Copenhagen, Denmark; 3Department of evaluation of octreotide acetate on kidney tissue in streptozotocin (STZ) induced Cardiology and Endocrinology, Frederiksberg Hospital University of diabetic rats. Copenhagen, Copenhagen, Denmark. Material and methods Twenty-four male Spraque–Dawley rats divided into 3 groups; control (C), diabetic (D) and diabetic with octreotide aceatate (DO). The all diabetic rats were Background treated with 4 IU/d human insulin. Octreotide acetate at the dose of 400 mg/kg per The growth hormone system (growth hormone, GH and insulin-like-growth- daily was applied intraperitoneally in DO groups rats. All rats were followed for a factor I, IGF-I) might be implicated in congestive heart failure (CHF). In month and sacrified after cardiac blood samples were obtained. Both kidneys of experimental models IGF-I increases cardiac contractility and reduces apoptosis all rats were obtained and weighted. All thin sections were stained with uranyl of myocytes exposed to ischemic injury. In clinical studies GH-therapy has been acetate and lead citrate and were examined by JEOL-TEM-1010 electron used in CHF. One previous population based investigation showed that low levels microscope and photo samples were obtained. of IGF-I was associated with an increased incidence of CHF. The result of this Results investigation was limited by lack of echocardiographic examination at baseline Mean kidney weights of diabetic rats was higher than control rats (1.15G0.12 and and the established riskmarker B-type natriuretic peptide (BNP) was not taken 1.68G0.26 g respectively, P!0.001). Mean kidney weights of diabetic rats plus into consideration. octreotide was also higher than control rats (1.29G0.11 g, P!0.02). Ultra- Objective structural findings of kidney were normal in control group. On the contrary, To examine the relationship between levels of IGF-I and the risk of development invagination in podocyte nucleus, dilation in golgi cystern and tubulus, of CHF. obliteration in pedicel and capillary fenestrata were seen in diabetic (D) group. Method In octreotide (DO) group; a marked increment in mesangial matrix, dissociation A population based prospective study of 584 individuals (age 50–89 years) among proximal tubulus cells and thickening in glomerular basement membrane without a history of CHF and with normal systolic function at baseline assessed were determined. by echocardiography (left ventricular ejection fraction R50%). Development of Conclusions CHF was ascertained after 5-years follow-up. Experimental diabetes mellitus may lead to ultrastructural lesions in kidney tissue Cox proportional hazard regression analyses were used for the risk calculations. in even relatively early period of diabetes, and although there was little beneficial Results are given by P values and hazard ratio, HR (95% confidence limits) per 1 changes, a long acting somatostatin analoque, octreotide acetate, could not standard deviation increase in logarithmically transformed IGF-I level. prevent development of diabetic nephropathy. Results Nineteen patients developed CHF (3.3%). They had significantly higher baseline levels of age-adjusted IGF-I levels compared to the rest of the population, 89 vs 72 ng/ml, PZ0.01 (IGF-I adjusted to a 70-year old individual). Age-adjusted IGF-I was associated to increased risk of development of CHF, HRZ1.64 (1.15–2.35), PZ0.007. A multivariable model adjusted for age, levels of N-terminal proBNP (NT-proBNP), the presence of hypertension, atrial fibrillation and diabetes did not attenuate the association, HRZ1.67 (1.16– P364 2.40), PZ0.006. Measurement of neutralising antibodies to human interferon-b by Conclusions quantitative analysis of type 1 interferon inducible 6–16 mRNA In a large middle-aged and elderly normal population high level of IGF-I was an Melanie Moore, Anthony Meager, Meenu Wadhwa & Chris Burns independent riskfactor for development of CHF. The result was unexpected and in NIBSC, Potters Bar, UK. contrast to a previous reported protective role of IGF-I.
Therapeutic interferon-b (IFN-b) preparations have been approved for treatment for multiple sclerosis (MS). However, the development of neutralising antibodies (NAbs) against IFN-b in MS patients reduces therapeutic efficacy. Early detection of NAbs is critical for the modification of treatment regimes. IFN-b exerts its P366 biological effects by binding to receptors on target cells and stimulating the Effects of growth hormone and of insulin-like growth factor-I on iron- expression of IFN-b-inducible genes. Measurement of endogenous mRNAs for induced lipid peroxidation in rat liver and porcine thyroid homogenates these genes can form the basis of functional bioassays. In this study we have used Agnieszka Kokoszko1, Jan Dabrowski1, Janusz Szosland2, two approaches, quantitative reverse transcription-polymerase chain reaction Andrzej Lewinski1 & Malgorzata Karbownik-Lewinska2 (qRT-PCR) and branched DNA (bDNA) technology to develop efficient, sensitive 1Department of Endocrinology and Metabolic Diseases, Medical University and robust non-viral assays for the quantification of IFN-b NAbs in patients with of Lodz, Lodz, Poland; 2Department of Oncological Endocrinology, MS. We show that the rapid (4 h) induction of the type I IFN-inducible 6–16 Medical University of Lodz, Lodz, Poland. mRNA in A549 lung carcinoma cells is quantifiable by qRT-PCR and by bDNA assays. The induction of 6–16 mRNA is sensitively and reproducibly 2C 2C C concentration-dependent for IFN-b stimulation and is comparable for real-time Bivalent iron (Fe ), which initiates the Fenton reaction (Fe CH2O2CH / 3C † PCR and bDNA. In both assay systems, a sigmoidal dose response curve was Fe C OHCH2O), is frequently used to experimentally induce oxidative obtained within the range 0.6–625 pg/ml IFN-b with a maximal response obtained damage to macromolecules. Growth hormone (GH) and the main mediator of its between 156 and 625 pg/ml IFN-b. This is in broad agreement with data from action – insulin-like growth factor-I (IGF-I) – are involved in oxidative processes, antiviral assays in which maximum protection was obtained between 78 and lipid peroxidation (LPO) included.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
The aim of the study was to evaluate the effect of GH and/or IGF-I on iron- Ghrelin and leptin were measured during 3 h OGTT in 52 GHD (21f/31m, median induced LPO in rat liver and in porcine thyroid homogenates. In order to age 51.5 years (range 27–82)). Twenty-two GHD were on GH substitution (GH-sub) determine the effect of GH and/or IGF-I on basal LPO, the homogenates were for a median of 10 years (2–42). Thirty patients were not substituted for at least 2 incubated in the presence of GH (100, 10, 1.0, 0.1, 0.01, 0.001, 0.0001 mg/ml) or years (non-sub). Leptin was measured using an immunfluorometric in-house assay, IGF-I (1000, 100, 10, 1.0, 0.1, 0.01, 0.001, 0.0001 mg/ml) or GH (100 mg/ml)C total serum ghrelin by a radioimmunoassay (Phoenix Pharmaceuticals, USA). Body IGF-I. In order to study their effects on iron-induced LPO, the homogenates were composition was measured by dual-energy-X-ray-absorptiometry. 2 2 incubated with FeSO4 (15 mMor40mM, for the liver and for the thyroid, Age and BMI (GH-sub 26 kg/m (21–42) versus non-sub 29 kg/m (22–66)) were respectively)CH2O2 (0.1 mM or 0.5 mM, for the liver and for the thyroid, not significantly different between GHD groups. Fat mass was significantly higher in respectively) and, additionally, with GH and/or IGF-I. The level of LPO was non-sub (37% (20–52) vs 31% (13–54), P!0.01), so were basal leptin (16 mg/l (3.3– expressed as the amount of malondialdehydeC4-hydroxyalkenals (MDAC4- 89) vs 7.5 mg/l (0.5–130), P!0.05) and the area-under-the-curve (AUC) of leptin HDA). GH and/or IGF-I did not affect basal LPO in either tissue. In rat liver (P!0.05). Baseline ghrelin (GH-sub 145 ng/l (83–280) vs 113 ng/l (61–270)) and homogenates, GH did not affect iron-induced LPO in any way, whereas IGF-I AUC of ghrelin were slightly but not significantly lower for non-sub compared to (0.001, 0.0001 mg/ml) enhanced the process. In porcine thyroid homogenates, GH-sub. Leptin and ghrelin decreased significantly after glucose (maximum at GH, in its lowest two concentrations, completely prevented, whereas in other used 60 min) in both groups (P!0.001). The lower fat mass of GH-subcaused by lipolytic concentrations, it enhanced iron-induced LPO. In turn, IGF-I, in all the used GH might lead to lower leptin levels. The reason for decreasing leptin levels during concentrations, enhanced iron-induced LPO in the porcine thyroid. In conclusion, OGTT in both groups remains unclear. Ghrelin levels were not significantly different GH and/or IGF-I may directly contribute to oxidative balance in the liver and in between groups possibly due to the counterbalance between the suppressive effect of the thyroid under physiological conditions but, in case of induced oxidative stress, GH and the stimulating effect of reduced fat mass. GH has no effect on ghrelin they may reveal prooxidative effects, which fact does not support their application regulation during OGTT. in the treatment of disorders associated with increased oxidative damage.
P367 Protective effects of growth hormone and of insulin-like growth factor-I against lipid peroxidation in iron sensitive rat tissue P369 Agnieszka Kokoszko1, Jan Dabrowski1, Janusz Szosland2, 1 2 New occurrence of diabetes mellitus in patients with adult onset GH Andrzej Lewinski & Malgorzata Karbownik-Lewinska deficiency (GHD) on GH therapy is dependent on the presence of 1Department of Endocrinology and Metabolic Diseases, Medical University 2 metabolic syndrome at baseline: data from the Hypopituitary Control of Lodz, Lodz, Poland; Department of Oncological Endocrinology, and Complication Study (HypoCCS) Medical University of Lodz, Lodz, Poland. Andrea Attanasio1, Daojun Mo2, Philippe Chanson3,KenHo4, Whitney Woodmansee2, David Kleinberg5 & Eva Marie Erfurth6 2C C 3C † 1Cascina del Rosone, Agliano Terme, Italy; 2Lilly Research Laboratories, Iron participates in the Fenton reaction (Fe CH2O2CH /Fe C OHC Indianapolis, USA; 3Department of Endocrinology, Biceˆtre University H2O), the most basic reaction of oxidative stress. This transition metal is required 4 to keep oxidative balance, although iron overload is associated with enhanced Hospital, Le Kremlin-Biceˆtre, France; Garvan Institute of Medical Research, Sydney, Australia; 5New York University School of Medicine, oxidative damage and cancer initiation. Growth hormone (GH) and insulin-like 6 growth factor-I (IGF-I) are also involved in oxidative processes, lipid New York, USA; University Hospital, Lund, Sweden. peroxidation included. The aim of the study was to evaluate the in vivo effect of GH, IGF-I and/or iron on Patients with adult onset GHD (AO-GHD) manifest features of the metabolic lipid peroxidation in different rat tissues. syndrome (MetS) (abdominal obesity, dyslipidemia and insulin resistance), a Male Wistar rats were administered iron as ferrous sulphate (FeSO4; 3 mg/100 g condition associated with increased risk of diabetes mellitus (DM). b.w., on the 8th day of the experiment) and/or GH (0.2 IU/100 g b.w., once daily, We assessed metabolic status before and after 2 years of GH treatment and the for 8 days), and/or IGF-I (2 mg/100 g b.w., once daily, for 8 days). The level of de novo C C occurrence of DM in 712 patients with AO-GHD from HypoCCS drawn lipid peroxidation products – malondialdehyde 4-hydroxyalkenals (MDA 4- from the US (32.2%) and Europe (67.8%). Patients were divided into four BMI HDA) – was measured spectrophotometrically in rat brain, lung, small intestine, categories (!25, 25–!30, 30–!35, R35 kg/m2), and MetS defined by the liver, kidney, testis, spleen, and serum. National Cholesterol Education Program (NCEP) criteria. De novo DM was Among several examined tissues, only the small intestine and the brain appeared recorded from reporting of a new event and/or newly initiated diabetes treatment. to be sensitive to oxidative effects of either GH, or IGF-I and/or iron. The baseline prevalence of MetS was 43.0% with a linear increase across BMI Iron injection significantly increased lipid peroxidation only in the rat small intestine categories from 11.0% to 73.9%. The baseline prevalence of DM was related to and that effect was completely prevented by either GH or IGF-I. In the rat brain, GH BMI and the presence or absence of pre-existing MetS, being 3.1 vs 18.8% for a significantly decreased the basal lipid peroxidation, whereas IGF-I, either used alone BMI !25 kg/m2 and 6.7 vs 43.5% for a BMI R35 kg/m2, respectively. GH or together with iron, significantly increased lipid peroxidation level. treatment did not change the prevalence of MetS (43.0 vs 44.2%). In those In conclusion, not all rat tissues are equally sensitive to iron-induced lipid without pre-existing MetS (nZ406), DM developed in 0.0, 2.4, 0.0 and 0.0% for peroxidation, with only small intestine revealing such a property. GH and IGF-I BMI categories !25, 25–!30, 30–!35 and R35, respectively. In those with possess some ability to prevent iron-induced oxidative damage in iron sensitive MetS (nZ306), DM developed in 7.7, 11.9, 6.3 and 18.8% for the same BMI tissues, whereas contributing by themselves to oxidative imbalance in other tissues. categories, respectively. In summary, the prevalence of MetS is high in adults with GHD and is unchanged by 2 years of GH treatment. However, pre-existing MetS and BMI were strong determinants of the development of DM. Patients with AO-GHD with pre- existing MetS are at increased risk of developing DM during GH treatment, a risk that is worsened by increasing BMI. Greater vigilance should be exercised for P368 early identification and therapy of DM in these patients. Leptin and ghrelin serum levels during an oral glucose tolerance test in patients with growth hormone deficiency with and without growth hormone substitution Josefine Roemmler, Maren Kuenkler, Baerbel Otto, Martin Bidlingmaier & Jochen Schopohl Department of Internal Medicine of the University of Munich, Innenstadt, Endocrinology, Munich, Germany. P370 In GH deficiency (GHD), fat mass is elevated compared to normal subjects. Leptin is Associations of anthropometric parameters with serum IGF-1, TSH, positively related to fat mass, BMI and food intake, while ghrelin correlates prolactin and testosterone levels negatively. During an oral glucose tolerance test (OGTT), leptin increases in obese Nele Friedrich1, Antje Steveling1, Matthias Nauck1, Georg Brabant2, subjects and generally does not change in normal weight subjects. Ghrelin decreases Henry Vo¨lzke1 & Henri Wallaschofski1 during OGTT. We performed a cross-sectional study in order to investigate the 1Ernst-Moritz-Arndt University, Greifswald, Germany; 2Christie Hospital, influence of GH-substitution on leptin and ghrelin in GHD. Manchester, UK.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Background P372 Obesity is a major risk factor for the development of chronic diseases and a Acromegaly is associated with high plasma fibrinogen and C reactive determinant of cardiovascular disease. Divergent associations between obesity protein values after normalization of growth hormone and IGF-1 and hormonal changes have been reported. The objective of the present study was Nele Friedrich, Dennis Nonnenberg, Elisabeth Spilcke-Liss, Henry Vo¨lzke, to analyse the associations between different anthropometric measurements and Marcus Do¨rr & Henri Wallaschofski serum hormone levels including insulin-like growth factor 1 (IGF-1), thyroid- Ernst Moritz Arndt University, Greifswald, Germany. stimulation hormone (TSH), prolactin, and testosterone. Methods A total of 2186 women and 2111 men aged 20–79 years from the population- Background based cross-sectional Study of Health in Pomerania (SHIP) were included in the Acromegaly is associated with increased morbidity and mortality from analyses. Serum IGF-1, TSH, prolactin, and testosterone levels were determined cardiovascular disease. Several studies indicate that reduction of growth hormone by immunochemiluminescent procedures. Body height, weight and waist as well (GH) to !1 mg/l or normalization of serum IGF-I reduces mortality to expected as hip circumferences were measured. Body mass index (BMI), waist-to-hip ratio levels. Inflammatory markers, such as C-reactive protein (CRP) or haemostatic (WHR), and waist to height ratio (WHtR) were calculated. markers, such as fibrinogen have emerged as important cardiovascular risk Results markers in the general population. Our analyses revealed negative associations between all considered anthropo- Objective and design metric parameters and serum IGF-1 levels in women and men as well as serum The objective of the present study was to assess serum levels of high sensitive testosterone levels in men. Furthermore, whereas in women anthropometric CRP and fibrinogen in patients with normalized GH and IGF-1 values after parameters except BMI and hip circumferences were positively associated to treatment compared to the background population. This case-control study serum TSH and prolactin levels, no such associations were present in men. included 32 patients (18 women) with acromegaly after successful treatment and Conclusion 128 controls of a population-based study matched by sex and age. Our results argue for interrelated hormone production and secretion Results associated with visceral fat. Furthermore, our analyses displayed that the We detected a higher body mass index (30.3 vs 27.2 kg/m2; PZ0.02) and more use of visceral fat measurements like waist circumference, WHR and WHtR cases of diabetes (23 vs 9%; PZ0.05) in patients with acromegaly compared to should be preferred for the assessment of associations between body fat and controls. However, there was no differences for hypertension, smoking and lipids hormone levels. between both groups. Patients revealed normalized but even higher mean IGF-1 values than controls (129.5 vs 232.7 ng/ml; P!0.05). Moreover, patients with acromegaly showed higher values of high sensitive CRP and fibrinogen. After adjustment for confounders, patients with acromegaly had higher odds of serum CRP and fibrinogen values compared to controls. In a linear regression model, elevated fibrinogen values were positive associated with IGF-1 values and acromegaly. P371 Conclusion Normalized but higher IGF-1 values after treatment of acromegaly are associated The cytosine-adenine (CA) repeat polymorphism in the promoter with increased high sensitive CRP or fibrinogen values. This might be a possible region of the insulin-like growth factor-1 (IGF-1) gene is not associated explanation for the revealed increased all-cause mortality in acromegalic patients with the GH dose in GH-deficient adults compared to the general population even after treatment. Silke Meyer1, Carolin Bru¨ck1, Diana Ivan1,UteKo¨hler1, Stephan Scha¨fer1, Pascal Arp3, Aart J van der Lely2, Andre G Uitterlinden3 & Peter H Kann1 1Division of Endocrinology and Diabetology, University Hospital Giessen and Marburg GmbH, Philipps-University Marburg, Marburg, Germany; 2Department of Internal Medicine, Erasmus University Medical School, Rotterdam, The Netherlands; 3Department of Epidemiology and Biostatis- tics, Erasmus University Medical School, Rotterdam, The Netherlands. P373 Low insulin-like growth factor (IGF) I, IGF binding protein-3 and acid Objective labile subunit (ALS) levels in young ischemic stroke: a prospective case- A cytosine-adenine (CA)n microsatellite repeat polymorphism in the promoter control study region of the insulin-like growth factor-1 (IGF-1) gene has reported to be Carolina Di Somma1, Maria Cristina Savanelli1, Antonella Tufano2, associated with IGF-1 serum levels, birth weight, body height, bone mineral Francesca Rota1, Dario Nicola Di Minno2, Marianna D’Andrea1, density and risk for type 2 diabetes and myocardial infarction. Carriers and non- Gaetano Lombardi1, Giovanni Di Minno2 & Annamaria Colao1 carriers of the most frequent allele (length 192 base pairs (bp)) showed 1Department of Molecular and Clinical Endocrinology and Oncology, significantly different total IGF-1 serum levels. This polymorphism may directly Naples, Italy; 2Department of Clinical and Experimental Medicine, Naples, or indirectly influence growth hormone (GH)-mediated regulation of IGF-1 Italy. secretion. Aim of this study was to test the hypothesis that the 192 bp polymorphism is associated with the GH dose of GH-deficient adult patients receiving recombinant Animal and observational studies suggest that the IGF axis is involved in GH-treatment. the pathogenesis of ischemic stroke; moreover, endogenous IGF-I could Patients and methods influence the evolution of ischemic stroke in humans and thereby contribute The 192 bp polymorphism was determined in 133 German adult patients (66 men, to an improved clinical and functional outcome. To assess and correlate the 67 women; mean age 45.4 yearsG13.1 S.D.; majority Caucasian) with IGF-I axis with biochemical parameters in young patients experiencing GH-deficiency (GHD) of different origin, derived from the prospective KIMS ischemic stroke (32 aged 15–45 years,19F, BMI: 25.5G3.4 kg/m2), we Pharmacogenetics Study (approval was obtained from the local ethical evaluated IGF-I, IGFBP-3, ALS, homocysteine, antithrombin, anticardiolipin committee). Patients received GH-treatment for 12 months with finished dose- antibodies (ACA), lupus anticoagulans (LAC), Protein S and C, fibrinogen titration of GH and standardized IGF-1 measurements. GH dose after one year of levels and lipid profile 6–12 months after stroke. The results were compared treatment, IGF- and IGF-SDS values and anthropometric data were analyzed by with those of 32 age, BMI and sex matched controls. IGF-I levels were 192 bp polymorphism genotypes (homozygotes for the 192 bp allele; hetero- lowerinpatientsthanincontrols(86.3G76.6 vs 262.9G50.5 mg/l; zygotes; non-carriers). P!0.001) and lower than 2 SD in 24 patients (75%). IGFBP-3 and ALS Results levels were also significantly reduced in patients than in controls (3394.8G The genotype distribution followed Hardy-Weinberg-equilibrium (PZ0.06). 801 vs 3782G762.8 ng/ml, P!0.05; 10.2G3.8 vs 21.2G27.5 mg/ml, Genotype groups showed no significant differences in the required GH dose after PZ0.000; respectively. Conversely as expected, homocysteine, total 1 year of GH-treatment (PZ0.61), IGF-1 serum concentrations (PZ0.78) and cholesterol and fibrinogen levels were higher in patients than in controls IGF-1 SDS (PZ0.93) after adjusting for the confounding variables gender, age (P!0.001). Significant difference was found between patients and controls and body mass index. in Protein S (P!0.001) and C (P!0.05), while no difference was found in Conclusion ACA and LAC levels between two groups. In addition in the patients’ The 192 bp polymorphism was not associated with the responsiveness to group, IGF-I levels were significantly correlated with homocysteine levels exogenous GH in GHD adults. As effects of non-GH factors on the IGF-1 levels (rZ0.411, P!0.05). (insulin-levels, sex steroids, nutrition, liver function) in GH-deficient patients In conclusion a significant impairment of IGF-I and ALS secretion was were minimized, GH-driven regulation of IGF-1 levels seems not to be influenced found in young patients 6–12 months after ischemic stroke. Whether this by the 192 bp polymorphism in these patients. represents a causal or casual finding remain to be clarified.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P374 P376 Pituitary hormone axes in constitutionally tall adolescents Overexpression of IGFBP-2 in transgenic mice affects muscle protein Galina Melnitchenko1, Dmitry Koloda1, Vyacheslav Pronin1, accretion, skeletal myofibre growth and metabolism Anatoly Tiulpakov2, Evgeny Gitel1, Zurab Ordzhonikidze3, C Rehfeldt1, U Renne 1, E Wolf2 &AHo¨flich1 Vladimir Pavlov3 & Vladimir Preobrazhensky4 1Research Institute for Biology of Farm Animals, Dummerstorf, Germany; 1I M Sechenov Moscow Medical Academy, Moscow, Russian Federation; 2Institute of Molecular Animal Breeding and Biotechnology, Ludwig- 2Endocrinology Research Center of Federal Agency for Provision of High Maximilian University, Munich, Germany. Technology Medical Aid, Russia, Moscow, Russian Federation; 3Moscow Sports Medicine Research Center, Moscow, Russian Federation; 4Medical Rehabilitation Center of Federal Agency for Public Health and Human To elucidate the functional role of IGFBP-2 for in vivo skeletal muscle growth Services, Moscow, Russian Federation. and function, skeletal muscle cellularity and metabolism as well as body growth and composition have been studied in a transgenic mouse model overexpressing IGFBP-2. Postnatal growth rate of transgenic mice (nZ20) was clearly reduced Objective from day 21 of age by 6–8% (P!0.05) compared with non-transgenic controls To evaluate the pituitary hormone axes in adolescents with constitutional tall (nZ37). At the final day of live (day 72 of age) body protein and moisture were stature (CTS). lower, whereas fat percentage was higher in the IGFBP-2 transgenes (P!0.05). Materials and methods The weights of the lower leg and of the M. rectus femoris (RF) were reduced by About 120 patients (54 males and 66 females) with CTS aged 9.6–16.5 years 14% (P!0.0001), which was associated with higher DNA (P!0.05) at (13.6G2.7 years, meanGS.D.) were enrolled in this study. Sixty-eight normal unchanged RNA and protein concentrations in RF. The reduction in muscle subjects (24 males and 44 females) aged 9.8–16.2 years (13.1G2.1 years), who mass resulted mainly from slower growth of myofibres in size as seen from were comparable in socioeconomic and nutritional terms, served as controls. smaller cross sectional areas (by 12%; P!0.01), but not from decreases in the Growth hormone, insulin-like growth factor-I (IGF-I), IGF-binding protein-3 number of fibres. Analyses of metabolic fibre type composition and enzyme (IGFBP-3), luteinizing hormone, follicle-stimulating hormone and prolactin activities revealed that muscle metabolism was shifted to the glycolytic pathway levels were measured. of energy generation. The proportion of white (glycolytic) fibres was increased at Results the expense of intermediate (oxidative/glycolytic) fibres and, likewise, the In comparison with controls, CTS children showed a slightly lower concentration activity of lactate dehydrogenase (LDH) was elevated (P!0.01). All differences of IGFBP-3 and a higher concentration of IGF-I but these differences were not observed between transgenic and non-transgenic mice were more pronounced in significant. In contrast the IGFBP-3/IGF-I molar ratio was significantly lower males as derived from significant genotype by sex interactions. The results (0.7G0.1 vs 1.1G0.2; P!0.001) in CTS children than in controls. The suggest that IGBP-2 inhibits postnatal skeletal muscle growth and modifies concentrations of other pituitary hormone in CTS-affected subjects were not muscle metabolism. significant different from those determined in controls. Conclusions This study has demonstrated that in CTS the most components of pituitary hormone axes are normal, but the IGFBP-3/IGF-I molar ratio is increased, and, therefore, a greater availability of free IGF-I for target tissues may be responsible for overgrowth in CTS. Neuroendocrinology P377 Turner syndrome: body composition and psychological state Lina Lasaite, Danute Lasiene & Liudvikas Lasas Institute of Endocrinology of Kaunas University of Medicine, Kaunas, Lithuania.
Introduction Turner syndrome (TS) is female genetic disorder arrising from loss of P375 X-chromosome material, associated with characteristic physical neuropsycholo- TIMP-1 regulates the secretion of soluble VEGF receptor 1 in human gical features. endothelial cells Objective Joseph Neulen & Karin Motejlek Examine peculiarities of body composition, cognitive functions, emotional state, Gynecology Endocrinology, University Hospital, Aachen, Germany. quality of life (QoL) of TS patients after discontinued growth hormone (GH) therapy. Patients and methods Objectives Eighteen girls (age 21.47G4.09 years) with diagnosis of TS established in Vascular endothelial growth factor (VEGF) and its soluble receptor (sVEGFR-1) childhood. GH therapy for at least five years (discontinued immediately to the are key regulators in human ovarian angiogenesis. VEGF promotes blood vessel beginning of the study). growth while sVEGFR-1 is a VEGF antagonist. A promising candidate in Height, weight, waist-to-hip ratio, body composition, cognitive functions (trail sVEGFR-1 regulation is TIMP-1 (tissue inhibitor of metalloproteinases 1), which making test, TMT), emotional state (profile of mood state, POMS), QoL (special is involved in extracellular matrix remodelling. The aim of our research is to questionnaire for growth disturbances) in TS patients were compared to that of determine if TIMP-1 influences sVEGFR-1 secretion in endothelial cells. controls. Methods Results Pooled human endothelial cells were seeded in 24-multiwell plates. Twenty- Height (148.8G5.7 vs 168.4G5.1 cm, P!0.001), weight (50.4G7.9 vs 61.3G four hours afterwards, TIMP-1 was downregulated in the cells by RNA 8.6 kg, P!0.001) in TS girls were significantly lower than in controls, but interference using four TIMP-1 siRNAs (small interfering RNAs) and two differences in body mass index were not significant. Lean body mass (36.31G unspecific siRNAs. After four days incubation, TIMP-1 and sVEGFR-1 4.02 vs 47.02G4.47 kg, P!0.001), water body mass (27.37G1.73 vs 32.39G concentrations were quantified in culture supernatant by enzyme-linked 2.52 kg, P!0.001) in TS patients were significantly lower than in controls. immunosorbent assay (ELISA). Control endothelial cells were used without Waste-to-hip ratio in TS girls was significantly higher (0.82G0.06 vs 0.74G0.04, additional treatment. P!0.001) than in controls. Results In emotional state tension-anxiety (10.6G7.2 vs 6.7G3.9, PZ0.02), depression- As shown in ELISA assays, TIMP-1 concentration in the endothelial culture dejection (14.7G11.9 vs 8.5G6.3, PZ0.02) were significantly higher, vigour- supernatant was significantly reduced between 65% and 78% by using the four activity (13.1G4.8 vs 16.1G4.4, PZ0.04) significantly lower in TS patients than TIMP-1 siRNAs when compared to untreated control cells. According to this, in controls. TMT score (96.9G44.6 vs 58.1G15.4, PZ0.001) was significantly sVEGFR-1 concentration was also significantly decreased between 39% and higher (worse psychomotoric speed) in research group than in controls. QoL 69% in the cell culture supernatant by using the specific siRNAs. Endothelial (9.5G5.2 vs 6.3G4.2, PZ0.03) in TS girls was significantly worse than in cells transfected with the unspecific siRNAs, however, showed similar TIMP-1 healthy. and sVEGFR-1 amounts like untreated controls. Conclusion Conclusion In conclusion, TS patients after discontinued GH therapy has lower height, The amount of soluble VEGF receptor 1 was significantly reduced in the TIMP- weight, higher waist-to-hip ratio, lower lean body mass and water body mass, 1 knockdown experiment. Therefore, sVEGFR-1 secretion in endothelial cells impaired cognitive functioning, altered emotional state, lower quality of life in can be regulated by TIMP-1. comparison to normal girls of the same age.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P378 1Department of Neurosurgery, University of Giessen and Marburg GmbH, 2 Can early evening melatonin treatment prevent relapse after sleep Campus Giessen, Giessen, Hessen, Germany; Department of Endo- deprivation? crinology, University of Giessen and Marburg GmbH, Campus Giessen, Arcady Putilov & Konstantin Danilenko Giessen, Hessen, Germany. Research Institute for Molecular Biology and Biophysics and Institute of Internal Therapy, Novosibirsk, Russian Federation. Objective In order to explain physical, cognitive and psychological disorders after traumatic Patients with winter depression (seasonal affective disorder) respond beneficially brain injury (TBI), several studies have implicated a major role of posttraumatic to sleep deprivation and bright light, but the mechanisms of these responses pituitary insufficiency (prevalence 25–70%). Aim of this study was to determine remain unknown. The study was designed to test whether afternoon/evening the correlation between cerebral tissue damage, corresponding initial findings on melatonin can prevent further relapse after sleep deprivation (presumably due to a radiographic imaging and pituitary insufficiency versus psychological disorders pharmacologically induced advance shift of circadian phase). Compared to phase (like fatigue, nervousness, depression or excitability). advancing by alteration of sleep-wake schedule or by bright light exposure, the Material and methods melatonin intake is a more tolerated treatment procedure, and it provides a About 171 patients with TBI had been contacted, 55 (32%) agreed to participate possibility of blind comparison between chronotherapeutic and placebo in the study. Hormonal stimulation tests had been performed, either if the basal treatments. The depression was scored in 16 female patients with winter hormone screening revealed an abnormality or if the patient answered ‘yes’ in at depression and 17 age-matched female controls before and after total night sleep least one question of the pituitary questionnaire. deprivation and after subsequent 6-day administration of melatonin (0.5 mg) or The following data had been included into a multivariate analysis: initial GCS, placebo under double blind conditions. The melatonin intake was scheduled at GOS, pituitary questionnaire, age, prevalence of pituitary insufficiency and initial 17:00 in order to produce a phase advance of circadian rhythms. Sleep deprivation findings on radiographic imaging. resulted in 38% reduction of depression score in patients, but it did not reduce Results depression score in controls. After the subsequent treatment with placebo or Overall, 14 out of 55 patients (25.4%) presented with pituitary insufficiency; melatonin slight but significant improvement of mood was found in controls. one of them with two hormonal deficits. Neuropsychological changes e.g. These treatments also stabilized the antidepressant response to sleep deprivation nervousness, excitability and depressive episodes were present in 67% of the in patients. However, neither differential effect of melatonin and placebo on patients. depression score nor alteration of habitual sleep timing was found in patients and Conclusion controls. We conclude that the study results do not provide evidence for About 67% of the patients developed neuropsychological disorders after TBI, antidepressant potential of melatonin in patients with winter depression under whereas only 25% of the patients revealed any type of pituitary dysfunction. This realistic clinical conditions. The finding of stabilization of mood in patients with might lead to the assumption, that general brain tissue damage has more influence, placebo suggests the contribution of psychological factors to therapeutic action of regarding the development of psychological disorders after TBI, than pituitary this and other innovative treatments for winter depression. The study was dysfunction. supported by the Russian fund of the Society for Light Treatment and Biological Rhythms.
P379 Reduction of food intake by insulin detemir in comparison to regular human insulin P381 Manfred Hallschmid, Kamila Jauch-Chara, Hendrik Lehnert, Jan Born & Werner Kern Review of pituitary adenomas diagnosed in Burgos (Spain) University of Luebeck, Luebeck, Germany. Elena Garcia, Maria Pilar Alvarez, Victor Garcia-Hierro, Laura De la Maza, Estefania Santos, Javier Pi, Luis Castillo & Enrique Ruiz Hospital de Burgos, Burgos, Spain. Systemic insulin is considered to serve as a major negative feedback signal in the central nervous regulation of food intake. Accordingly, euglycemic infusion of regular human insulin (RI) has been shown to reduce hunger in a dose dependent Introduction fashion. Due to its increased lipophility, the long-acting insulin analogue insulin Pituitary adenomas are the most common cause of sellar masses from the third detemir (DI) might cross the blood–brain barrier faster and in higher quantities decade on, accounting for up to 10 percent of all intracraneal neoplasms. than RI and exceed stronger anorexigenic effects. To test this hypothesis, we Objective measured food intake after DI and RI administration. 15 healthy, normal-weight To review pituitary adenomas diagnosed in Burgos. men were examined in two hyperinsulinemic euglycemic clamp experiments Patients and methods taking place in the morning after an overnight fast. In both conditions, an insulin It was a retrospective study in which we reviewed a total of 90 pituitary adenomas bolus injection (DI, 90 mU/kg body weight; RI, 17.75 mU/kg) was followed by a detected in Burgos from 1983 to our days. steady 90 min insulin infusion (2.0 vs 1.0 mU/kg per min). To compensate for the Results relatively slower onset of the action of DI, a higher dosage was chosen to induce About 65% were macroadenomas and 35% were microadenomas. At the moment G comparable peripheral effects of both compounds. Mean blood glucose levels of diagnosis the median size of macroadenomas was 2.9 1.9 cm and of G during the clamp period were likewise comparable between conditions microadenomas 0.5 0.3. Macroadenomas had similar frequency in both sexes (P!0.384). Twenty minutes after infusion, subjects were allowed to eat ad (30 cases in men and 29 cases in women) while microadenomas were diagnosed libitum from a standardized breakfast buffet. ID reduced total food intake in more frequently in women (26 vs 5 in men). The most frequent type was the non- comparison to RI (1257G82 vs 1560G139 kcal, P!0.04). This effect was also functioning adenoma (42 cases), followed by lactotroph adenoma (20), observed for the intake of protein (PZ0.004), tended to be observed for the intake corticotroph adenoma (12), somatotroph adenoma (11), thyrotropin-secreting of carbohydrates (PZ0.063) but not of fat (PZ0.201). Although systemic adenoma (4) and gonadotroph adenoma (1). Corticotroph, lactotroph and contributions to the observed effects cannot be ruled out, our data suggest that tyrotropin-secreting adenomas were detected more frequently in women. compared to regular human insulin, insulin detemir induces stronger effects on The youngest at the moment of detection were the patients with corticotroph G brain networks that control food intake. They further support the notion of insulin adenomas (35 18 years). The oldest ones were the non-functioning G as an anorexigenic feedback signal in the central nervous regulation of energy adenomas (57.7 16 years). The biggest ones were the non-functioning adenoma G G G homeostasis. (2.6 2.4 cm), followed by lactotroph (2.5 1.5), somatotroph (2.3 0.8) and thyrotrophin secreting adenomas (2G0). Conclusions In our study we have a great number of macroadenomas and lactotroph adenomas are not the most frequent adenoma’s type. It could be due to the way we have selected our patients. We have used the information that was recorded in our P380 hospital’s data base. These patients are the ones that were treated with surgery or Pituitary insufficiency after traumatic brain injury and the coherence radiotherapy, so many patients with lactotroph microadenomas have been lost. with psychological disorders Three of our four thyrotropin-secreting adenomas died from hemorrhage Dorothee Wachter1, Katja Guendling1, Matthias F Oertel1, Hilmar Stracke2 complications. This association has not been described before. & Dieter-Karsten Boeker1
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P382 P!0.01. Fasting total ghrelin (pg/ml) was similar in patients and control group, 916G132 vs 844G169, PZNS. Fasting acylated ghrelin levels (pg/ml) were also Residual adverse vascular risk and oxidative stress in treated adult G G panhypopituitarism similarinbothgroups,65 13 vs 74 14 (Figure 1). In both groups, total ghrelin 1 2 1 levels decreased during OGTT, and nadir total ghrelin was lower than fasting total Annice Mukherjee , Val Charlton-Menys , Peter Trainer , G G ! G G Jelena Chobotova2, Paul Durrington1 & Stephen Shalet1 ghrelin: patients 916 132 vs 747 95, P 0.05; controls 844 169 vs 625 90, 1 2 P!0.05 (Figure 2). Also, in both groups, acylated ghrelin levels decreased during Christie Hospital, Manchester, UK; University of Manchester, Manche- G G ster, UK. OGTT, with nadir being lower than basal levels: patients 65 13 vs 42 6, P!0.05; controls 74G14 vs 37G4, P!0.05 (Figure 3). We have found a negative correlation between fasting ghrelin (both total and acylated) and insulin levels (both Background fasting and post OGTT). Adult hypopituitarism is associated with premature vascular mortality for which Conclusions the underlying mechanisms are unknown but untreated GH deficiency is proposed Our data suggest that circulating total and acylated ghrelin in acromegaly is as a potential contributor. regulated by insulin and not by GH hypersecretion. Objectives To characterise vascular risk, including paraoxonase-1 (PON1; an antioxidant enzyme which preserves LDL against oxidation), in adults with treated panhypopituitarism. Study subjects The study had full ethics approval. Data are presented as meanGS.D. or median P384 G (quartiles). Twenty-one panhypopituitary adults (group 1, aged 45 15 years), on Hypothalamic–pituitary insufficiency following infectious diseases of stable pituitary replacement (O9 months), including GH and 43 controls of G the central nervous system similar age (group 2, age 49 11 years) were studied. Stephan Schaefer1, Nina Boegershausen1, Silke Meyer1, Diana Ivan1, Results Karsten Schepelmann2 & Peter Herbert Kann1 IGF-I SDS pre-GH replacement was K4.9 (K7.3, K2.95) and on stable GH 1 K K C Division of Endocrinology and Diabetology, Phillipps University Hospital, replacement was 0.2 ( 0.68, 1.03) in group 1 (normal range 2to 2). Nine Marburg, Germany; 2Department of Neurology, Marburg, Germany. patients (5 female, age 52G15 years) from group 1 had prolactin levels persistently below 50 mU/l. Median total daily glucocorticoid replacement was hydrocortisone 20 mg or equivalent. Triglycerides were higher in group 1 Hypothalamic–pituitary insufficiency may have diverse causes. Infectious compared with group 2 (2.02 (0.98–5.1) vs 1.09 (0.48–5.7) mmol/l; P!0.001, as diseases of the central nervous system (CNS) may also affect the hypothalamus were CRP levels (3.0 (1.7–6.8) vs 1.1 (0.1–11.0) mg/l; P!0.005). HDL levels and/or the pituitary, although this has not been reported very often and not yet were lower in group 1 (1.17G0.28 vs 1.51G0.43 mmol/l; P!0.005) as was been studied systematically. It was the aim of this study to determine the PON1 activity (60 (27–278) vs 129 (27–438) nmol/ml per min; P!0.005). Total incidence of hypothalamic–pituitary insufficiency in patients with previous cholesterol, calculated LDL, ApoB, ApoB/A1, Lp(a), adiponectin were similar infectious diseases of the CNS of different etiology. between groups. BMI (32G6vs25G4 kg/m2; P!0.001) and insulin levels Patient series. Basal and stimulated (insulin tolerance test) pituitary function (26.5 (1–123.7) vs 15.9 (5.6–25.8) mU/ml; P!0.05) were significantly higher in testing was performed in 19 patients (13 males, 6 females, 38.7G11.7 years) with group 1. Within group 1, insulin levels were lower in the prolactin deficient previous neuroborreliosis, encephalitis or meningitis of mild to moderate clinical subgroup (21.3G19.9 vs 53.1G38.1 mU/ml, PZ0.03) but prolactin levels course following an interval of 26.1G13.1 months after the acute event. correlated strongly with BMI (rZ0.78; P!0.005) only in prolactin non-deficient Four patients (21%, two males, two females) showed an isolated corticotrophic subjects. insufficiency (peak cortisol !181.25 mg/l). In patients reporting self-experienced Conclusions fatigue (including all patients with a corticotrophic insufficiency) peak cortisol Treated adult hypopituitarism is associated with residual adverse vascular risk concentrations were lower than in patients not reporting fatigue (165.4G38.9 vs during stable optimised conventional pituitary replacement, including GH. The 213.6G18.4 mg/l; PZ0.002). Two patients (11%, two males) showed an isolated observations may relate to the presence of associated obesity. Lower PON1 borderline gonadotrophic insufficiency (basal testosterone between 2.4 and activity in panhypopituitarism is of interest because reduced PON1 activity is 3.0 mg/l). No patient had a somatotrophic or thyrotrophic insufficiency or diabetes associated with oxidative stress and increased cardiovascular risk. insipidus, all had prolactin concentrations within the reference range. Conclusions Hypothalamic-pituitary dysfunction may develop in a relevant proportion of patients after infectious diseases of the CNS. Especially self-reported persisting fatigue might be suggestive for the presence of a corticotrophic insufficiency. The P383 clinical picture of some patients might be misinterpreted as an ordinary Is total and acylated ghrelin secretion after oral glucose modified by postencephalitic syndrome. Further prospective studies investigating patients acromegaly? after infectious diseases of the CNS and the effects of hormone replacement Fernando Cordido4,2, Manuel Penı´n1, Luisa Isidro1, Rosa Nemin˜a3, therapy are warranted. Susana Sangiao3, Ovidio Vidal1, Teresa Martı´nez1 & Garcı´a-Buela Jesu´s1 1Department of Endocrinology. Hospital Juan Canalejo, A Corun˜a, Spain; 2Laboratory. Hospital Juan Canalejo, A Corun˜a, Spain; 3Department of Investigation. Hospital Juan Canalejo, A Corun˜a; Spain; 4Department of Medicine. A Corun˜a University, A Corun˜a, Spain. P385 The choice of therapy in acromegaly: results of treatment at a tertiary Introduction care hospital Although involved in feeding and weight homeostasis, stimulation of pituitary Ma Luisa Isidro1, Jose´ Antonio Castro1, Manuel Penı´n1, Jacinto Armenta1 & GH secretion is the best established action of stomach-produced hormone ghrelin. Fernando Cordido2 However, its role in regulation of GH secretion is not yet clear. Some evidence 1Hospital Juan Canalejo, La Corun˜a, Spain; 2University of A Corun˜a, indicates that circulating concentrations of GH and/or IGF-I could influence La Corun˜a, Spain. ghrelin levels. The pathophysiology of ghrelin secretion in acromegaly (specially aftar an oral glucose tolerance test (OGTT) is unclear. Objectives Objective To study circulating fasting acylated and total ghrelin levels, and their response to The aim of our study was to investigate the characteristics of the acromegalic an OGTT in active acromegalic patients and normal control subjects matched for patients followed at a tertiary Universitary Hospital and to evaluate the results of age, sex, and BMI, and their relation with glucose, insulin, and GH. the recommended treatment protocols. Patients and methods Patients and methods We included nine patients with active acromegaly, and nine age, BMI and percentage All our acromegalic patients were included (nZ48; 27 women). Demographic, body fat matched healthy subjects as controls. Patients with any degree of hormonal, visual and imaging data at diagnosis and during follow-up, as well as hypopituitarism were under appropriate and stable hormone replacement therapy. treatments applied, were recorded. We obtained blood samples for glucose, insulin, GH, total ghrelin and acylated Results ghrelin at times 0, 30, 60, 90 and 120 min after 75 g of oral glucose. In 73.0% of the patients acromegaly was due to a pituitary macroadenoma. Of Results those under periodic surveillance, 68.2% were operated (60% of them in our Fasting GH and IGF-I were statistically different between patients and controls: hospital, 40% in other hospitals) and 36.4% were submited to radiotherapy. At the GH (mg/l) 6.7G1.4 vs 0.8G0.4, P!0.01; IGF-I (ng/ml) 414G75 vs 86G6, time of the study 88.6% of the patients were receiving medical therapy, 28.2% of
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 them as first-line treatment. Following actual criteria (Melmed et al. 2005), only (average 13.3G9.2 months; range 3–30 months). Eighteen patients were one patient was cured by surgery. Considering age and sex-matched normal operated, one was irradiated after the operation and two patients were primarily concentrations of IGF-I as a criteria of control, surgery resulted in disease control treated with lanreotide. Eight out of twenty patients (40%) were replaced for in 10% of the operated patients, while medical treatment controlled the disease in hypopituitarism. Four patients with mixed somatotrophe-lactotrophe adenomas 76.9% (P!0.05). This percentage was 75.0% in the group of patients who and hyperprolactinemia were additionally treated with dopamine agonists. received medical therapy as adjuvant of surgery and/or radiotherapy and 81.8% In 75% of patients (15/20) IGF-1 levels (xGS.D.) decreased significantly during in the group of patients who received medical treatment as first-line treatment treatment with lanreotide from 591.6G294.4 to 346.7G160.8 ng/ml, PZ0.0002. (PZNS). After surgery visual function improved in 6 patients, hypopituitarism In 35% (7/20) of patients normalization of IGF-1 levels was achieved and in improved in 6, and some degree of de novo hypopituitarism developed in 5. another 30% (6/20) regression of the pituitary tumor rest was evident on the Results of the surgical procedures performed in our centre were similar to the control MRI scans. Four patients (20%) achieved both normalization of IGF-1 results obtained in other hospitals. Of those who received medical therapy as first- levels and regression of the tumor rest. One patient achieved shrinkage of the line treatment, the tumor size decreased in 45.5% and in the rest no significant tumor rest with no decrease in IGF-1 level. Four patients (20%) did not respond to changes were observed during follow-up. treatment with lanreotide. Conclusions As for tolerability, one patient discontinued treatment with lanreotide after first Not all centres obtain the results reported in the literature in terms of disease injection due to chest discomfort and hypotensive reaction and was excluded from control and morbidity after surgical treatment of growth hormone secreting the study. Others tolerated lanreotide well. tumors. It is possible that in some hospitals first-line medical treatment should be In conclusion Somatuline Autogel 120 mg is an effective and well tolerated chosen, unless the patient has visual disturbances, as long as it is not clear that therapy for acromegaly. partial surgical removal of the tumor significantly improves response to medical therapy or that it reduces its costs.
P388 Smoking causes increased androgen levels in perimenopausal women P386 Sokratis Karaoulanis1, Andreas Rizoulis2, Eleni Ntamani3, Katerina Rizouli3, Nikos Liakos3, Athanasios Xiromeritis1, Zoi Nasika1, Isolated GH deficiency of adult-onset in the KIMS database: Aleksandros Papadimitriou4 & Nikiforos Angelopoulos1 prevalence, clinical presentation, and response to GH replacement 1Department of Psychiatry, University of Thessaly, Larissa, Greece; Felipe Casanueva1, Roger Abs2, Vera Popovic3, Maria Koltowska-Hagg- 2Department of Medicine, Psychiatric Hospital of Athens, Athens, Greece; strom4, Bjorn Jonsson5, Bernhard Saller6 & Ione Kourides7 3Biochemical Laboratory, University Hospital of Larissa, Larissa, Greece; 1Endocrine Division, University of Santiago de Compostela, Santiago de 4Department of Neurology, University of Thessaly, Larissa, Greece. Compostela, Spain; 2Department of Endocrinology, University of Antwerp, Edegem, Belgium; 3Neuroendocrine Unit, University Clinical Center, 4 Belgrade, Serbia; KIMS Medical Outcomes, Pfizer Endocrine Care, Introduction 5 Stockholm, Sweden; Department of Women’s and Children’s Health, Several studies have investigated determinants for androgen levels in men, but 6 Uppsala University, Uppsala, Sweden; EBT Ophthalmology/Endocrine few studies have included women. Epidemiological evidence has suggested that 7 Care, Pfizer Global Pharmaceuticals, London, UK; WW Endocrine Care cigarette smoking has an anti-oestrogenic effect in women, but the effects of Team, Pfizer Inc., New York, USA. smoking on steroid hormone metabolism are not fully understood. We investigated whether there is a relationship between androgen levels and smoking in perimenopausal women. Of the w12 500 GH treated subjects with adult-onset GH deficiency (GHD) in Material and methods KIMS (Pfizer International Metabolic Database), 3744 with multiple pituitary We examined 75 perimenopausal women, 30 were smokers and 45 were non- hormone deficiencies (MPHD) and 367 (9%) with isolated GHD (iGHD) were smokers. All women were between the ages 40 and 55 and presented with a eligible for baseline analysis. Subjects met the following inclusion criteria: history of menstrual cycle irregularity of at least 6 months duration but not longer 1) never received GH prior to entry in KIMS, 2) had stimulation tests with insulin than 1 year of amenorrhea. We measured plasma testosterone (T), dehydroepian- or glucagon (GH!3 mg/l), arginine (GH!0.4 mg/l), or arginineCGHRH (cut- drosterone sulphate (DHEAs), follicle stimulating hormone (FSH), luteinizing offs based on BMI), 3) had organic disease as the cause of hypopituitarism. About hormone (LH) and estradiol (E2) levels in these perimenopausal women. 60–65% of subjects in both groups had pituitary adenomas. At baseline iGHD Pearson’s correlations were applied to evaluate the relationship between plasma subjects were younger than MPHD subjects (46.7 vs 48.7 years, P!0.01), had a hormone levels and smoking. shorter history of GHD (1.4 vs 2.1 years, P!0.001), a lower lean body mass (53.6 Results vs 56.3 kg, P!0.05) but similar BMI, a higher IGF-I SDS (K1.2 vs K1.7, The smokers had a higher level of testosterone and DHEAs than the non-smokers P!0.001), and a worse QoL-AGHDA score (12.8 vs 11.6, P!0.05). (P!0.01). Serum FSH, LH and E2 were similar in the two groups. Longitudinal analysis after 2-years of GH replacement compared to baseline Conclusions showed a similar response in the iGHD (nZ180) group compared to the MPHD Our results demonstrate that perimenopausal women who smoke have a higher (nZ2140) group, the only difference being a more pronounced increase in IGF-I serum concentration of testosterone and DHEAs than non-smokers. These results SDS (2.2 vs 1.7, P!0.001). Significant changes in the iGHD group were confirm previous reports that cigarette smoking does not affect serum estradiol in observed: waist (94.0 vs 95.2 cm, P!0.05; LDL cholesterol (3.4 vs 3.7 mmol/l, perimenopausal women and also support previous findings of increased levels of P!0.001); triglycerides (1.8 vs 2.0 mmol/l, P!0.02); QoL-AGHDA score some adrenal steroids in postmenopausal women smokers. (improving from 13.0 to 8.4, P!0.001); IGF-I SDS (0.5 vs K1.2, P!0.001). In conclusion: iGHD patients should receive GH replacement since they respond as well as MPHD patients.
P389 Body fat excess and GH-stimulated levels in adult patients with Prader– P387 Willi syndrome Efficacy of slow release formulation of lanreotide (Somatuline Autogelw Graziano Grugni1, Antonino Crino`2, Paride Bertocco1, Alessandro Sartorio1 120 mg) in patients with acromegaly: single center experience & Paolo Marzullo1 Dragana Miljic, Marina Nikolic-Djurovic, Mirjana Doknic, Sandra Pekic, 1Istituto Auxologico Italiano Foundation, Research Institute, Verbania, Marko Stojanovic & Vera Popovic Italy; 2Ospedale Bambino Gesu`, Research Institute, Palidoro-Rome, Italy. Institute of Endocrinology, University Clinical Center, Belgrade, Serbia. The GH response to standard provocative tests is significantly lower in adult Somatuline Autogelw 120 mg (SATG, Ipsen, Sweeden) is a high dose sustained patients with Prader–Willi syndrome (PWS) than obese controls with similar release aqueous gel formulation, supplied in a prefiled syringe and given by deep body mass index (BMI). Nevertheless, BMI is an inadequate measure of body subcutaneous injection. The aim of this cross-sectional hospital based study, composition in PWS, because PWS harbour a higher fat mass than simple obesity, approved by the local ethical committee, was to investigate efficacy and under the same degree of weight excess. This study evaluated either the GH tolerability of SATG given every 4 weeks in patients with active acromegaly. response to combined GHRHCarginine administration and the fat body mass, by Twenty patients (9f, 11m) aged 42.9G17.8 (range 17–68 years) with active dual energy X-ray absorptiometry, in a group of 11 PWS adults (8 females, aged acromegaly were treated with lanreotide in our center for median of 15 months 20.1–41.1 years), in comparison to those obtained in a group of 10 patients with
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 essential obesity (8 females, aged 23.5–45.8 years), matched for BMI and consumption during REM sleep, we examined the effects of glucose infusion on percentage of total body fat (FM%). The study protocol was approved by the local nocturnal HPA axis activity during wake and sleep periods. Ethical Committee. Statistical analysis was performed by t-test for unpaired data, Methods and findings and using analysis of variance for parametric and nonparametric (Mann–Whitney Accordingtoa2!2 design, healthy men were infused with glucose test) data, where appropriate. Mean (CS.E.M.) FM% was similar in PWS and (4.5 mg/kg!min) and saline, respectively, during sleep (nZ9) or total sleep obese subjects (53.0C1.5 vs 51.5C1.0, respectively). The GH response to deprivation (nZ11). Circulating concentrations of ACTH, cortisol, glucose, GHRHCarginine was significantly lower in PWS patients (GH peak 5.4C insulin, and leptin were measured and food consumption from a breakfast 1.3 mg/l; area under the curve (AUC) 311.2C72.5 mg/l per h) than obese subjects buffet presented on the subsequent morning was assessed. Independent of (GH peak 21.0C4.1 mg/l, P!0.005; AUC 1241.1C272.8 mg/l per h; P!0.01). sleep, nocturnal secretion of ACTH and cortisol was suppressed by glucose In PWS group, the GHRHCarginine induced GH rise in patients with del15q11– infusion (glucose vs saline: ACTH, 11.93G0.77 vs 13.60G1.08 pg/ml; q13 was significantly higher than those observed in subjects with UPD15 (GH cortisol, 5.21G0.92 vs 7.20G0.79 mg/dl; each P!0.05). In the sleep group, peak 7.7C1.7 mg/l vs 2.7C1.0 mg/l, P!0.05; AUC 458.5C91.0 mg/l per h vs glucose infusion enhanced REM sleep while reducing the time spent in 134.4C46.0 mg/l per h, P!0.02). These findings suggested that GH secretory sleep stage 2 (each P!0.05). Sleep deprivation per se was associated with a pattern is different in PWS adults when compared to patients with simple obesity reduction in leptin levels compared to sleep (P!0.05). Following nocturnal and that reduced GH secretion is not exclusively related to adiposity in PWS glucose infusion, food intake was reduced in comparison to placebo in the subjects. In addition, our data seem to indicate that GH secretory pattern is wake but not in the sleep group (P!0.05 and PO0.82, respectively). significantly different in PWS individuals having separate genetic subtypes. Conclusions Our findings indicate that nocturnal HPA axis activity is blunted by increased plasma glucose concentrations, suggesting that the brain regulates nocturnal ACTH and cortisol release in response to the level of energy available in the form of blood glucose. Sleep does not appear to be critically involved in this glucose/glucocorticoid feedback loop. P390 Cardiovascular risk factors in adult onset growth hormone deficiency (AO-GHD) without growth hormone replacement: follow-up period seven years Sandra Pekic Djurdjevic, Mirjana Doknic, Dragana Miljic, Marina Nikolic Djurovic, Marko Stojanovic & Vera Popovic Neuroendocrine Unit, Institute of Endocrinology, University Clinical P392 Center, Belgrade, Serbia. Macroprolactinemia seems to have a positive effect on platelet activation through ADP stimulation Inan Anaforoglu1,2,3, Eda Ertorer1,2,3, Ilknur Kozanoglu1,2,3, Birsel Unal1,2,3, Patients with hypopitutarism have higher cardiovascular morbidity and mortality 1,2,3 1,2,3 rates than general population, as manifested by elevated fasting lipids and insulin Filiz Haydardedeoglu , Neslihan Bascil Tutuncu & Nilgun Guvener Demirag1,2,3 resistance. The aim of our study was to evaluate the lipid levels and insulin 1 responses during oral glucose tolerance test (OGTT) in adult onset growth Division of Endocrinology and Metabolism, Faculty of Medicine, Baskent University, Ankara, Turkey; 2Division of Hematology, Faculty of Medicine, hormone deficiency (AO-GHD), without growth hormone replacement during a 3 follow-up period of seven years. Ten hypopituitary patients with operated non- Baskent University, Ankara, Turkey; Department of Clinical Biochemistry, functioning pituitary adenoma were investigated (5 female/5 male, mean age: Faculty of Medicine, Baskent University, Ankara, Turkey. 42.5G4.2 years; duration of hypopitutarism 14.3G2.5 years). Mean BMI at the G 2 beginning of the study was 27.9 1.7 kg/m , while after seven years-follow-up Objective G 2 O period was 28.6 1.1 kg/m , P 0.05). At baseline, cholesterol, triglyceride and Platelet activation is a recently recognized characteristic of prolactin, which HbA1c levels were measured and OGTT was performed. Mean peak, delta and functions through the potentiation of ADP-induced P-selectin expression on areas under the curve (AUC) of glucose and insulin levels during OGTT were platelets. Studies in hyperprolactinemic patients demonstrated atherosclerotic analyzed. The mean cholesterol level (6.1G0.5 mmol/l) and mean triglyceride G G disorders related to insulin resistance; convenient milieus for platelet activation. level (1.8 0.3 mmol/l) did not change after seven years of follow-up (6.7 To investigate the association between hyperprolactinemia and platelet activation 0.6 mmol/l and 1.8G0.3 mmol/l, respectively, PO0.05). The mean delta glucose G G related to P-selectin expression, we studied on hyperprolactinemic and level (4.1 0.6 mmol/l) and mean AUC glucose level (775 65 mmol/l per normoprolactinemic patients. 120 min) were significantly higher after seven years of follow-up compared with G G Method these values at baseline (2.3 0.5 mmol/l and 605 54 mmol/l per 120 min, After exclusion of any factor that might interfere with platelet functions, 32 naı¨ve respectively, P!0.05). The HbA1c level was significantly higher after seven G G hyperprolactinemic and 33 age-body mass index-matched normoprolactinemic, years of follow-up compared with baseline level (5.8 0.1 vs 5.1 0.1%, non-smoking premenopausal women were included; 30.6G8vs29.8G7.7 years, P!0.05). There were no differences in insulin responses during OGTT during the G G 2 G G G 26.8 5.4 vs 24.8 5.2 kg/m , prolactin 1889.8 886 vs 335.9 117.9 mU/lt. follow-up period, compared with baseline (mean delta insulin, 59.2 26.6 vs Measurements regarding insulin sensitivity; waist circumference, blood pressure, 70.2G18.5 mU/l, PO0.05; mean AUC insulin, 4763G1610 vs 5965G O fasting plasma glucose, insulin and lipids were also matched. The flow-cytometry 1271 mU/l per 120 min, P 0.05). In conclusion, AO-GHD have significantly method was used to determine the ADP stimulated P-selectin expression of higher HbA1c levels and glucose response during OGTT after seven years of the platelets. Serum prolactin was measured before and after polyethylene follow-up, possibly due to ageing. glycol precipitation (PEG) in hyperprolactinemic group. The diagnosis of macroprolactinemia was regarded as certain if the prolactin recovery in a serum was !40%. Results The ADP stimulated P-selectin expression of the platelets was higher in hyperprolactinemic group; 14.2G15.5% vs 6.7G5.2%, (PZ0.01). The P391 frequency of macroprolactinemia was found to be 29%. There was a Nocturnal HPA axis activity is blunted by increased plasma glucose significant correlation between prolactin levels and ADP stimulated Z ! concentrations P-selectin expression before PEG (r 0.3, P 0.02). The ADP stimulated Christian Benedict1, Manfred Hallschmid1, Werner Kern3, Bernd Schultes2, P-selectin expression rates were similar between macroprolactin negative Z Z Hendrik Lehnert3 & Jan Born1 (true hyperprolactinemia) (n 21) and macroprolactin positive (n 11) G G Z 1Department of Neuroendocrinology, University of Lu¨beck, Lu¨beck, subgroups; 13.6 16.4% vs 15.3 14.4% (P 0.7). It kept being higher G Z G Germany; 2Interdisciplinary Obesity Center East-Switzerland, Kantonsspi- than the controls in both subgroups; 13.6 16.4%, (P 0.03) and 15.3 Z tal St Gallen, St Gallen, Switzerland; 3Internal Medicine I, University of 14.4%, (P 0.005), respectively. Lu¨beck, Lu¨beck, Germany. Conclusion Platelet activation is involved in the pathogenesis of atherosclerotic disorders related to insulin resistance. In this study, performed on completely matched Background group of cases regarding insulin sensitivity markers, hyperprolactinemia itself Secretory activity of the hypothalamo-pituitary–adrenal (HPA) axis typically has been detected to bring an increased risk for platelet activation. It has also increases during the second half of nocturnal sleep. Assuming that this rise in been clearly demonstrated that macroprolactinemia may cause platelet ACTH and cortisol levels occurs in response to the negative energy balance aggregation just as true hyperprolactinemia. induced by nocturnal fasting and concomitant increases in cerebral glucose
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P393 Results At baseline, 18 patients (51.4%) and two controls (5.7%; P!0.0001) had IRS. A study of the serotoninergic tone in healthy subjects and diabetic Z patients treated by a clinical-paedagogic approach (Group Care) or The patients with IRS had a longer estimated duration of GHD (P 0.006), lower IGF-I SDS (PZ0.002) and higher IMT (PZ0.041) than those without IRS. Mean traditional care ! Marina Trento1, Paola Tibaldi1, Marcella Balbo2, Claudia Kucich1, IMT was significantly higher in the patients with (P 0.001) and without IRS 1 1 1 1 (PZ0.004) than in controls. During the study period, the use of lipid lowering Margherita Basile , Enrica Borgo , Michela Tomelini , Pietro Passera , ! Roberta Giordano2, Emanuela Arvat2, Franco Cavallo3 & Massimo Porta1 drugs (92.3%, vs 13.6% and 34.3%, P 0.0001), glucose lowering drugs (69.2% 1 2 vs 31.4% and 22.7%; PZ0.016) and of anti-hypertensive drugs (61.5% vs 20.0% Laboratory of Clinical Paedagogy, Turin, Italy; Division of Endo- ! crinology, Turin, Italy; 3Department of Public Health and Microbiology, and 4.5%; P 0.0001) was higher in Group B patients than in controls and in Turin, Italy. Group A patients. After 5 years, IGF-I levels were normal in all Group A patients and remained lower than K1 SDS in 10 of 13 Group B patients. IMT at right and left common carotids significantly decreased only in Group A, while it Background and aims significantly increased in controls and non significantly in group B patients. Alterations of mood and depression may be associated with type 2 diabetes The prevalence of IRS significantly reduced only in group A patients, non (T2DM) and impaired glucose metabolism in non-diabetic people. Central significantly reduced also in group B patients while slightly increased in controls. serotoninergic activity may modulate glucose tolerance via neuroendocrine Conclusions effectors. The serotoninergic tone was assessed by measuring the hormonal Severely GHD men have more frequently IRS and increased IMT at common carotid response to a selective serotonin reuptake inhibitor, citalopram, in non-diabetic arteries than sex- and age-matched controls. Only in GH replaced GHD patients after subjects and patients with T2DM followed by either a traditional approach or a 5 years was observed decreased IMT and decreased prevalence of IRS. clinico-paedagogic intervention (Group Care) proven to improve quality of life and reduce anxiety. Materials and methods Ten healthy subjects (age 53.20G3.92; malesZ5) and 13 patients with T2DM (age 60.92G3.52, known duration 17.38G5.85, malesZ10), 7 followed by Group Care and 6 by traditional care, underwent infusions of either citalopram 20 mg or saline over 120 min, in random order, at 8.30–9.00 am after overnight fasting. Samples were taken from an antecubital vein every 15 min for 4 h to P395 measure circulating glucose, insulin, ACTH, free cortisol, DHEA, growth Dopamine receptor expression and dopamine agonist effectiveness in hormone (GH) and prolactin. Hormonal responses were calculated as differences corticotroph pituitary tumors: comparison with clinical, biochemical between the areas under the curves after saline and citalopram (D-AUC). radiological and pathological features of patients with Cushing’s disease Results Rosario Pivonello 1, Wouter W de Herder2, Diego Ferone3, Johan M Kros4, Citalopram increased ACTH and cortisol more than saline in healthy subjects Maria Laura Del Basso De Caro5, Gaetano Lombardi1, Annamaria Colao1, (P!0.026 and P!0.011, respectively) and diabetic patients treated by Group Leo J Hofland2 & Steven WJ Lamberts2 Care (P!0.056 and P!0.038) but not in those followed by traditional care. The 1Department of Molecular and Clinical Endocrinology and Oncology, responses of DHEA, GH, prolactin, insulin and glucose to citalopram did not Federico II University, Naples, Italy; 2Department of Internal Medicine, differ significantly from those to saline in any of the 3 groups. However, in Erasmus Medical Center, Rotterdam, The Netherlands; 3Department of the healthy subjects, basal glucose levels correlated directly with the GH D-AUC Endocrinological and Metabolic Sciences, University of Genova, Genova, (rZ0.820; P!0.004) and inversely with the insulin D-AUC (rZK0.822; Italy; 4Department of Pathology, Erasmus Medical Center, Rotterdam, The P!0.003). The correlation between basal glucose and GH D-AUC was preserved Netherlands, 5Department of Pathology, Naples, Italy. in diabetic patients (rZ0.637; P!0.026), in whom HbA1c correlated with basal glucose (rZ0.657; P! 0.015) and the insulin D-AUC (rZ0.864; P! 0.012), and the glycaemic D-AUC correlated with that of cortisol (rZ0.698; P!0.012). Dopamine receptors (DR) are expressed in the majority of corticotroph Conclusions pituitary tumors and the dopamine agonist cabergoline is effective in These results suggest that serotoninergic tone may modulate glucose metabolism controlling cortisol hypersecretion in around 50% of patients with Cushing’s through opposite effects on ACTH, cortisol, insulin and GH secretion. Diabetes disease (CD). In order to characterize the tumors expressing D2 receptors may blunt the response of the pituitary-adrenal axis, though not in patients and the profile of patients which might respond to the treatment with D2 followed by a long-term intervention model that encompasses clinical as well as agonists, the current study has the aim to correlate D2 receptor expression cognitive and emotional factors. and the effects of cabergoline with clinical, biochemical and radiological features of patients, as well as to pathological features of tumors removed form the patients. The study included 72 patients with CD. In all patients, D2 receptor expression, evaluated by immunohistochemistry (IHC), was correlated with the pathological features of the tumors and the charac- P394 teristics of the patients, whereas in a subgroup of them, D2 receptor expression, evaluated by RT-PCR, or the cabergoline responsiveness was Growth hormone (GH) treatment on atherosclerosis: results of a 5 years correlated with the pathological features of the tumors and the charac- open, prospective, controlled study in male patients with severe GH teristics of the patients. The results of the study demonstrated that D2 deficiency receptor expression is significantly associated with the presence of neural 1 1 2 Annamaria Colao , Carolina Di Somma , Stefano Spiezia , pituitary tissue close to the tumors and/or nerve fibers within or surrounding 1 1 1 Silvia Savastano , Francesca Rota , Maria Cristina Savanelli , the tumors, presumably expression of the tumor origin from the intermediate 1 1 Marianna D’Andrea & Gaetano Lombardi zone of the pituitary gland, as well as with the presence of a corticotroph 1 Department of Molecular and Clinical Endocrinology and Oncology, hyperplasia rather than adenoma at the histological evaluation, and PRL 2 ‘Federico II’ University of Naples, Naples, Italy; Emergency Unit, ‘S Maria staining within the tumor. Moreover, dividing the tumors according to the degli Incurabili’ Hospital, Naples, Italy. intensity of D2 staining, those with the highest D2 expression, are also associated with lower age, longer disease duration, a relative resistance to dexametasone and CRH and higher prevalence of hyperprolactinemia, Background together with an undetectable tumor at the imaging techniques and failure Severe GH deficiency (GHD) is associated with, increased cardiovascular (CV) at neurosurgery. The initial response to cabergoline treatment was also risk and intima-media thickness (IMT) at major arteries. associated with some of these characteristics of patients and tumors. Objective However, the long-term responsiveness to cabergoline treatment was only To investigate the long-term (5-years) effects of GH replacement on insulin associated with the tumor expression of the short isoform of D receptor resistance (IR) syndrome (IRS) (at least two of: triglycerides levels R1.7 mmol/l, 2 and/or D receptors. In conclusion, the current study demonstrated that the HDL-cholesterol levels %1.0 mmol/l, blood pressure above 130/85 mmHg, 4 corticotroph tumors expressing D receptors derive from either the fasting glucose 6.1–7 or 2 h after glucose 7.7–11.1 mmol/l), and common 2 intermediate zone or the anterior lobe of the pituitary gland. Moreover, carotid IMT. whereas the tumors originating from the intermediate zone generally express Design higher number of D receptors and are associated to the best initial Interventional, open, prospective, controlled. 2 responsiveness to cabergoline treatment, those with the expression of short Patients isoform of D , deriving from both the intermediate zone and the anterior About 35 men with severe GHD aged !50 years (standard replacement therapy 2 lobe of the pituitary gland are associated with a long-term responsiveness to plus GH was given to 22 (Group A) and except GH in 13 (Group B)) and 35 cabergoline treatment. healthy men age-matched with the patients as control.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P396 P398 The effects of growth hormone deficiency following moderate and Genetic and clinical analyses in an Italian series of idiopathic severe traumatic brain injury on cognitive functions hypogonadotropic hypogonadism Marko Stojanovic1, Sandra Pekic1, Dragan Pavlovic2, Vladimir Zivkovic1, Marco Bonomi1, Francesco Antonica1, Anna Cariboni2, Marta Busnelli1, Branko Djurovic3, Vladimir Jovanovic3, Milica Medic-Stojanoska4, Anna Pia3, Giorgio Borretta3, Paolo Beck-Peccoz1, Csilla Krausz4, Mirjana Doknic1, Dragana Miljic1, Marina Djurovic1, Carlos Dieguez5, Roberto Maggi2 & Luca Persani1 Felipe Casanueva6 & Vera Popovic1 1Department of Medical Sciences, Univesrity of Milan, Istituto Auxologico 1Institute of Endocrinology, University Clinical Center, Belgrade, Serbia; Italiano IRCCS and Fondazione Ospedale Ospedale Policlinico di Milano 2Institute of Neurology, University Clinical Center, Belgrade, Serbia; IRCCS, Cusano Milanino, Milano, Italy; 2Institute of Endocrinologia, 3Institute of Neurosurgery, University Clinical Center, Belgrade, Serbia; University of Milan, Milano, Italy; 3Santa Croce and Carle Hospital, Cuneo, 4Institute of Endocrinology, University of Novi Sad, Novi Sad, Serbia; Italy; 4Department of Clinical Physiopathology, Univesrity of Florence, 5Department of Physiology, University Santiago de Compostela, Santiago Firenze, Italy. de Compostela, Spain; 6Endocrine Section, Complejo Hospitalario, University Santiago de Compostela, Santiago de Compostela, Spain. Idiopathic hypogonadotropic hypogonadism (IHH) is a rare and heterogeneous disease due to defects of GnRH secretion or action. IHH could be associated or Hypopituitarism, in particular growth hormone (GH) deficiency, is common not with anosmia respectively identifying the Kallmann’s syndrome (KS) or the among survivors of traumatic brain injury (TBI). We investigated normosmic IHH (nIHH). So far numerous causative genetic defects have been neurobehavioral consequences of TBI-induced GH deficiency (GHD) in 61 described, but very recent molecular genetic studies and animal models have patients (aged 37.7G1.7 years, 44 male/17 female) at least one year (mean, opened novel perspectives. We are studying a series of 16 KS (14M,2F) and 18 3.9G0.6 years) after moderate and severe TBI (mean GCS score 10.6). All nIHH (14M,4F). All patients have normal karyotype, low/normal gonadotropins patients were tested with standard neuropsychological battery (MMSE, TMT, in the presence of low sex-steroid levels and a blunted LH/FSH response after RAVLT, RCF, BNT and WCST for executive cognitive functions). Serum GnRH injection. FGFR1, Ebf2, PROK2, PROKR2 genes were examined in all samples for IGF-I, T4, testosterone (in males), prolactin and cortisol were cases whereas GnRHR and GPR54 gene analysis was limited to nIHH. The coding taken at baseline and the GH/IGF-1 axis was evaluated by GHRHCGHRP-6 sequences of GnRHR, Ebf2 and GPR54 showed no abnormalities. Two novel test. Three TBI patients with multiple pituitary hormone deficiencies were mutations of PROKR2 (V158I, V334M) and one of PROK2 (G62D) gene were adequately replaced (except for GH). According to the established peak GH found in 1 nIHH female, 1 KS male patients and 1 nIHH male patient, cut-off for normality O20 mcg/l and cut-off for severe GHD !10 mcg/l, TBI respectively. The analysis of FGFR1 gene showed results of particular interest. patients were divided in two groups: severely GHD (nZ9, mean GH peak: The mutation D200E was found in two unrelated patients discordant for osmic 5.4G1.0 mcg/l) and those with normal GH secretory capacity (GHS, nZ52, function and bimanual synkynesia. The mutation F210X was instead found in 1 mean GH peak: 34.4G2.5 mcg/l). GHD TBI patients performed on WCST nIHH male patient that did not undergo puberty. This patient had a brother also with significantly lower number of achieved WCST categories compared to affected with nIHH and absent pubertal development that was found to carry the GHS TBI patients (2.9G0.5 vs 5.1G1.0, P!0.05). Furthermore, GHD TBI same mutation. This mutation was therefore inherited from one of the parents who patients have performed with more perseverative responses compared to GHS had had a normal puberty and was still unaffected at an age beyond 30 years. TBI patients (38.1G2.1 vs 31.6G3.9, P!0.05). In other tested cognitive These variations are present in the heterozygous state in the patients according to variables there were no significant differences between GHD and GHS TBI the reported mechanism of haplo-insufficiency. The variable neurological patients. A significant inverse correlation was observed between GH peak phenotype (osmic function and bimanual synkynesia) associated with the same response to the GHRHCGHRP-6 test and number of perseverative responses FGFR1 mutation and the highly variable IHH penetrance in our family represents on WCST (PZ0.05). In conclusion, GHD is a frequent consequence of TBI additional arguments in favour of a multiple genetic origin of these defects. and can substantially influence executive cognitive functions, as demonstrated by neuropsychological testing.
P399 P397 Four years of growth hormone (GH) therapy improves markers of cardiovascular risk in GH deficient (GHD) survivors of childhood acute Pharmacological prevention of long-term neuroendocrine and beha- lymphoblastic leukaemia (ALL) vioral changes in prenatally stressed rats Cecilia Follin & Eva Marie Erfurth Alexander Reznikov, Nadezhda Nosenko, Larisa Tarasenko & Petr Sinitsyn Institution of Clinical Sciences, Lund, Sweden. Institute of Endocrinology and Metabolism, Kyiv, Ukraine. Survivors of childhood (CO) ALL treated with prophylactic cranial radiotherapy Maternal stress modifies fetal programming of neuroendocrine development and (CRT) often exhibit (GHD) and increased cardiovascular risk. The aim of this behavior. These effects are mediated by maternal and fetal corticosteroids and study was to evaluate the effect of 4 years of GH therapy on cardiovascular risk opioids. We evaluated an ability of pharmacological prevention of long-term factors in 16 former ALL patients and to compare them with matched population behavioral and hypothalamic–pituitary–adrenal (HPA) disorders in adult rat controls after 4 years. offspring induced by daily 1 h maternal immobilization during the last gestational Sixteen former CO ALL patients (womenZ8), aged 24–37 years, treated with week. Dexamethasone (Dex; 0.1 mg/kg per day) or naltrexone (Ntx; 10 mg/kg per CRT (18–24 Gy) and chemotherapy with confirmed GHD and controls were day) treatments prior to pregnant rats stressing prevented impairment of studied at baseline. After 4 years of GH therapy (median 0.5 mg/day) the copulatory behavior (increase of mounting latency, decrease of ejaculatory investigations were repeated in the patients and in the control subjects. rates etc.) in adult male offspring. Both Dex and Ntx exerted protective effect with Four years of GH treatment increased the serum IGF-1 significantly into the mid- regard to diminishing adrenocortical and hypothalamic nordarenaline responses normal range (SDS IGF-1 0.3) in the former ALL patients (PZ0.03). Compared to an acute stress as well as decrease of stress-induced activation of GABAA and to baseline, a significant decrease in the plasma levels of glucose (PZ0.03), GABAB receptors tested with muscimol and baclofen in those animals. apoprotein B (apo B) (PZ0.03) and the ratio apo B/apoprotein A1 (apo A1) In prenatally stressed female rats, Ntx prevented enhancement of adrenocortical (PZ0.006). Also HDL cholesterol (PZ0.03) and apo A1 (PZ0.05) increased response to an acute sress while no protective effect of Dex has been found. One significantly compared to baseline levels. Comparison between patients and of the long-term consequences of prenatal stress was an impairment of controls after 4 years showed no significant difference. There was no difference in adrenocortical response to noradrenaline infusion into the third brain ventricle: fatmass at baseline between patients and controls and four years of GH treatment it was significantly diminished in females and increased in males. These changes did not change fatmass in the patients. The blood pressure showed no significant were not observed both in males and females treated prenatally with Dex or Ntx. difference in patients after four years of GH. We concluded that Dex blockade of endocrine response to stress or Ntx blockade In conclusion, 4 years of GH therapy to former CO ALL patients resulted of opioid receptors can prevent pathological changes in sexual behavior and HPA in significant improvements in the plasma levels of glucose, apo B, apo noradrenergic and stress reactivity in prenatally stressed rats in gender-related A1, apoB/apoA1 and HDL, indicating a positive effect of GH on manner. cardiovascular risk.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P400 P402 Impaired microvascular reactivity and endothelial function in patients Effect of hyperprolactinemia in male patients consulting for sexual with Cushing’s syndrome dysfunction Vikto´ria Durovcova´1, Martin Pra´zny´1, Jana Jezˇkova´1, Eva Horova´1, Corona Giovanni1, Edoardo Mannuci2, Alessandra Fisher1, Va´clav Ha´na1, Jan Kvasnicka2, Ladislav Pecen3, Josef Marek1, Jan Sˇkrha1 & Francesco Lotti1, Valdo Ricca3, Giancarlo Balercia4, Luisa Petrone1, Michal Krsˇek1 Gianni Forti1 & Mario Maggi1 13rd Department of Internal Medicine, 1st Faculty of Medicine, Charles 1Andrology Unit, University of Florence, Florence, Italy; 2Diabetes Section University, Prague, Czech Republic; 21st Department of Internal Medicine, Geriatric Unit, University of Florence, Florence, Italy; 3Pychiatric Unit, 1st Faculty of Medicine, Charles University, Prague, Czech Republic; University of Florence, Florence, Italy; 4Endocrinology Unit4, Polytechnic 3Institute of Informatics of the Czech Academy of Science, Prague, University of Marche, Ancona, Italy. Czech Republic. Objectives It is well known that hypercortisolism is associated with increased morbidity and The physiological role of prolactin in male sexual function has not been mortality caused predominantly by vascular and atherosclerotic complications. completely clarified. Aim of this study is the assessment of clinical features and of The effect of hypercortisolism on microvasculature is less known. The aim of this conditions associated with hyperprolactinemia in male patients consulting for study was to evaluate skin microvascular reactivity (MVR) in relation to arterial sexual dysfunction. hypertension, diabetes mellitus and other possible influencing factors (fibrino- Design and methods lysis, oxidative stress and endothelial function) in patients with Cushing’s A consecutive series of 2146 (mean age 52.2G12.8 years) male patients with syndrome (CS). sexual dysfunction was studied. Several hormonal and biochemical parameters Twenty-nine patients with active CS, 10 patients at least 6 months after successful were studied along with validated structured interviews (ANDROTEST and operation and a group of 16 control subjects were studied. Skin MVR was SIEDY). Mild hyperprolactinemia (MHPRL; PRL levels 420–735 mU/l or measured by laser Doppler flowmetry during post-occlusive (PORH) and thermal 20–35 ng/ml) and severe hyperprolactinemia (SHPRL, PRL levels O735 mU/l, hyperemia (TH). Selected parameters of fibrinolysis, oxidative stress and 35 ng/ml) were considered. endothelial activity were determined as well. Results We found an impaired microvascular reactivity in patients with CS. Maximal MHPRL and SHPRL were found in 69 (3.3%) and in 32 (1.5%) patients perfusion during PORH and TH was significantly lower in patients with arterial respectively. Mean age and the prevalence of gynecomastia were similar in the hypertension (P!0.01, P!0.05, respectively) as was the velocity of perfusion two groups and in subjects with normal prolactin values. MHPRL was not increase during PORH and TH (P!0.05). The most expressed impairment of confirmed in almost one half of the patients, after repetitive venous sampling. microvascular reactivity was present in patients with combination of arterial Hyperprolactinemia was associated with the current use of antidepressants, hypertension and diabetes mellitus. Impaired fibrinolysis, increased oxidative antipsychotic drugs and benzamides. SHPRL was also associated with hypoactive stress and endothelial dysfunction were present in patients with hypercortisole- sexual desire (HSD), elevated TSH, and hypogonadism. The association between mia, however, increased concentration of ICAM-1 was found also in patients after HSD and SHPRL was confirmed after adjustment for testosterone, TSH levels and operation as compared to controls (P!0.05). It documents the presence of use of psychotropic drugs (HRZ8.60 (3.85–19.23); P!0.0001). In a 6 -months persistent endothelial dysfunction also in cured patients. follow up of patients with SHPRL testosterone levels and sexual desire were Based on the obtained results, we conclude that the impairment of microvascular significantly improved by the treatment. reactivity in hypercortisolism can be modulated by many factors but the most Conclusions important is the presence of arterial hypertension. The combination of arterial Our data indicate that SHPRL, but not MHPRL, is a relevant determinant of HSD. hypertension and diabetes mellitus led to the most decreased microvascular Gynecomastia does not help in recognising hyperprolactinemic subjects, while reactivity in patients with Cushing’s syndrome. the use of psychotropic medications and HSD are possible markers of disease. Study was supported by the grant IGA Ministry of Health Czech Republic No. In case of MHPRL, repetitive venous sampling is strongly encouraged. NR/9438-3 and approved by local Ethical Committee.
P403 P401 Effects of 6 months growth hormone treatment in GH deficient patients Serum and glucocorticoid-induced kinase 1 mediates basal and (GHD) long after traumatic brain injury (TBI) stimulated POMC transcription in pituitary corticotrophs Edwige Yollin1, Odile Kozlowski2, Pierre Fontaine1, Marc Rousseaux2 & Marie Helene Reiter, Greisa Vila & Anton Luger Christine Cortet-Rudelli1 Division of Endocrinology and Metabolism, Department of Internal 1Department of Endocrinology and Diabetology, Clinique Marc Linquette, Medicine III, Medical University of Vienna, Vienna, Austria. CHRU, Lille, Nord, France; 2Department of Reeducation, Hoˆpital swynghedaw, CHRU, Lille, Nord, France. Cushing’s tumours are ACTH-producing neoplasms of the pituitary gland. Their ACTH-oversecretion is autonomous and does not respond to the canonical We studied 84 patients with neuropsychological disabilities at least 1 year after inhibition of the hence also elevated cortisol. Current research in identifying new TBI. 24 patients had severe GHD (29%). The aim of this study was to evaluate the drug targets is mainly focused on designing therapeuticals that directly inhibit effects of six months GH treatment on quality of life and metabolism in this ACTH over-secretion from the adenoma. Serum and glucocorticoid-induced group. kinase 1 (Sgk1) is an early target gene of glucocorticoids in all cells studied. It is a GH treatment was initiated in 17 patients (71%), planned with 3, declined by one, PKB/Akt-like kinase that acts downstream of the phosphoinositol-3-kinase contra-indicated in 2, 1 patient moved. It lasted more 6 months in 16 of them (14 (PI3K) signal transduction pathway. PI3K is related to increased cell proliferation men, mean age 36G12, mean delay after TBI 75G4, O36 months for 15 and hormone secretion in corticotrophs, and a target of recent drugs that reduce patients). GHD was isolated (nZ6) or associated with ACTH deficiency (nZ9) ACTH oversecretion. and/or TSH deficiency (nZ3). GH treatment was initiated after the susbstitution We present here that Sgk1 is expressed in pituitary corticotrophs and localised in of other deficiencies, at 0.3 mg/day. Dosage was increased in 25%, decreased in the perinuclear cytosol, as demonstrated by immunohistochemistry. Quantitative 25%. We suspected a defect of observance in 4 patients.The mean dosage at 6 RT-PCR reveals that stimulation of the murine corticotroph tumour cell line AtT- months was 0.3 mg/d (0.2-0.4). IGF1 levels significantly increased (301.9G101.9 20 with dexamethasone induces a rapid increase of Sgk1 transcription, vs 190.4G65.4 ng/ml, P!0.001) and were normal in 94% of patients. accompanied by a reduction of the transcription of pro-opiomelanocortin Before GH treatment, QoL-AGHDA questionnaire score was not different in (POMC). In parallel, dexamethasone induces a translocation of Sgk1 to the patients with severe or no GHD (13.4G7.2 vs14.5G6.8). However we observed nucleus, as shown by Western blotting. Transient over-expression of Sgk1 in AtT- after GH treatment a significant decrease of QoL-AGHDA questionnaire score 20 cells is associated with reduced POMC transcription. Moreover, siRNA- (9.7G7.8 vs 14.4G7.4, P!0.001), demonstrating an improvement of the quality mediated down-regulation of Sgk1 causes an increase in POMC mRNA levels. of life. In summary, Sgk1 is a downstream target of dexamethasone in corticotroph cells. Waist circumference (97G15.6 vs 98.9G16.4 cm), BMI (26.9G5.5 vs 27.7G It controls basal and stimulated POMC expression and is a potential drug target 5.6 kg/m2), fasting glucose (0.84G0.08 vs 0.87G0.11 g/l), triglyderid level for the treatment of Cushing’s disease. Ongoing investigations are aiming to fully (1.14G0.42 vs 1.21G0.37 g/l), LDLc level (1.08G0.21 vs 1.10G0.25 g/l) and characterise the role of Sgk1 in corticotroph cells. HDLc level (0.44G0.08 vs 0.46G0.07 g/l) had not significantly changed after GH treatment.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
These results illustrate that it is important to diagnose GHD in patients with concentration (100% sensitivity). Non-luteal phase women (4/4) were correctly previous TBI, because of its high frequency and the positive effect of GH excluded (100% specificity). Salivary progesterone identified 5/7 women in the treatment on the quality of life, even in this group. Results after 1 year GH luteal phase (71% sensitivity). Non-luteal phase women (3/4) were mostly treatment including the dual-energy X-ray absorptiometry will be presented for excluded (75% specificity). the congress. Conclusion Only in 7/11 (64%) of the participating women the presence of the luteal phase was confirmed by hormone testing. Therefore, hormone testing seems to be justified in neuropsychological research. Classification by serum progesterone alone was as good as classification by progesterone, estradiol, LH and FSH P404 combined. Serum progesterone determination seems to be superior to salivary quantification. In our study an adjusted reference interval for salivary Total and cause-specific mortality in patients from the KIMS database: progesterone would improve sensitivity of the salivary progesterone assay, direct evidence for a beneficial effect of GH replacement therapy on however specificity would not change. mortality in adult GH deficient patients Anders Mattsson1, Maria Koltowska-Haggstrom1, Bernhard Saller2, Patrick Wilton3 & Rolf Gaillard4 1Pfizer Health AB, KIMS Medical Outcomes, Stockholm, Sweden; 2Pfizer Global Pharmaceuticals, EBT Endocrine Care, London, UK; 3Pfizer Inc, Endocrine Care, New York, USA; 4CHUV, Division of Endocrinology, P406 Lausanne, Switzerland. Malignant diseases in our patients with acromegaly Elisa Moya Chimenti, Cristina A´ lvarez Escola´, Beatriz Lecumberri Santamarı´a, Alberto Ferna´ndez, Marı´a Garcı´a Domı´nguez & Luis Felipe Growth hormone (GH) replacement in adults with severe GH deficiency (GHD) Pallardo Sa´nchez has well established beneficial effects on the cardiovascular risk profile. Whether La Paz Universitary Hospital, Madrid, Spain. this is associated with reduced mortality is still unclear. The present study addresses this question by analysing mortality data in KIMS (Pfizer international metabolic database) and is based on 9610 patients (47% females), accumulating Background 37882 patient-years of follow-up. There were 257 recorded deaths against 255.1 Acromegaly, a chronic disease caused by excess secretion of growth hormone expected. Overall all-cause mortality rate was not different from the population (GH), has been known to reduce patients life expectancy. This increase in rate (standardized mortality ratio (SMR) 1.01, 95% CI 0.89–1.14). However, this morbility and mortality is not only due to cardiovascular, respiratory or ratio varied significantly with attained age at follow-up (!45 years: SMR 4.35, cerebrovascular disorders, but also to an increased risk for cancer. 45–69 years: SMR 0.84, R70 years: SMR 0.64). Female gender, craniopharyn- Subjects and methods gioma or malignancy as underlying disease, pre-treatment with radiotherapy, and The aim of this study was to describe the associated malignant diseases among our diabetes insipidus were associated with a significantly increased mortality rate. fifty acromegalic patients. Clinical features of these patients (age, gender, No significant association was seen for age at onset of pituitary disease, number of smoking status, Diabetes and Hypertension prevalence) were recorded, as well as pituitary deficits in addition to GHD, as well as the presence of ACTH-, TSH-, or relevant details concerning acromegaly (ethiology, mean age of diagnosis, LH/FSH-deficiency. IGF-I SDS levels at one year of GH replacement therapy, therapy and metabolic control of disease). The associated neoplasm and its reflecting the adequacy of GH treatment, were significantly associated with relation with the onset of acromegaly was also analysed. mortality (P!0.0001). Each unit increase in IGF-I SDS was associated with a Results 20.7% decrease of SMR. Poisson regression analyses identified gender, attained Seven (3 men, 4 women; mean age: 67G12.5 year) of a total of fifty patients with age, etiology of GHD, pre-treatment radiotherapy, diabetes insipidus and IGF-I acromegaly (19 men, 31 women; mean age: 56.2G16.4 year) had a malignant SDS after 1 year of GH treatment as independent significant factors influencing disease. None of the seven were active smokers, two suffered from diabetes and all-cause mortality. Overall, deaths from cardiovascular and cerebrovascular four from HTA. Their mean age diagnosis of acromegaly was 62.3G12.8 year disease and malignancies were most common; their rate, however, was not with a mean duration of acromegalic disease of 4.6G4.7 year. They had different from the normal population rate. In conclusion, the significant been treated with transsphenoidal surgery for their GH secreting pituitary association between IGF-I SDS levels during GH treatment and mortality rates macroadenoma and active acromegaly was found on 6 of them. Colorectal, breast provides the first direct evidence for a beneficial effect of GH replacement on and thyroid carcinoma were each observed on two different patients whereas mortality in GHD patients. prostatic carcinoma was recorded on one. These diseases appeared before acromegaly in five patients and during its follow-up on two. Conclusions In our acromegalic series, 14% have a second malignant disease with a higher prevalence of colorectal, breast and thyroid neoplasm. The first two agree with what has been reported in literature, whereas the association between thyroid P405 carcinoma and acromegaly is still to be discussed. Large-scale studies are needed Performance characteristics of serum and salivary hormone quantifi- to draw conclusions relating to cancer risk. cation for luteal phase confirmation in behavioural studies Gunnar Brandhorst1, Kathrin Behrens2, Sophie Hinrichs2, Kirsten Jordan2, Michael Oellerich1 & Nicolas von Ahsen1 1Department of Clinical Chemistry, Go¨ttingen, Germany; 2Department of Medical Psychology and Medical Sociology, Go¨ttingen, Germany. P407 Pituitary abscess: a case report Objective Andrzej Darczuk1, Malgorzata Trofimiuk1, Justyna Gil1, To investigate gender differences in spatial orientation and verbal memory we Alicja Hubalewska-Dydejczyk1, Wlodzimierz Mnich2 & Dariusz Adamek3 conducted a study in 21 healthy young women and men (eleven women). 1Departament, Collegium Medicum, Jagiellonian University, Krakow, Participating women were required to be in the mid-luteal phase of the cycle. Poland; 2Neurosurgery and Neurotraumatology Departament, Collegium Hormone profiling for behavioural studies is often performed in saliva samples to Medicum, Jagiellonian University, Krakow, Poland; 3Neuropathology avoid venous blood sampling. We have compared simultaneously collected blood Departament, Collegium Medicum, Jagiellonian University, Krakow, and saliva samples to confirm the presence of the luteal phase. Poland. Methods Serum and saliva samples were collected from eleven healthy women without oral contraceptive pill (age range 21–26 years) in mid-luteal phase (calculated from Pituitary abscess is a very rare entity, only 200 cases (mostly the complication of self-stated cycle lengths) at 0 and 2 h. Serum progesterone, estrogen, LH and FSH the pituitary surgery) has been described so far. were determined on a Modular E170 system (Roche, Mannheim). Salivary We want to present the case of pituitary abscess arising from Rathke’s cyst. progesterone and estrogen were determined by LIA (IBL, Hamburg). Case report Biochemical evaluation of the cycle phase was done according to the Seventy-years-old female treated due to clinical depression, was admitted to the manufacturers’ reference intervals. First-tier was progesterone concentration. Endocrinology Department because of profound hyponatremia (serum Natrium If inconclusive, estrogen and gonadotropin concentrations were second-tiers. 119 mmol/l). She was diagnosed with plurihormonal anterior pituitary Results insufficiency. After implementation of substitution with hydrocortisone and By combined judgement of all parameters 7/11 women were in the luteal phase. levothyroxin hyponatremia resolved. Pituitary MR revealed expansive tumor, All 7 women were correctly classified using only the serum progesterone hyperintensive on T2-weighted images, suggesting the Rathke’s cyst. Mild
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 hyperprolactinaemia was attributed to the pituitary stalk compression by the in acromegalic patients treated with transsphenoidal surgery (TS) alone to those tumour and the treatment with antidepressants. The patient was referred to the obtained from patients treated with TS followed by CR. We retrospectively Neurosurgery Department, where the tumor was removed by the transsphenoidal compared these two outcome groups and carried out a story recall test that approach. Histopathological evaluation revealed a cyst filled with non-specific included free and stimulated recalls, immediately and 20 minutes after auditory granulation and fibrous tissue and planoepithelial metaplasia of the cyst wall. The presentation. 66 patients, 26 men and 40 women, aged 55.2G12.4 years, with an tumour invaded the sphenoid sinus. The surgery was complicated by late average duration of symptoms before diagnosis of 5.1G3.7 years, were included cerebrospinal fluid leakage. in this study. Forty-two patients were treated only by TS and 24 received Conclusions additional CR. There were no significant differences between groups in sex, age, Pituitary tumor may be a difficult diagnostic dilemma, particularly in the absence average duration of symptoms before diagnosis, and mean GH and IGF-1 levels of the general symptoms. Although sellar abscess is extremely rare, it may be before TS (18.1 and 21.1 mg/l for GH, and 820.1 and 889 mg/l for IGF-1, suspected in patient with invasive cystic lesion in the pituitary. The correct respectively in both radiated and not radiated groups). Although there were more diagnosis may be made only based on histopathological examination. pituitary deficits in the radiated group when their verbal memory was assessed, the prevalence of growth hormone deficiency was similar in both groups, as well as the percentage of patients meeting cure criteria. The CR group performed significantly worse in the immediate recall, either free, with mean scores based on age-adjusted normative data of 23.4 and 39.2, for CR and not CR groups Z Z P408 (P 0.001), or after questions, showing scores of 23.3 and 39.3 (P 0.001). These differences increased in the delayed recall, where mean scores were 20.6 Effects of weight gain on serum adiponectin, leptin and ghrelin and 40.2 for free recall (P!0.0001), and 18.1 and 42.2 after questions concentrations in patients with anorexia nervosa (P!0.0001). In our study, postoperative CR in patients with acromegaly is Ayse Kubat Uzum1, Basak Yucel2, Beyhan Omer3 & Nese Colak Ozbey1 associated with a decrease in verbal memory function when compared to TS 1Division of Endocrinology and Metabolism, Department of Internal alone. Medicine, Faculty of Medicine, Istanbul University, Istanbul Istanbul, Turkey; 2Department of Psychiatry, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey; 3Department of Biochemistry, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey. P410 Objective The role of inferior petrosal sinus sampling for ACTH-dependent The aim of this study is to determine serum concentrations of adiponectin (ApN), Cushing’s syndrome leptin and ghrelin in different stages of anorexia nervosa (AN) and to Elizabeth Chua2, Nimalie Perera1 & Julie Hetherington1 evaluate their relationships between biochemical, hormonal and anthropometric 1Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia; parameters. 2University of Sydney, Sydney, New South Wales, Australia. Materials and methods The study is composed of four groups. Group 1: Treatment-naı¨ve patients with a recent diagnosis of AN (n: 19), Group 2: The weight recovered (10% increase in Objective body weight compared with baseline) subgroup of group 1 at the end of a mean Inferior petrosal sinus sampling (IPSS) with CRH stimulation is considered the 117.72G98.14 days of follow-up (n: 12), Group 3: Recovered patients with a gold standard for the differential diagnosis of ACTH-dependent Cushing’s previous history of AN but normal menstrual cycles and body weight at the syndrome. The aim of this study is to evaluate its role in confirmation and present time (n: 10), Group 4: constitutionally thin healthy young women with lateralisation of a pituitary source in suspected Cushing’s disease (CD). normal menstrual cycles (n: 10). Blood samples were obtained for measurements Methodology of biochemical parameters, ApN, leptin and ghrelin and body composition was Nine patients with CD with indeterminate MRI underwent IPSS from August determined by bioimpedance analysis. 2004 to February 2007. Three were being assessed for recurrent disease. The Results following parameters were evaluated: i) Central- to- Peripheral ACTH gradient Mean age of group 1 was significantly lower compared with group 4 (19.6G3.6 for localisation, ii) Inter-petrosal sinus gradients for lateralisation, iii) Surgical years versus 24.0G2.8 years, P!0.001). Although serum leptin concentrations histopathology, and iv) Post-operative clinical course. were significantly lower in group 1 patients compared with group 3 and 4 (5.6G Results 10.8 ng/ml; 10.9G6.9 ng/ml and 6.1G1.7 ng/ml respectively; P!0.05 for A Central- to- Peripheral ACTH gradient of R2.0 was found in 7/9 patients at R comparisons), leptin/fat mass (kg) ratios were significantly higher in group 1 base line and a gradient of 3.0 in all patients after CRH stimulation, confirming R patients compared with constitutionally thin controls (4.3G4.6 ng/ml per kg pituitary source of ACTH excess. Inter-petrosal sinus gradient of 1.4 was versus 1.1G0.5 ng/ml per kg, P!0.01). Leptin/fat mass ratio decreased observed in 8/9 patients at base line and in all patients after CRH stimulation. This significantly after weight regain in 12 patients (3.5G2.2 ng/ml per kg versus correlated with lateralisation of the excess ACTH source in all patients 1.7G1.4 ng/ml per kg, P!0.05). Adiponectin/fat mass ratio was significantly undergoing their first resection resulting in remission. For recurrent CD patients, higher in group 1 patients compared with controls. No significant difference was the site of resection was made intra-operatively based on macroscopic appearance observed among subgroups with respect to ghrelin concentrations. In the whole and frozen section. The IPSS lateralisation did not appear to have influenced the group leptin concentrations correlated significantly and positively with fat mass decision. Two had pituitary adenoma confirmed, however all three did not achieve (kg), body mass index (BMI). Adiponectin and ghrelin concentrations showed remission. significant negative correlations with BMI. Conclusion Conclusion IPSS can help confirm the location and even lateralise the source of ACTH Increased leptin concentrations indexed to fat mass in AN patients may contribute production. In patients undergoing their first resection, the results are useful to to anorexia and may play a pathogenetic role. direct surgeons to the appropriate site of excision (100% sensitivity and The present work was supported by the Research Fund of Istanbul University. specificity). For patients with recurrent disease, IPSS was useful in confirming the Project No:503/05052006. source of excess ACTH. However, its role in determining and guiding the site of surgical excision still warrants further investigation.
P409 Evaluation of verbal memory function in acromegalic patients treated P411 with or without conventional radiotherapy after transsphenoidal Comparison of visceral adipose tissue content between diabetic and surgery nondiabetic acromegalic patients Beatriz Lecumberri1, Javier Estrada2, Jose´ Garcı´a-Urı´a2, Tijen Yesim1, Tayyibe Saler1, Sema Ucak1, Mustafa Yenigun2, Luis Felipe Pallardo1 & Toma´s Lucas2 Esra Ataoglu 2 & Yuksel Altuntas1 1La Paz University Hospital, Madrid, Spain; 2Puerta de Hierro University 1Sisli Etfal Education and Research Hospital, Istanbul, Turkey; 2Haseki Hospital, Madrid, Spain. Education and Research Hospital, Istanbul, Turkey.
The impairment of cognitive function found in patients treated for pituitary Acromegaly is known to be associated with insulin resistance. Visceral adipose adenomas has been associated with the effects of conventional radiotherapy (CR). tissue is increased in patients with insulin resistance and we aimed to investigate a Our aim was to compare the results of an examination of verbal memory function visceral adipose tissue content as a possible marker of insulin resistance in
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 diabetic and nondiabetic acromegalic patients. We compared 16 diabetic and 16 P414 nondiabetic acromegalic patients for fasting blood glucose (FBG), insulin and Autoimmune hypophysitis and isolated corticotrophin deficiency visceral adipose tissue content calculated from abdominal computer tomography. Alfonso Gentil, Toma´s Martin, Alberto Torres, Isabel Serrano, All patients were active acromegalic. Diabetic patients were well controlled with Cristobal Morales, Silvia Maraver, Guiillermo Martinez de Pinillos, diet alone or diet and oral antidiabetic drugs. Diabetic patients were significantly G G Z Juan Manuel Garcia-Quiros & Angel Sendon older than nondiabetics(51.94 10.17 vs 41.38 13.43 years, P 0.018). GH and Virgen Macarena Hospital, Seville, Spain. IGF-1 levels were similar in both groups. Visceral adipose tissue content did not differ between diabetic and nondiabetic patients. Age, GH, IGF-1, FBG and fasting insulin were not correlated with adipose tissue content. In conclusion, Introduction concomittant well controlled diabetes might not affect visceral fat content in Isolated ACTH failure is a rare disorder characterized by a secondary adrenal acromegalic patients and this might be at least partly explained by high GH and failure and a considerable deterioration of the general state. In adults the has been IGF-1 levels. established related to cranial traumatism and to autoimmune hypophysitis (AH). It has been pointed out that the isolated failure of pituitary tropin in the context of a AH, could end with a global pituitary failure. Objective Evaluation of the shortage of isolated ACTH as a way of presentation of the AH. P412 Materials and method There will be described two cases of selective failure of ACTH (cases 1 and 2), A non-functioning pituitary carcinoma with cerebellar metastases with an acute beginning of the symptoms, and its development along time. They Inmaculada Gavila´n 1, Jose´ Ortego1, Cristina Coserria1, Jose´ Gil2, 3 4 1 will be compared with three cases of HA with combined hormone secretion Ana Rodrı´guez , Miguel Japo´n & Manuel Aguilar alterations (cases 3, 4 and 5) with a more silent course. 1Department of Endocrinology, Puerta del Mar Hospital, Ca´diz, Spain; 2 The nomination of the pituitary antibodies was carried out by indirect Department of Neurosurgery, Puerta del Mar Hospital, Ca´diz, Spain; immunofluorescence technique, using human pituitary (cases 3 and 4) or 3Department of Radiology, Puerta del Mar Hospital, Ca´diz, Spain; 4 primates ones (cases 1, 2 and 5). Department of Pathology, Virgen del Rocı´o Hospital, Sevilla, Spain. Results
Pituitary carcinomas are rare but represent a particular challenge to clinical practice. We report a case of pituitary carcinoma with metastatic disease in a Auto- separate non-contiguous foci within the central nervous system. A 64 year old immune man presented with a large non-functioning pituitary adenoma manifesting as thyroid Years of headache, third pair of cranial nerves paralysis, panhypopituitarism and impaired Cases Age Sex disease control MRI pituitary Clinical features visual acuity in 1996.The tumour was grossly removed through a right pterional 1 33 F yes 1 pituitary gland Syncope, hypoglycemia craniotomy. Conventional radiotherapy for the residual tumour was performed in normal amenorrheoa 2 40 F yes 5 pituitary gland General fatigue, 1997. Follow-up magnetic resonance (MR) imaging revealed a residual tumour normal headache, amenor- close to the left cavernous sinus and in the posterior sellar region. New signs of rheoa mass effect with headache, ataxia and dismetria developed in 2006. A MR showed 3 40 M no 15 pituitary gland Polyserositis, decreased normal libido and potency a tumour located in the cerebellar vermis, which was excised by suboccipital 4 28 F no 11 symmetric General fatigue, ame- craniotomy. Histological examination of the specimen revealed typical pituitary enlargement norrheoa, headache adenoma. The post-surgical MR revealed only a residual tumour in the sellar 5 37 F no 19 symmetric Headache, amenor- region. Other studies including chest radiography, abdominal ultrasound, enlargement rheoa vertebral column MR, octreoscan and positron emission tomography (PET) did not show any other metastases. Conclusions: this case documents an 11 year history of a rare non-functioning pituitary carcinoma which metastasized in Corti- cerebellum and shows that pituitary carcinomas may present as typical pituitary FT4 TSH PRL GH IgF-1 ACTH sol LH FSH E adenomas which may reveal their malignant character with distant metastases Cases ng/dl m/ml ng/ml ng/ml nmol/l pg/ml nmol/l m/ml mU/ml pg/ml T ng/ml only as time progresses. Distant lesions should be removed for histological 1 0.94 8.8 12.5 1.5 54 13.6 46 8 9 23 evaluation to plan the subsequent management. 2 0.97 12 4 0.2 7 27 271 3 9.7 3 0.48 4.1 3.7 1.4 4.20 1 120 0.74 1.4 34 4 0.85 0.620 54 1.3 13 487 0.20 0.57 0.20 5 0.62 1.87 41 1.13 10 15.7 333 0.2 2.4 0.54
Conclusion The isolated failure of ACTH is able be the way of presentation of an autoimmune P413 hypophysitis, although the disease could or could not turn into a panhypopituitar- ism. In this case this may be its debut clinic manifestation. Impact of hyperglycaemia on carotid intima-media thickness in acromegaly Tayyibe Saler1, Tijen Yesim1, Sema Ucak1, Mustafa Yenigun2, Esra Ataoglu2, Hakan Kocoglu1 & Yuksel Altuntas1 1Sisli Etfal Education and Research Hospital, Istanbul, Turkey; 2Haseki Education and Research Hospital, Istanbul, Turkey. P415 Heel pad thickness in diabetic and nondiabetic acromegalic patients Acromegaly is known to be associated with both increased cardiovascular Tayyibe Saler1, Tijen Yesim1, Sema Ucak1, Mustafa Yenigun2, mortality and carbohydrate intolerance. The aim of our study is to compare Esra Ataoglu2, Hakan Kocoglu1 & Yuksel Altuntas1 intima-media thickness, a marker of atherosclerosis in active acromegalic patients 1Sisli Etfal Education and Research Hospital, Istanbul, Turkey; 2Haseki with and without diabetes. 32 active acromegalic patients (M/ F: 15/17, 16 Education and Research Hospital, Istanbul, Turkey. diabetic and 16 nondiabetic) were assessed for fasting blood glucose (FBG), insulin, growth hormone, insulin-like growth factor 1 and carotid intima-media thickness (IMT). Diabetic patients were significantly older than nondiabetic Increased heel pad thickness can be used as a marker of soft tissue enlargement in patients (51.94G10.17 vs 41.38G13.43 years, PZ0.018). Diabetes was acromegalic patients. We aimed to investigate if concomittant hyperinsuline- diagnosed after the onset of acromegaly in all subjects in diabetic group and mia/and or diabetes secondary to insulin resistance in acromegaly contribute to well-controlled with diet and/ or oral antidiabetic drugs. IMT was significantly the enlargement of heel pad. We compared heel pad thickness in 16 diabetic and higher in acromegalic patients with diabetes compared to nondiabetic group 16 nondiabetic active acromegalic patients using X-ray images. All of the (0.72G0.16 vs 0.60G0.08 mm; PZ0.018). GH and IGF-1 levels were similar in diabetics were well controlled with diet and/ or oral antidiabetic drugs. GH and both groups. In whole group, age and FBG was correlated significantly with IMT IGF-1 were similar in both groups. Heel pad thickness did not differ between (rZ0.438; PZ0.015 and rZ0.444; PZ0.014, respectively), GH, IGF-1 and diabetic and nondiabetic acromegalic patients (21.93G3.54 vs 22.92G3.80 mm, fasting insulin were not. In conclusion, advanced age and hyperglycemia seems PZ0.489) and was not correlated with fasting blood glucose, insulin, GH and to have a significant impact on the progression of atherosclerosis in the course IGF-1. In conclusion, diabetes secondary to acromegaly did not affect soft tissue of acromegaly. enlargement represented by heel pad thickness.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P416 P418 Perioperative steroid treatment is not routinely required in endoscopic Consequences of isolation stress on glucocorticoid regulating genes and transphenoidal surgery for clinically non functioning pituitary behavioural response in postnatal pigs adenomas (NFPA) Ellen Kanitz, Birger Puppe, Margret Tuchscherer, Torsten Viergutz, Renato Cozzi1, Giovanni Lasio2, Giovanni Felisati1 & Roberto Attanasio2 Armin Tuchscherer & Theresa Blank 1Endocrinology, Ospedale Niguarda, Milan, Italy; 2Pituitary Unit, Istituto Research Institute for the Biology of Farm Animals, Dummerstorf, Galeazzi, Milan, Italy; 3ENT Chair, Polo S.Paolo, University of Milan, Germany. Milan, Italy. Early life events can have short and long-term effects on neuroendocrine, Steroids are still widely prescribed in pituitary trans-sphenoidal surgery (TSA). autonomic, and behavioural responses to stress and appear to play an important Pituitary-adrenal/thyroid/gonadal functions were prospectively evaluated in 72 role in the etiology of stress-related disorders. Glucocorticoids are thought to be consecutive NFPA pts (20–87 years, 37 M) before and after endoscopic-TSA (E- key mediators of these brain-endocrine-immune connections. We investigated the TSA) (63 at first operation, 9 at re-operation). All had macroadenoma with effects of a short-term social isolation (4 h) of domestic piglets at different days of suprasellar extension: impinging optic chiasma in 28, extending into cavernous age (7, 21, 35) both on behavioural alterations in open-field tests and on sinus (CS) in 23, giant in 12. Hydrocortisone was infused peri-operatively only in modifications in the expression of genes regulating glucocorticoid response in pts with pre-op 0800 am cortisol (F) !8 mg/dl (arbitrary cut-off). After E-TSA stress-related brain regions. Evaluation of glucocorticoid receptor (GR), clinical picture, F, electrolytes, FT4 and diabetes insipidus (DI) were checked at mineralocorticoid receptor (MR), 11b-hydroxysteroid dehydrogenase 1 and 2 1–3 days, testosterone in M or menses/FSH in women at 1 month, ACTH 1 mg- (11b-HSD1 and 11b-HSD2) mRNA expression by real-time RT-PCR revealed induced F peak (F-ACTH) and MRI at 3 months. A wide resection (O90%) was significant differences in quantity of these genes in hypothalamus, hippocampus performed in all pts, up to empty sella in 60%. Post-op follow-up lasted 1–11 and amygdala. The social isolation caused a significant increase in ACTH and years (median 5) and regrowth occurred in 5 points with CS invasion. The greater cortisol concentrations and an increase of behavioural arousal. The increased the adenoma size, the worse the pre-op and post-op pituitary function. Central activity of the HPA axis and the behavioural alterations were associated with hypogonadism (HypoG) and hypothyroidism (HypoT) were detected in 80.5% distinct changes in gene expression in the limbic system. The hypothalamic GR, and 40.3% before and in 77.8% and 47.2% of pts after E-TSA. Permanent DI MR and 11b-HSD1 mRNA levels significantly increased in piglets exposed to occurred in 13.9%. F was 11.4G3.9 before and 11.5G4.3 mg/dl after E-TSA. Pre- isolation stress, whereas in the amygdala the MR mRNA expression significantly op hypocortisolism (HypoA) did not change in 14 points (19.4%, all had also decreased. There was also a significant increase of HSD1 mRNA in isolated hypoT and hypoG), and was detected in 6 (10.3% of those with previously normal piglets in hippocampus on day 7 of age, but the 11b-HSD2 mRNA levels were not adrenal function) at the first post-op control. No patient whose pre-op F was O influenced by social isolation in the brain regions. In conclusions, psychosocial 8 mg/dl failed, and no patient but 1 whose pre-op F was !8 mg/dl achieved the stress in form of a short-term social isolation in piglets caused age-dependent and required 18 mg/dl F-ACTH cut-off. In conclusion, pituitary-adrenal function is region-specific modifications in mRNA levels of stress-related genes in the brain usually preserved in NFPA, and only seldom is impaired after complete tumor accompanied by changes in open-field behaviour indicating adaptive arousal and removal by E-TSA; the first 1–3 day post-op control reveals the few cases experienced distress. Therefore, we suggest that psychosocial stress effects should impaired by E-TSA. We recommend peri-operative steroid treatment only In pts be considered in livestock handling practices (e.g. the weaning of piglets). with pre-op subnormal F levels, and to evaluate clinical picture and morning F on post-op day 1–3 for guidance about replacement treatment.
P419 Demography, characteristics and outcome of acromegaly at King Hussein medical centre amman Jordan Omar Malkawi1, Fares Haddad1, Ahmad Omari1, Amer Sharbaji2, P417 Alia Izzat1, Abdelkarim Khawaldeh1, Reem Qadah1, Abdullah Aleyadeh1 & Pituitary deficiencies after autologous bone marrow transplantation Khaldon Srehein1 Sandra Lesven1, Claire Josseaume1, Manuel Dolz1, Emmanuel Sonnet1, 1Endocrine Department-King Hussein Medical Center, Amman, Jordan; Nathalie Roudaut1, Christian Berthou2 & Veronique Kerlan1 2Neoursurgical department -KHMC, Amman, Jordan. 1CHU Brest Service d’endocrinologie, Brest, France; 2CHU Brest Service d’hematologie, Brest, France. Acromegaly is a chronic debilitating disease due to long term exposure to elevated levels of growth hormone (GH) which leads to excessive growth of both Development in autologous bone marrrow transplantation (auto-BMT) has skeletal and soft tissues. It is slowly progressive with 30% increase in mortality improved survival, but new endocrine complications now emerge. If primary rate for cardiovascular disease, respiratory complications and malignancies. The thyroid and gonadal deficiencies are documented in medical literature, pituitary estimated prevalence of the disease is 40 cases per million with 3–4 new cases per deficiencies are less well-known, especially in adults. The aim of the study was to million populations per year. Acromegaly most commonly presents between the investigate pituitary function in patients who survived at least one year after third and fifth decade with 6–10 years delay in diagnosis. Effective treatment can transplantation for malignant haematologic disorders by a prospective study. improve the survival to that of aged matched population. In 2003 a core of Material and methods neuroendocrie-pituitary clinic was established at KHMC with a central referral Thirty patients (17 male, 13 female) were studied. Age at transplantation ranged unit for all satellite army hospital across the county. from 7 to 67 years. Preparation of patients had included total body irradiation Aim (TBI) in eight patients, only cytotoxic drug in 22 patients. In 17 patients, To assess the outcome of medical and surgical treatment of our group of immunotherapy (interferon and interleukine-2) was used. Corticosteroid Acromegalics and to evaluate predictor factors of cure. treatment had been stop for at least 6 month. Prospective hormonal analysis was Patients and methods effectuated, including basic dosages (TSH, T4L, IGF1, FSH, LH, E2/T, PRL), and Fifty one patients with acromegaly were studied; one elderly patient refused all dynamic test of hypothalamus-pituitary axis (HPA) with insulin tolerance test modalities of treatment. Random GH and mean GH to OGTT, IGF1, and IGFBp3 (ITT) on GH and cortisol or adrenocorticotropin (ACTH) test (corticotrophin 1 mg were assessed prior and after treatment as well as radiological findings. Age, IV) if contraindication or insulin resistance. duration of acromegaly, body weight, skin fold thickness and tumor size were Results evaluated as predictors of favorable outcome. Seven patients (24.1%) had central hypothyroidism. Secondary adrenal Results insufficiency was diagnosed in 2 subjects. GH deficiency was diagnosed in 7 There were 28males and 23 females with mean age of 43.4G11.9 years (range subjects (1 severe, 6 partial). Eight no menopausal women before allo-BMT had 24–74). The duration of disease was 7.7G8.7 years and of follow up was 9.4G primary ovarian insufficiency. Four male presented central hypogonadism. 8.55 years (0.5–22). Ninety percent of patients were having macro adenomas. The Sixteen patients (64%) had one pituitary deficiency, 1 had 2 deficiencies and 2 had mean GH to OGTT (pre versus post op) was 19.7G13.9 ng/ml versus 4.4G7.8 3 deficiencies. No global HPA deficiency was found. (P!0.0003), IGF1 was 815.5G303.7 versus 415.1G326.7 (PZ0.016) and Discussion IGFBp3 is 7.6G2.7 vs 5.6G2.2 mg/ml (PZ0.049). One third of patients Two majors factors seem to be important for developing endocrine dysfunctions: achieved cure the rest is still active. Seventeen patients are medically treated by conditioning treatment before auto-BMT: TBI and cytotoxics drugs or Somatostatin analogues, 16.7% of whole group achieved cure on treatment. Eight corticosteroid used before BMT. Considering these results, a systematic screening patients received radiotherapy; 50% of them achieved cure. Mean HGH for the of pituitary deficiencies after auto-BMT could be proposed in order to improve group receiving medical treatment (SSA) was 20.33G12.71 ng/ml versus 8.11G patient quality of life after transplantation. 10.2 post follow up period. A GH of !15 ng/ml and age !40 years were found to be the strongest predictors of favorable outcome in this cohort.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Conclusions The study population consisted of 42 pituitary adenomas obtained after Cure rate is modest when compared with international rates. Younger age group transsphenoidal surgery and 12 normal pituitary glands with autoptic origin and lowest growth hormone levels are the strongest favorable predictors to cure. (NPG). Based on the hormonal pattern and immunohistochemical studies Our patients are presenting late with aggressive tumor which limit the cure rate. 9 adenomas were classified as corticotropinomas, 12 were somatotropinomas Medical therapy achieved acceptable cure rate and plays an important role as (GHomas), 6 prolactinomas and 15 non-functioning pituitary adenomas adjunctive therapy after surgical resection of pituitary tumor. A multidisciplinary (NFPAs). approach toward acromegaly management is recommended. Expression studies demonstrated that 5/12 GHomas and a single NFPA showed high GIPR expression compared to NPG in which low levels were detected. Similarly, low levels were observed in all other samples. The evaluation of clinical and biochemical parameters of acromegalic patients, revealed that for the only three high-GIPR expressing subjects, for which P420 the OGTT was available, a paradoxical increase of GH after oral glucose load was observed. Such an effect was never observed in low-GIPR Sleep quality in patients of a primary health care unit and its expressing subjects. relationships with antropometric parametters This data together lead us to hypothesize that in GHomas, GIPR may be Angela Pen˜alva, Gretel Lichtenstein & Carmen Cadarso possibly involved in the mechanism of GH-regulation exerted by the University of Santiago de Compostela, Galicia, Spain. glucose, whereas it probably does not play any role in the pathogenesis of the other pituitary adenomas. Further studies are mandatory to establish the real role of GIPR in acromegaly. Objective To study the sleep quality in patients of a primary health care unit and Its relationship with anthropometric parameters as sex, age, BMI and waist circumference. Participants and methods One hundred and twenty-two patients arrived spontaneously and correlatively for P422 consultation. The Pittsburgh sleep quality index questionnaire (PQ5I) was used to Macroprolactinaemia in men investigate the patients sleep quality in the last month. The PQ5I explores seven Larisa K Dzeranova, Ekaterina N Giniyatullina, Ludmila Y Rozhinskaya, aspects: C1) subjective sleep quality; C2) sleep latency; C3) sleep duration; Nikolai P Goncharov & Anna D Dobracheva C4) sleep efficiency; C5) sleep disturbances; C6) use of specific medication; National Research Centre for Endocrinology, Moscow, Russian Federation. C7) daytime disturbances. The PQ5I provides a score (0-3) of these seven components and a global PQ5I score in a (0-21) scale. A higher score indicates poor sleep quality. Background Statistical study It is known women suffer from macroprolactinaemia more frequently than men. Descriptive statistic, ANOVA and Pearson correlation was used to value the Often men with unclear genesis of hyperprolactinaemia have normal or a little relationship with anthropometric parameters. depressed Testosterone level. High macroprolactin level in blood serum can Results explain this type of hyperprolactinaemia. Sleep quality Materials and methods PQ5I global score indicates that 52.1% of the patients are ‘good sleepers’, the Sixty-four men with hyperprolactinaemia (Prl O600 mU/l) were studied. others display sleep disturbances in some components. Components: C1) 73% of Clinical, biochemical and MRI methods were used. Prl and Testosterone levels patients considers that their sleep is good or very good; C2) 17.3% needs more were determined by fluorescence method. MonPrl was determined by PEG- than one hour for sleep onset; C3) the sleep hours average were 6–7 h per night; precipitation (Delfia; Finland). Macroprolactin level was calculated from Prl and C4) 68% have a good sleep efficiency; C5) for the 91%, of them present some monPrl data. After investigation of 35 healthy men with normoprolactinaemia sleep disturbances; C6) 12% need sleep medication every day; C7) for the 90%, reference value were estimated: 74–390 mU/l. A recovery of macroprolactin their sleep quality does not entail any diurnal activities dysfunction. more than 60% was accepted as macroprolactinaemia. Sleep quality and anthropometric measures Results Patients sleep quality deteriorate with age, being more evident in women. Poor Macroprolactinaemia was founded in 11 (I group) of 64 cases (17.1%). True sleepers, have greater BMI and waist circumference. The relationship among poor hyperprolactinaemia was founded in 53 (II group) of 64 cases. All patients of II sleep quality, less sleep hours and BMI is more evident in women, whereas this group have been taken cabergoline (median of dose – 2.5 mg/week). Median of same relationship related to the waist circumference is more important in men. Prl level in I group was 2356 mU/l. Median of Testosterone level was 10.4 nmol/l. Conclusions The microadenomas were revealed in 3 men, macroadenomas – in 6 patients. In our patients poor sleep quality and total sleep hours reduction are associated to Clinical symptoms (libido impairment, reduced sexual potency) were founded in higher BMI and waist circumference. 9 men, they all had increased monPrl level (978 mU/l). That is why all of these patients have been taken cabergoline treatment (Median dose-1.25 mg/week). In 2 patients from I group monPrl level was normal and dynamic control carried out. After 6 months median of Prl level was 689 nU/l, testosterone level- 14.1 nmol/l. There were no clinical symptoms in all 9 men. monPrl level was P421 normal in all patients (median-265 mU/l). Positive dynamics of the tumors volume was noted in 5 patients with macroadenomas (from 2.5 to 1.9 cm3) and in Glucose-dependent insulinotropic polypeptide receptor (GIPR) in 2 patients with microadenomas (from 0.9 to 0.5 cm3). human pituitary adenomas Conclusions Gianluca Occhi1, Marco Losa2, Nora Albiger1, Massimo Scanarini3, This investigation revealed that macroprolactinaemia is founded in 17.1% in men Jacopo Del Verme3, Franco Mantero3 & Carla Scaroni1 with tumorous and not tumorous hyperprolactinaemia. MonPrl level was higher 1Division of Endocrinology, Department of Medical and Surgical Sciences, than reference value in 9 of 11 patients with macroprolactinaemia and they were Hospital/University of Padova, Padova, Italy; 2Pituitary Unit, Department of treated by cabergoline. But cabergoline dose in I group was greatly lower than in Neurosurgery, Istituto Scientifico San Raffaele, Universita` Vita-Salute, II group. Therefore efficiency estimation should be determined on monPrl level, Milano, Italy; 3Division of Neurosurgery, Hospital/University of Padova, not on Prl level. Padova, Italy.
Glucose-dependent insulinotropic polypeptide (GIP) receptor is a member of the G protein-coupled receptors family. According to its incretin properties, GIPR is expressed in tissues such as pancreas, stomach and adipose tissue. However GIPR P423 expression pattern appears to be broader, as it was detected in other tissues such as Age-dependent expression of ret receptor from perinatal life to heart, lung and the central nervous system, thus suggesting either novel ligands adulthood for GIPR or novel actions for GIP. Moreover, in some patients with food- Montserrat Garcı´a-Lavandeira, Esther Dı´az-Rodrı´guez, Carlos Die´guez dependent Cushing’s syndrome, ectopical expression of GIPR was demonstrated Gonzalez & Clara A´ lvarez Villamarin being sufficient for inducing symptoms of hypercortisolemia and the formation of Universidad De Santiago De Compostela, Santiago De Compostela, Spain. a benign adrenocortical tumor. For such reasons, and in order to establish its possible involvement in pituitary adenomas tumorigenesis, GIPR expression was investigated in a large cohort of The RET/GFRa/GDNF system displays a wide distribution in tissues such as pituitary adenomas. nervous system, kidneys, intestine or testis. RET has been implicated in human
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 pathologies. RET is a tyrosine-kinase receptor activated by four ligands GDNF, P425 NTN, ART and PSPN through four co-receptors GFRa1, 2, 3 and 4 respectively. Tests of growth hormone (GH) status in severe GH deficiency: do they Activation of the receptor leads to cell differentiation or proliferation. Our group identify a similar phenotype? Insight from the KIMS database has shown that RET is expressed specifically in the somatotrope (GH) adult cell Andrew Toogood1, George Brabant2, Michael Buchfelder3, Ulla Feldt- population within the pituitary, both in rats and in humans (Urbano, Rasmussen4, Maria Koltowska-Haggstrom5, Bjorn Jonsson6,A˚ se Krogh Endocrinology2000; Japon, JCEM2002) and provided evidence that RET Rasmussen4, Dominique Maiter7, Bernhard Saller8 & Beverly Biller9 expression controls the number of somatotropes in vivo inducing apoptosis (vs 1Department of Medicine, Queen Elizabeth Hospital, Birmingham, UK; survival) through overexpression of Pit-1 (Can˜ibano, EMBOJ2007). 2Department of Endocrinology, Christie Hospital, Manchester, UK; Here we characterize the mRNA levels of RET receptor by q-RT-PCR during the 3Neurochirurgische Klinik, Universita¨t Erlangen-Nu¨rnberg, Erlangen, maturation of the pituitary from birth to adulthood. Germany; 4Department of Endocrinology, Rigshospitalet, Copenhagen, Adenopituitaries of 24 hour, 10, 20, 30, 60 (adults) and 90 days-old rats were Denmark; 5KIMS Medical Outcomes, Pfizer Endocrine Care, Stockholm, isolated and frozen. Sweden; 6Department of Women’s and Children’s Health, Uppsala Specific primers were used for: GRFa2, a positive control of inmature gland since University, Uppsala, Sweden; 7Faculte de Medecine, UCL, Brussels, is expressed in embryonic pituitary (Golden, ExpNeurol1999); Pit-1, essential for Belgium; 8Pfizer Global Pharmaceuticals, EBT Endocrine Care, London, development of somatotropes, lactotropes and thyrotropes; GH, a control of UK; 9Neuroendocrine Unit, Massachusetts General Hospital, Boston, USA. pituitary growth maturation. Expression of GFRa2 was high in newborn pituitaries and decreased with age. Opposite, GH levels were low during the first 10 days and they doubled its A GH peak of 3 mg/l during the insulin tolerance test (ITT) is considered the gold expression at 20 days around puberty remaining high through adulthood. It was standard for identifying adults with severe GH deficiency. Alternative stimuli observed that Pit-1 and Ret showed similar patterns of expression: both were such as arginine (AST) and glucagon (GST) are also employed but produce lower expressed at birth at low quantities; at 10 days a peak of RET expression was seen GH peaks than the ITT in normal subjects. Despite this, 3 mg/l is used as the decaying at 20 days; Pit-1 also increased its expression at 10 days but peaked at diagnostic threshold for these tests, raising the possibility that severe GH 20 days to decay later. deficiency is being diagnosed inappropriately. In summary, during growth expression of RET precedes a Pit-1 surge of We studied 4584 patients enrolled in KIMS (3070 underwent an ITT, 1320 an expression just before the GH raise characteristic of puberty. This suggests that AST and 910 a GST at diagnosis) to determine whether these patients exhibited a RET controls somatotrope cell generation in the pituitary. similar phenotype. Interquartile ranges of GH peaks achieved during the ITT were determined (1st !0.12, 2nd 0.13–0.39, 3rd 0.4–0.99, 4th 1.0–3.0 mg/l). These limits were applied to the AST and GST. Comparisons were made in the 1st and 4th quartiles between the AST vs ITT and GST vs ITT for the following clinical variables: BMI, IGF-I SDS, cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, waist:hip ratio and quality of life (QoL-AGHDA). quartile. AST vs ITT: BMI was higher (30.6 vs 28.8 kg/m2, P!0.0001) in the AST group. GST vs ITT: IGF-I SDS was lower (-1.9 vs -2.8, PZ0.003), HDL was higher (1.1 P424 vs 1.2 mmol/l, PZ0.025) and triglycerides were lower (2.7 vs 2.3 mmol/l, PZ0.003) in the ITT group. quartile. AST vs ITT: BMI was higher in the AST Midnight salivary cortisol (MSC) to assess the outcome of transsphe- group (29.0 vs 28.0 kg/m2, PZ0.035). GST vs ITT: Quality of life was worse in noidal surgery (TSS) in Cushing’s disease (CD) the GST group (15 vs 12, P!0.0001). 1 ¨ 2 1 ´3 Carmen Carrasco , Joel Coste , Laurence Guignat , Marie-Annick Dugue , None of the other parameters was significantly affected in either quartile. ´ 4 1 ˆ 1 Stephane Gaillard , Xavier Bertagna & Jerome Bertherat Using a diagnostic threshold of 3 mg/l, the AST and GST identified GHD patients 1 ˆ ˆ Assistance Publique Hopitaux de Paris, Hopital Cochin, Department of with similar features to those defined by the ITT. This is reassuring for future Endocrinology, Reference Center for Rare Adrenal Diseases, Paris, France; studies on the impact of GH replacement in the KIMS database. 2Assistance Publique Hoˆpitaux de Paris, Hoˆpital Cochin, Department of Biostatistic, Paris, France; 3Assistance Publique Hoˆpitaux de Paris, Hoˆpital Cochin, Department of Hormonal Biochemistry, Paris, France; 4Hoˆpital Foch, Department of neurosurgery, Suresnes, France.
Introduction P426 MSC is a simple and reliable mean to diagnose hypercortisolism, yet its value to Enos, P22phox and apoE gene polymorphism associations with asses the outcome of treatment has rarely been addressed. circulating hormone levels in the elderly Objective Olga Ianas1, Dana Manda1, Constantina Heltianu2, Anca Sima2, Compare MSC and other classical parameters, to assess the outcome of TSS Monica Raicu2, Marcela Covic3 & Constantin Dumitrache1 in CD. 1C.I. Parhon Institute of Endocrinology, Bucharest, Romania; Patients and methods 2N. Simionescu Institute of Cellular Biology and Pathology, Bucharest, Sixty-eight patients from a single Center operated for CD between 1996 and Romania; 3Ana Aslan Institute of Geriatry and Gerontology, Bucharest, 2006. Outcome was assessed between 6–12 months post TSS. Remission Romania. was defined as: morning plasma cortisol !50 ng/ml and/or insufficient response to ACTH; or normal urinary free cortisol (UFC!90 mg/d) together with midnight plasma cortisol !75 ng/ml and normal suppression to Objective dexamethasone. Morning plasma cortisol at day five post TSS (TSS C5) The aim of this study was the identification of eNOS (G894T), p22phox (K930 was also retrospectively analysed. A/G) and apoE gene polymorphisms associated with the impact of age-dependent Results endocrine changes. The 73.5% of the patients achieved remission. MSC was significantly lower Subjects and methods remission group (group 1, nZ50) than of failure (group 2, nZ18): 0.7G Subjects, both genders, were recruited and classified into the three groups: 0.4 ng/ml (mean GS.D., range: 0.4–2.2 ng/ml) versus 6.5G6.6 ng/ml (range: (1) 100 subjects aged 55–80C years with mild cognitive impairment (MCI) 2.1–27.2 ng/ml), P!0.001. Similarly, UFC was significantly lower in group 1 (MMSE!28); (2) 165 age-matched subjects without cognitive impairment than in group 2: 14G19 mg/d (range: 2–105 mg/d) versus 307G304 mg/d (MMSEO28); (3) 93 healthy subjects under 55 years. Serum cortisol, 17-OHP, (range: 20–1070 mg/d), P!0.001. Retrospectively, morning plasma cortisol at DHEA, DHEAS, androstendion, estradiol, estrone, testosterone, free testosterone, TSSC5wasloweringroup1thaningroup2:26.8G46.4 ng/ml (range: 10– DHT, SHBG, inhibin A and inhibin B, LH, FSH, Prl, GH, IGF1 were measured. 270 ng/ml) versus 136.6G85.6 ng/ml (range:14–298 ng/ml), P!0.001. MSC Gene polymorphisms were assayed by using RFLP technique. was correlated to UFC (r 0.618, P!0.001), as well as to morning plasma Results cortisol at TSSC5 (r 0.410, P!0.001). For the diagnosis of remission the The frequency of genotypes and alleles of eNOS and p22phox in studied groups performances (specificity-sensitivity) of the different measurements were as were not significantly different. Distribution of 32 allele of apoE gene was higher follows: MSC (cut off of 2 ng/ml) 100%–98%; morning plasma cortisol in MCI (28.3%) as compared with healthy ones (14.6%) or adults (9.6%). Rare post TSS C5 (cut off 18 ng/ml) 92.9%–26%; UFC (cut off of 90 mg/day) allele apoE 34 presented a higher frequency in MCI (17%) as compared with 70.6%–21%. healthy ones (12.5%). Raised plasma cholesterol and triglycerides were found in Conclusion 32 and 34 carriers in MCI. In the group of adult subjects the eNOS polymorphism MSC is a valid marker of remission after TSS for CD, with better was significantly associated with cortisol (t2Z10.36; PZ0.006), DHEA sensitivity and specificity than UFC or early morning plasma cortisol (t2Z7.62; PZ0.02) and DHEAS (t2Z6.94; PZ0.03. In the elderly, the eNOS immediately after TSS. variant correlated significantly with BMI (t2Z6.47; PZ0.04) and FSH (t2Z6.93; PZ0.03); p22phox was associated at the border of significance with
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
DHEAS (t2Z5.68; PZ0.058) and ADION (t2Z5.84; PZ0.054). Multivariate P!0.03 versus MA). In YA, CT infusion was followed by significant increase in regression analysis for eNOS G894T in the presence of associated variables ACTH and F (P!0.05 versus placebo), while no significant hormonal changes were showed that DHEA (ORZ0.82; 95%CIZ0.69–0.98; PZ0.032) and FAI (ORZ observed for DHEA, PRL and GH. In MA, CT increased both ACTH and F (P!0.03 0.95; 95%CIZ0.9–1.0; PZ0.034) were associated with age. versus placebo) and the hormonal responses were higher than in YA (P!0.05); Conclusions no significant effect on DHEA, PRL or GH was reported. In ES, ACTH and The frequency of 32 and 34 variants of apoE gene raised in the elderly, particularly F response toCT were lowerthan inMA and similar to that in YA, while DHEA, PRL in those with MCI. The correlation between DHEA with age seemed to be and GH were not modified. These preliminary findings indicate that the corticotrope influence by the presence of both T allele of eNOS G894T and G allele of p22phox. response to citalopram is amplified in middle age but not in aging, a described condition of HPA hyperactivity. This suggests that the neuroendocrine effects of citalopram are clearly age-related, showing a transient hypersensitivity to SSRI during middle age.
P427 Is increase in bone mineral content caused by increase in skeletal muscle mass/strength in adult patients with growth hormone (GH) treated GH P429 deficiency? A litterature analysis Variable effects of preproTRH(178–199) on ACTH secretion by human Oliver Niels Klefter & Ulla Feldt-Rasmussen corticotrope tumors National University Hospital, Copenhagen, Denmark. Francesca Pecori Giraldi1, Samantha Pesce1, Paola Maroni1, Marco Losa2 & Francesco Cavagnini1 1Chair of Endocrinology, Department Endocrinology, University of Milan, Growth hormone (GH) has a well known anabolic effect on skeletal muscles, and 2 patients with GH deficiency (GHD) are characterised by a reduced muscle mass, Ospedale San Luca, Istituto Auxologico Italiano, Milan, Italy; Division of but also reduced bone mineral density (BMD) and content (BMC), which have Neurosurgery, Ospedale San Raffaele, Milan, Italy. been ascribed to GHD per se. Correspondingly, the increase in bone and muscle mass by GH therapy has been seen as separate GH influences on bones and PreproTRH (178–199), a 22-aminoacid cleavage product of the TRH prohormone, muscles, respectively. The aim of this study was therefore to investigate if has been postulated to act as an ACTH-releasing inhibitor. Indeed, in vitro evidence changes in BMD/BMC in adult patients with GHD could be due to a muscle indicates that this peptide may inhibit basal and stimulated ACTH secretion in rodent modulating effect, and if treatment with GH would primarily increase muscle anterior pituitary primary cultures and cell lines (Redei 1995, Revskoy 2001), mass and strength with a secondary increase in BMD, thus supporting the current although not all studies concur (Nicholson 1996). Aim of the present study was to test physiological concept that mass and strength of bones are mainly determined by the effect of preproTRH(178–199) in human tumoral corticotropes. dynamic loads from the skeletal muscles. Methods A literature review resulted in 34 clinical trials, published during the period 1996– Twenty-four human ACTH-secreting pituitary tumors were collected during 2006, and fulfilling the criteria for investigating variables related to the surgery, dispersed and established in culture. After a 3–5 day attachment period, development in muscle mass, muscle strength, and BMC/BMD in adult GHD cells were incubated with 10–100 nM rat preproTRH(178–199), with 10 nM human patients treated with GH. CRH or with 10 nM dexamethasone (all from Sigma Co., St. Louis, USA) and Three out of four trials found significant increases in muscle mass compared to medium samples collected after 4 and 24 h for measurement of ACTH baseline, while eight out of 11 trials found significant increases in one or more concentrations by IRMA. ACTH secretion was standardized to % unchallenged measures of muscle strength compared to baseline. The largest increase in muscle wells (Zcontrol). mass was observed during the first 12 months of treatment. Nineteen out of 26 Results trials found significant increases from baseline values in BMC or BMD in one or A clear inhibition of ACTH secretion at 4 and 24 h was observed in 12 specimens more body regions. The significant increases in BMD and BMC occurred after (for 10 nM ppTRH: 70.3G4.52% control at 4 h and 83.4G5.33% control at 24 h; 12–18 months of treatment, i.e. usually later than the increase in the muscle for 100 nM ppTRH: 70.1G3.93% control at 4 h and 84.8G4.88% control at 24 h), measurements. Only 5 clinical trials studied both muscle and bone variables whereas a mild and short-lasting stimulatory effect was observed in the other concomitantly in GH treated adult GHD patients. None of these studied the tumors (for 10 nM ppTRH: 128.6G9.45% control at 4 h and 104.7G4.26% control relationship between the changes in muscle and bone measurements. at 24 h; for 100 nM ppTRH: 108.4G3.42% control at 4 h and 103.3G3.63% In conclusion, although in vitro studies have shown that GH has a direct effect on control at 24 h). Interestingly, the effect of preproTRH(178–199) was significantly bone remodelling, current physiological concepts and the results of clinical trials correlated with the potency of dexamethasone inhibition while no association with from the past 10 years suggest that the anabolic changes in muscle mass and CRH stimulation was observed. muscle strength may also contribute to changes in BMC and BMD in the GH Conclusions treated adult GHD patients. Studies addressing this particular issue are, however, Our study in a large series of human corticotrope tumors shows that preproTRH needed to clarify the relative contribution of mechanisms. (178–199) exerts variable effects on tumoral ACTH secretion, closely linked to sensitivity to glucocorticoid negative feedback. Further studies might shed light on its usefulness as an inhibitor of ACTH secretion by human corticotrope adenomas.
P428 Neuroendocrine effects of citalopram, a selective serotonin re-uptake inhibitor (SSRI), during lifespan in humans P430 Rita Berardelli1, Enrica Margarito2, Federica Ghiggia2, Andreea Picu1, Endocrine features of aging and cognitive function in women Lorenza Bonelli1, Marcella Balbo1, Roberta Giordano1, Mario Bo2 & Dana Manda1, Suzana Vladoiu1, Roxana Rosca1, Oltea Joja1, Carmen Trifu- Emanuela Arvat1 Iordachescu1, Marcela Covic2, Florentina Halici2 & Olga Ianas1 1Division of Endocrinology and Metabolism, Department of Internal 1C.I. Parhon Institute of Endocrinology, Bucharest, Romania; 2A. Aslan Medicine, University of Turin, Turin, Italy; 2Section of Geriatrics, Department Institute of Geriatry and Gerontology, Bucharest, Romania. of Medical and Surgical Disciplines, University of Turin, Turin, Italy. Objective Central serotoninergic activity (CSA) is known to influence the hypothalamus– An on-going epidemiological populational study examined hormone balance pituitary–adrenal (HPA) axis, and a CSA loss seems to play a role in human brain during aging in women, and – whether there was a difference in endogenous aging and in etiologyoffunctionalhypercortisolism and depression, whose incidence serum sex hormone levels between a postmenopausal women group with increase with advancing age. Citalopram (CT), a SSRI, has been considered a good moderately cognitive impairment and healthy age-mached women group. tool to evaluate CSA in humans. Aim of this study was to evaluate the Subjects and methods neuroendocrine response to CT in healthy adult subjects during lifespan. We One hundred and sixty-three women aged 25 to 80 years were classified into three evaluated ACTH, cortisol (F), DHEA, PRL and GH secretion following placebo or groups: (1) 44 subjects aged 55–80 years with moderately cognitive impairment acute i.v. CT infusion (20 mg over 120 min) in 12 young (YA, age: 29.2G1.7 years), (MMSE!28); (2) 73 age-matched subjects without cognitive impairment 10 middle aged (MA, 53.2G1.3 years) and 12 elderly subjects (ES, 69.3G0.9 years). (MMSEO28); (3-control) 44 healthy subjects under 44 years. Total morning Blood samples were taken every 150 for 2400. During placebo, ACTH, F, PRL, and levels of serum 17-OHP, DHEA, DHEAS, androstendion, estradiol, estrone, GH levels were not different in the three groups, while DHEA secretion showed a progesterone, testosterone, free testosterone, DHT, SHBG, inhibin A and inhibin clear age-dependent reduction, starting from middle age (AUC, meanGSEM, YA: B, LH, FSH, Prl, TSH, GH, IGF1, insulin, cortisol and thyroid hormones were 2420.7G205, MA: 938.3G94.4 mg/l per min, P!0.01 versus YA; ES: 674.5G62.5, measured.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Results In this work, we analyzed the possible interaction between GHRH and GHS-R1a There was a marked decline of sex steroid metabolism associated with an increase as well as the subsequent intracellular pathways. The results showed that GHRH of gonadotropins in postmenopausal women. All androgens and estrogens were induced, in a dose-dependent manner, a calcium mobilization from intracellular significantly decreased (P!0.001) with no significant change in SHBG levels; stores followed by a calcium influx through calcium channels at plasma gonadotropins (LH, FSH) were significantly increased (P!0.001). Also, membrane in HEK 293 cells stably transfected with GHS-R1a (HEK-GHSR1a), metabolic balance was significantly altered. The endocrine changes were an effect that was not observed in untransfected HEK 293 cells. Radioligand associated with a cognitive decline (PZ0.01); serum cortisol levels and thyroid binding and cross-linking studies revealed that GHRH-mediated response hormones showed a minimal overall change in basal levels with aging. In on calcium signal was mediated by GHS-R1a, showing that the presence of postmenopausal women with moderately cognitive impairment there was a GHRH increased the binding capacity of 125I-ghrelin. The administration decrease of serum thyroxine level (PZ0.006) but no significant differences in of GHRH stimulated the activation of the IP3 signalling pathway. Interestingly, estrogens and androgens levels compared to age-matched group; however, there GHRH potentiated ghrelin-induced IP3 mobilization. In addition, confocal was a higher rate in their decline. microscopy in CHO cells transfected with GHS-R1a tagged EGFP showed that Conclusions GHRH was able to induce the GHS-R1a endocytosis. In conclusion GHRH is able Endocrine deficiencies in postmenopausal women include a decrease in the to activate the GHS-R1a inducing an increase both in the ghrelin binding capacity peripheral levels of estrogens and androgens with an increase in LH, FSH and intracellular response. The regulation of the ghrelin-mediated signaling by associated with a cognitive decline. The moderately cognitive impairment did not GHRH could have implications in the GH secretion and could be an explanation significantly affect mean both sex steroid and gonadotropin levels. Finally, our of the observed synergistic effect of ghrelin and GHRH on GH secretion. results emphasize the complexities of hormone action, particularly related to estrogens and androgens associated with a cognitive decline during the menopausal and postmenopausal years. P433 Unusual pattern of pituitary insufficiencies following traumatic brain injury evaluated by insulin tolerance test P431 Michael Faust1, Julia Wille1, Christina Schumann1, Marcela Lippert- Effect of a six-month treatment with octreotide long acting repeatable Gruener2, Ralf I Ernestus2 & Wilhelm Krone1 (LAR) on mean platelet volume in patients with acromegaly 1Department of Internal Medicine II, University Hospital, Cologne, Reyhan Ersoy1, Kamile Gul1, Ihsan Solaroglu2, Ahmet Dirikoc1, Germany; 2Clinic of Neurosurgery, University Hospital, Cologne, Germany. Cevdet Aydin1, Cigdem Soydal1 & Bekir Cakir1 1Department of Endocrinology and Metabolism, Ankara Ataturk Education and Research Hospital, Ankara, Turkey; 2Department of Neurosurgery, There is growing evidence that pituitary failure is a common complication of Ankara Ataturk Education and Resarch Hospital, Ankara, Turkey. traumatic brain injury. However, prevalence of hypopituitarism following traumatic brain injury varies between 25 and 69% in the literature. Moreover, the pattern of involved hypothalamic/pituitary axes differs considerably in the Objective published trials. This might be due to small and inhomogeneous series of patients Mean platelet volume (MPV), is an indicator of platelet sizes, and an indirect and different test methods in previous studies. The aim of our study was therefore marker of platelet function and activity. In this study, we aimed to evaluate MPV to investigate a large cohort of patients using the gold standard insulin tolerance in patients with acromegaly, and to investigate the effects of octreotide long test (ITT). We included 90 patients at least 12 months after traumatic brain injury acting repeatable (LAR) on MPV after 6-month therapy. aged between 18 and 60 years in our trial. Patients were recruited from an out- Methods patient clinic specialized in neuro-rehabilitation. At baseline, beside physical Data of 25 patients with acromegaly (16 women; 9 men; mean age, 43.8G13.5 examination and routine laboratory testings, endocrine evaluation includes basal years) included in the study were searched retrospectively. The data at diagnosis measurement of LH, FSH, TSH, fT3, fT4, prolactin, IGF-I, testosterone in males of the patient group was compared with a control group of 30 people similar for and estradiol in females. In addition an ITT with intravenous administration of gender, mean age, body mass index, and co-morbid diseases. Eighteen patients of 0.1 IU/kg body weight of regular insulin was performed in each patient. Blood those had been unsuccessfully treated with surgery. samples for measurement of glucose, growth hormone (GH), ACTH and cortisol At the second stage of the study, the values of this patients with active acromegaly were drawn at K15, 0, 30, 45, 60 and 90 min. There was no complication during in postoperative period who receiving octreotide LAR 20–30 mg/month for at any test although all patients achieved adequate hypoglycemia. The prevalence of least 6 months for secondary treatment, were compared to the data of the control pituitary insufficiency is summarized in the following Table: group and control values at 6th month of the therapy. Results Total cholesterol, LDL-cholesterol, triglyceride and fibrinogen levels were Pituitary failure Diagnosed Substituted higher, while HDL-cholesterol levels were lower in patients than in controls. As a marker of platelet functions, when MPVs were compared, no significant ACTH-deficiency 35 (39%) 23 GH-deficiency 11 (12.2%) 8 difference was detected between patients with acromegaly and control group TSH-deficiency 2 (2.2%) 1 (8.90G1.48 vs 8.81G1.26, PO0.05). After 6 months of treatment with octreotide Hypogonadotropic hypogonadism 4 (4.4%) 3 LAR in 18 patients with acromegaly, a decrease in GH, IGF-1, LDL-cholesterol, Any pituitary failure 47 (52%) 35 triglyceride and fibrinogen levels were observed. Also, involution rate in MPV (8.93G1.25 vs 8,49G1.21, P!0.05) were found statistically significant. We conclude that an ITT is a safe diagnostic tool in patients after traumatic brain Conclusion injury. In 52% of these patients at least one pituitary axis deficiency was newly In this study, the first data about the effects of the disease and octreotide LAR, a diagnosed. In contrast to previous studies, the predominant pituitary failure was long-acting somatostatin analogue, on MPV were presented. MPV is not affected an ACTH-deficiency followed by GH insufficiency. in acromegaly patients, however, a decrease in MPV is observed following We conclude that an ITT is also a safe diagnostic tool in patients after traumatic treatment with octreotide LAR. brain injury. In 52% of these patients at least one pituitary axis deficiency was newly diagnosed. In contrast to previous studies, the predominant pituitary failure was an ACTH-deficiency.
P432 GHRH as a possible allosteric ligand of the ghrelin receptor GHS-R1a Marcos C Carreira, Jesus P Camin˜a, Mary Lage & Felipe F Casanueva P434 CIBER Fisiopatologı´a de la Obesidad y Nutricio´n (CB06/03), Instituto de Salud Carlos III. A´ rea de Investigacio´n, Complejo Hospitalario Universi- Hypopituitarism and features of the metabolic syndrome in patients with traumatic brain injury (TBI) tario de Santiago, Universidade de Santiago de Compostela, Santiago de 1 2 2 3 Compostela, Spain. Flavia Prodam , Valentina Gasco , Silvia Rovere , Claudio Perino , Graziella Golisano1, Arianna Busti1, Sara Belcastro1, Ginevra Corneli1 & Gianluca Aimaretti1 Ghrelin and GHRH are two hormones involved in the growth hormone (GH) 1Division of Endocrinology, Department of Clinical and Experimental secretion through their respective receptors. The growth hormone secretagogue Medicine, University of Piemonte Orientale, Novara, Italy; 2Division of receptor subtype 1a (GHS-R1a) is involved in biological actions exerted by Endocrinology, Department of Internal Medicine, University of Turin, 3 ghrelin triggering intracellular second messengers coupled to Gaq/11 protein. Turin, Italy; Don Gnocchi Rehabilitation Institute, Turin, Italy.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Objective P436 Hypopituitarism in adults may be a consequence of TBI, but in the acute or long Prolactin levels in patients with cirrhosis increase with severity of liver term management of TBI patients (ptx), endocrine evaluations are not usually disease included. Aim of this study was to investigate the prevalence of hypopituitarism Juraj Payer, Tomas Koller, Lahim Baqi & Jana Kollerova and metabolic syndrome in a population of 54 severe (nZ31) and moderate 5th Department of Internal Medicine, Faculty Hospital In Bratislava, (nZ23) TBI ptx (38 M, 16 F; age (meanGS.D.): 39.8G2.1 years) who had TBI Bratislava, Slovakia. more than 12 months before. Subjects and methods The ptx were studied in a multidisciplinary team with rehabilitation doctors, Background neurologists and endocrinologists. The whole ptx population underwent: Pituitary prolactin secretion is physiologically supressed by dopaminergic tonus (1) a basal evaluation of the hypothalamic–pituitary unit; (2) the dynamic from hypothalamus, which itself is under regulation by various hypothalamic evaluation of the GH/IGF-I axis through the GHRHCArginine test; (3) blood releasing factors. We Disturbed dopaminergic tonus in patients with liver glucose/insuline levels (HOMA index), and lipid profile; (4) anthropometric cirrhosis is suspected. evaluations. The aim of our study was to measure prolactin levels in patients with cirrhosis and Results to investigate the relatioship between the severity of liver disease and other The 27.7% ptx showed various degrees of hypopituitarism. In particular, 9.25% clinical and laboratory parameters with prolactin levels. had total, 7.4% multiple and 9.25% isolated hypopituitarism. Severe GH Patients and methods deficiency was present in 22.2% ptx, secondary hypogonadism, hypothyroidism, We investigated 114 consecutive patients (74 men, 40 women) with cirrhosis. The hypocortisolism and diabetes insipidus was present in 16.6, 12.9, 12.9 and 5.5%, diagnosis of cirrhosis was based on clinical and biochemical evidence and the respectively. In non-hypopituitaric ptx (39/54), features of the metabolic presence of esophageal varices and/or ascites with albumin gradientO11 g/l. syndrome were present as visceral obesity in 35.8% ptx, dyslipidemia in 10.2% Recorded variables were the routine clinical, biochemical and blood parameters, ptx, hypertension in 7.6% ptx and impairment in glucose/insulin metabolism in prognostic indices (Child-Pugh, MELD, variceal bleeding, portal hypertension 33.3% ptx. If we consider only hypopituitaric ptx (15/54), features of the stage) and insulin and prolactin levels. metabolic syndrome were present as visceral obesity in 60% ptx, dyslipidemia in Results 40% ptx, hypertension in 13.3% ptx and impairment in glucose/insulin Mean age was 57 (95% CI 54.98–59.08), cirrhosis was in 77.2%, 14%, 7.8% metabolism in 33.3% ptx. In all, 5/54 ptx had metabolic syndrome and 4/5 alcohol induced, cryptogenic and viral respectively. Mean Child-Pugh score was were hypopituitaric. 8.0 (95% CI 7.68–8.48), MELD score 11.4 (95% CI 10.05–12.73), 29% (95% CI Conclusions 21.1–38.4%) of patients had history of variceal bleeding. Mean prolactin levels Hypopituitarism and features of the metabolic syndrome are commonly were 14.79 (95% CI 13.12–16.45) mg/l. Patients with hepatic encefalopathy diagnosed in TBI ptx. Hypopituitarism per se worsen the metabolic condition comparing to patients without encefalopathy had significantly higer levels of of TBI ptx, suggesting particular care of these clinical aspects in the rehabilitation prolactin 19.41 vs 13.93 mg/l, PZ0.017. Prolactin levels were also significantly period after severe or moderate TBI. related to ascites degree, mean prolactin levels were 11.97 vs 15.56 vs 19.99 mg/l in patients with 1st, 2nd, 3rd degree of ascites respectively. In regression analysis prolactin levels were significantly dependent on Child-Pugh score (PZ0.016) or Meld score (PZ0.033). We found no impact of portal hypertension stage, gender nor etiology of cirrhosis on prolactin levels. Conclusions Prolactin levels increase significantly with severity of liver disease particularly in patients with ascites and hepatic encefalopathy. High prolactin level could therefore be considered as a negative prognostic marker of liver cirrhosis.
P435 Lymphocytic infundibulo-neurohypophysitis with diabetes insipidus and favorable evolution after glucocorticoid treatment 1 2 2 Maria-Christina Ungureanu , Ioana Luca , Mihai Grigoras , P437 Carmen Gorduza2, Carmen Vulpoi1 & Eusecie Zbranca1 1University of Medicine, Iasi, Romania; 2St Spiridon Hospital, Iasi, Pituitary dysfunction in patients after stroke Romania. Sandra Boehncke1,2, Kathrin Fischer1,2, Klaus Badenhoop1,2 & Matthias Sitzer1,2 1Department of Internal Medicine 1, Johann Wolfgang Goethe University Infundibulohypophysitis is an unusual inflammatory condition that affects Hospital, Frankfurt/M., Germany; 2Department of Neurology, Johann the infundibulum, the pituitary stalk and the neurohypophisis and may be a Wolfgang Goethe University Hospital, Frankfurt/M., Germany. part of a range that includes lymphocityc hypophysitis. It occurs mainly in women and most often presents in later stages of pregnancy. Infundibilo- hypophysitis usually presents with diabetes insipidus. The case of a 30-year- Hypopituitarism is a known complication of traumatic brain injury and old woman with diabetus insipidus diagnosticated in the third trimester of subarachnoidal bleeding. There are few data about pituitary dysfunction as a the pregnancy is reported. She was still taking synthetic ADH 3 years after complication of cerebral ischemia. This study aimed to investigate this issue. We delivery. Evaluated in our service we found a polydipsia-polyuria syndrome investigated the prevalence of pituitary dysfunction in patients with cerebral (10 liters without treatment, urine density 1002), that does not respond to ischemia (a. cerebri media: nZ19, thalamus: nZ4 multiinfarction syndrome: water deprivation test and respond to ADH administration. Sarcoidosis was nZ17) NIHSS varied between 1–8. 40 patients, 23 males and 17 females, (mean age excluded but the antecedents of tuberculosis and uncertain tuberculin test f: 60 years; m: 62.5 years; range 26–81 years) with a stroke 12–34 weeks prior to the did not exclude a cerebral tuberculosis lesion and the diagnostic was kept in study (median 20.5 weeks) underwent clinical examination, basal and combined mind. Magnetic resonance imaging in these patient reveal thickening of the releasing hormone testing (CRH, GHRH, LHRH) of the pituitary gland, including pituitary stalk, loss of hyperintense signal of the posterior pituitary and an TSH, free T4/T3, testosterone (males), estradiol (females), LH, FSH, cortisol, adenohypophysis of normal size. After three month of corticotherapy ACTH, GH, IGF 1, IGF-BP3 and depression testing. Growth hormone deficiency (beginning with Prednisone 100 mg/day, 2 weeks with progressive lowering (GHD) was defined as a GH response !6 ng/ml to GHRH. Secondary adrenal of the dose) the polyuro-polydipsic syndrome without treatment regress at insufficiency was defined as cortisol response !18.1 mg/dl to CRH. Pituitary 70 000 ml/day, the necessary dose of synthetic ADH dose decrease at deficiency was found in 67.5% (27/40) of the patients, 24 with one dysfunctional axis 0.2 mg/day and the IRM imagining reveals a half reduction of pituitary stalk and 3 with 2–3 dysfunctional axes. 26/37 (70.3%) had GHD (13!65 years, 13O65 in all diameters. No reactivation of tuberculosis was noted after corticoids. years). 2/40 (1 male, 1 female) had secondary hypogonadism (total testosterone Conclusions !241 ng/dl and estradiol !30 pg/ml and low gonadotropins). 5/40 patients had Diabetes insipidus with enlargement of pituitary stalk, with favorable evolution corticotrope insufficiency (2 complete, 3 stress insufficiency) and none had TSH- after glucocorticoid treatment is suggestive for infundibulohypophysitis; many deficiency. HADS testing was highly positive (O10) for depression in 24/40 (60%) of so called, ‘idiopathic DI’ in the past have probably autoimmune ethyology. and positive (8–10) in 5/40 (12.5%) patients. In summary we found pituitary For diagnosis a suggestive IRM imagingGpituitary biopsyGvasopressin-cell dysfunction in 67.5% of patients with predominantly GHD (in 13 patients maybe due antibodies are necessary. A prolonged follow-up of these patients is mandatory to age). These findings strongly suggest that patients who suffer from stroke should since other autoimmune diseases can occur later. routinely undergo pituitary testing.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P438 Introduction The activity of the somatotropic system displays a secretory maximum during early sleep which is also a period known to be important for memory consolidation. Blocking of the sleep-onset associated GH-surge by somatostatin did not affect memory performance but the contribution of growth hormone- releasing hormone (GHRH) to memory processes is unclear. Here we assessed the influence of intranasal GHRH on memory function in waking subjects during the Abstract withdrawn early part of the night. Methods Fifteen young and healthy men (mean age 23.5 years) were investigated while staying awake throughout the night. At 21.30 hours subjects received 600 mg GHRH or placebo (saline solution) by the intranasal route in a double-blind experiment. Declarative and procedural memory was examined with a word pair learning task and finger tapping, respectively. Mood and sleepiness were P439 measured by questionnaire (MDBF, Stanford sleepiness scale). Also hunger and A comparison between three automated chemiluminescence assays for thirst were monitored by a self-rating scale. Blood for determination of growth growth hormone: on the use of recombinant hGH as a primary hormone, cortisol, ACTH, insulin and blood glucose were collected in close calibrant intervals. Ayman M Arafat1, Matthias Mo¨hlig1, Martin O Weickert1, Frank Results H Perschel2, Johannes Purschwitz1, Joachim Spranger1, Christian GHRH in comparison with placebo did not improve memory consolidation as G J Strasburger3, Christof Scho¨fl4 & Andreas FH Pfeiffer1 expressed as difference (mean SEM) of recall performance between learning 1Department of Endocrinology, Diabetes and Nutrition, Charite´-University before substance administration (20.30 hours) and in the morning after having G Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany; 2Depart- spent the night awake (09.00 hours): word pairs: GHRH 72.3 4.1%; placebo G G G ment of Clinical Chemistry and Pathobiochemistry, Charite´-University 81.3 6.4%; finger tapping: GHRH: 105.9 4.7%, placebo: 99.2 4.9%. Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany; 3Depart- Conclusion ment of Clinical Endocrinology, Charite´-University Medicine Berlin, Memory consolidation during the early part of the night is not facilitated by the Campus Mitte, Berlin, Germany; 4Division of Neuroendocrinology, sleep associated peak activity of the somatotropic system which typically Department of Neurosurgery, Friedrich-Alexander-University Erlangen- parallels this period. Nuremberg, Erlangen, Germany.
Objectives GH measurements during OGTT have profound effects on therapy and follow-up management of acromegaly. To minimize the discordance between immunoas- says, it is recommended to calibrate them using 22 kDa-GH-preparation instead of the use of pituitary-derived calibrants. The aim of our study was to evaluate the between-method discrepancies in GH determinations by assays using different P441 calibrants considering further confounders like age, gender, and BMI. Cardiovascular risk profile in 81 acromegalic patients: a cross-sectional Methods clinical study GH was measured during a 75-g OGTT in 21 acromegaly patients (9 controlled; 6 Christina Dimopoulou1, Caroline Sievers1, Harald Schneider1, 2 men; age 34–63 years; BMI 25.8G0.7 kg/m ) and in 207 apparently healthy Josefine Ro¨mmler2, Jochen Schopohl2 &Gu¨nter Karl Stalla1 subjects (64 men; age 20–76; BMI 30G0.5) using three Chemiluminescence- 1Max Planck Institute of Psychiatry, Munich, Germany; 2Department of nd assays. Immulite2000 and Nichols were calibrated against NIBSC2 IS98/574 for Medicine (Innenstadt), Ludwig-Maximilians-University, Munich, Germany. hGH, whereas LIAISON used recombinant-hGH as a primary calibrant. The Nichols-assay was re-calibrated using rhGH-preparation. Results Objectives The results obtained with all assays were strongly correlated in both acromegaly Acromegaly is associated with elevated cardiovascular morbidity. Medical patients and controls (rZ0.96 and 0.99, respectively; P!0.001). The results treatment of acromegaly does not only lead to a normalisation of the somatotroph obtained with Immulite2000 were 2-fold higher than those obtained with axis, but can also negatively influence cardiovascular risk factors and LIAISON and Nichols; the readings of the two latter methods were in good comorbidities. agreement. In controls, nadir GH concentrations were (95% percentile) 0.25, 0.41 Methods and 0.2 for LIAISON, Immulite2000 and Nichols, respectively. Using cut-off In a cross-sectional study, we evaluated cardiovascular risk markers (glucose, limits of 0.5 mg/l (LIAISON) and 1 mg/l (Immulite2000) identified 92–100% of HbA1c, triglycerides, cholesterol, HDL, LDL, lipoprotein a, homocystein, CRP) patients with active disease and 67% of patients in remission. in relation to biochemical control and medical treatment modalities in 81 Both basal and nadir GH levels were significantly higher in females than in males acromegalic patients treated at the Endocrine Outpatient Clinic of the Max Planck (LIAISON: 1.3G0.17 vs. 0.46G0.1 mg/l and 0.13G0.01 vs. 0.1G0.02 mg/l, Institute of Psychiatry and the Department of Medicine (Innenstadt) of the P!0.001, respectively). Ludwig-Maximilians-University in Munich. In multiple regression analysis age, BMI and gender were independent predictors Results for both the basal and the nadir GH levels (standardized b: K0.2, K0.3 and 0.2, Biochemically controlled acromegalics (nZ47), compared to uncontrolled respectively). patients (nZ34), had significantly elevated total (Mean 222.2G35.1 vs. Conclusions 200.6G41.2 mg/dl; PZ0.033) and LDL cholesterol levels (Mean 146.6G32.4 Post-glucose GH-nadir values are assay-, gender-, age-, and BMI-specific. The vs. 124.4G40.8 mg/dl; PZ0.041) and lower homocystein levels (Mean use of rhGH as a primary calibrant is advisable to reduce the between-assay 11.7G4.0 vs. 14.3G6.8 mmol/l; PZ0.005), but no differences in glucose, differences in GH measurements. HbA1c, HDL, triglycerides, lipoprotein a, and CRP. IGF-1 correlated positively with HbA1c (PZ0.029), and GH nadir OGTT correlated positively with HbA1c (PZ0.040), triglycerides (PZ0.047), and lipoprotein a (PZ0.016), but not with glucose, CRP, cholesterol, HDL, LDL or homocystein. Somatostatin analogue (SA, nZ27) treatment in acromegalic patients was associated with lower total (Mean 192.8G30 vs. 219.0G40.2 mg/dl; PZ0.016) and LDL cholesterol (Mean 119.3G25.6 vs. 143.4G38.7 mg/dl; PZ0.016), but with elevated glucose (Mean P440 104.7G15.9 vs. 91.4G16.2 mg/dl; PZ0.014) and HbA1c levels (Mean 5.9G0.5 vs. 5.6G0.4%; PZ0.018) compared to patients not treated with SA. Finally, the Acute effects of the intranasal administration of growth hormone- pegvisomant treated group (nZ10) had lower HbA1c levels compared to releasing hormone (GHRH) on nocturnal memory consolidation in otherwise treated patients (Mean 5.5G0.3 vs. 5.7G0.5%; PZ0.042). waking young men Conclusions 1 1 1 1 Manfred Hallschmid , Ines Wilhelm , Christian Michel , Jan Born , Our results suggest that future treatment decisions should not only target 2 2 Hendrik Lehnert & Boris Perras biochemical control, but a thorough evaluation of long-term consequences on 1 Department of Neuroendocrinology, University of Lu¨beck, Lu¨beck, cardiovascular risks depending on the different acromegalic patient profiles 2 Germany; Department of Medicine I, University of Lu¨beck, Lu¨beck, should additionally guide the treatment algorithm. Germany.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P442 1Department of Neuroendocrinology, University of Lu¨beck, Lu¨beck, 2 Diurnal cortisol profile changes in the acute phase after aneurysmal Germany; Department of Medicine I, University of Lu¨beck, Lu¨beck, subarachnoid hemorrhage Germany. Eva Maria Poll, Azize Bostro¨m, Uli Bu¨rgel, Joachim Michael Gilsbach & Ilonka Kreitschmann-Andermahr Introduction University Hospital RWTH Aachen, Aachen, Germany. In elderly humans sleep disturbances are associated with an impaired nocturnal inhibition of the hypothalamo–pituitary–adrenal (HPA) axis and chronic diseases Cortisol dynamics have been found to be disturbed in acute illness. Despite like metabolic syndrome and depression. Recent experiments in young and reports on neuroendocrine disturbances after aneurysmal subarachnoid hemor- healthy subjects demonstrated that intranasal ANP inhibited stimulated cortisol rhage (SAH), data on cortisol dynamics in the acute phase of this illness are secretion during wakefulness whereas administration of intranasal insulin in the lacking. We evaluated diurnal cortisol rhythm in nZ25 patients 1 week (t ) and evening reduced cortisol levels in the morning after undisturbed sleep. 1 Methods 2–3 weeks (t2) after SAH. The study was approved by the local ethics committee. Cortisol and CBG were measured in serum, blood samples were drawn at 08:00, In a double-blind, placebo controlled experiment 19 healthy elderly (mean age 12:00, 16:00 and 20:00. Clinical parameters pertaining to the severity of SAH and 70.8 years, nine women, ten men) were treated in randomized order with clinical outcome were set in relation to the cortisol measurements. intranasal ANP (1 mg) or insulin (160 IU) or placebo (saline solution) at One week after SAH only 5/25 patients had normal diurnal variation of serum 22.30 hours. Sleep was assessed by polysomnography and blood samples were cortisol. 9/25 had no variation at all, 1/25 showed an inversed slope with low drawn in close intervals for determination of cortisol, ACTH and blood glucose. morning and high evening cortisol values. In 10/25 no clear pattern was Furthermore mood and memory as well as caloric intake in the morning after detected. experimental nights were investigated. Two weeks later, three of the initial 5 patients still had normal cortisol rhythms, Results the remaining two changed to an undetectable rhythm. 4 Patients with formerly The cortisol nadir values were lower in subjects treated with ANP or Insulin, but flat rhythms and one patient without a pattern at t had a normal variation at t . differences between experimental groups were statistically not significant 1 2 G G G In sum, 8/25 patients had a normal circadian variation 2–3 weeks after SAH. (mean S.E.M cortisol nadir (mg/dl): placebo: 2.26 0.17; ANP: 1.99 0.21; G The other patients provided no pattern (13/25) or a reversed slope (4/25). When Insulin: 2.10 0.18). No changes of mood, memory and caloric intake were comparing patients with normal slopes with those with no or an altered diurnal detected. Conclusion profile at t1, those with a normal profile had a significantly less severe hemorrhage (Fisher-CT-Score; Man–Whitney U-test, PZ0.042) and a shorter In this sample of healthy elderly our data do not support the hypothesis that intranasal ANP or insulin improves inhibition of nocturnal HPA-activity in aged hospital stay (PZ0.052). The same comparison at t2 showed that patients with normal slopes gained a better outcome measured by the Glasgow Outcome Scale humans. 3–12 months after SAH (PZ0.039). First analyses suggest that a normal diurnal cortisol profile in the acute phase of SAH may be associated with a less severe bleeding and may be a predictor of a better long-term outcome.
P443 P445 Pregnancy in the rat is a physiological state of leptin resistance Long-term treatment with dopamine agonists is not associated with Martha L Trujillo-G, Luz Casas-A & Carlos Die´guez-G increased prevalence of valvular heart disease in patients with prolactinomas Universidad de Santiago de Compostela, Facultad de Medicina, Santiago de 1 2 2 3 Compostela, Spain. Marleen Kars , Victoria Delgado , Eduard Holman , Richard Feelders , Jan Smit1, Hans Romijn1, Jeroen Bax2 & Alberto Pereira1 1Department of Endocrinology and Metabolic Diseases, Leiden University Pregnancy is a state of physiological hyperphagia and represents a good model to Medical Center, Leiden, The Netherlands; 2Department of Cardiology, unravel the mechanisms involved in feeding regulation. The hyperphagia is the Leiden University Medical Center, Leiden, The Netherlands; 3Section of main responsible for the positive energy balance in gestation, which is necessary Endocrinology, Department of Internal Medicine, Erasmus Medical Center, for maintaining maternal energy stores. The presence of high serum leptin levels Rotterdam, The Netherlands. and hyperphagia during pregnancy is a paradoxical event and reflects a state of leptin resistance. In order to evaluate the mechanisms for hypothalamic leptin resistance during pregnancy, we evaluated the response of food intake, Objective hypothalamic neuropeptides, and p-STAT3 levels to leptin administration in Treatment with ergot-derived dopamine agonists, pergolide and cabergoline, has pregnant rats. been associated with an increased frequency of valvular heart disease in Diestrous and pregnant rats (13 and 18 of gestation) were used in this study. Icv Parkinson’s disease. The aim of the present study was to assess the prevalence of and iv cannulae were implanted into third ventricle or in jugular vein respectively, valvular heart disease in patients treated with dopamine agonists for five days before treatments (icv:10 mg/rat, iv:100 mg/rat). Nocturnal food intake prolactinomas. was determined in rats fasted 6 hours before vehicle or leptin treatment. NPY and Design AgRP mRNA levels were determined by in situ hybridization using specific Cross-sectional study. antisense oligodeoxynucleotide probes labeled with 35S. Levels of p-STAT3 were Patients determined by western blot in rats fasted overnight which received iv or icv leptin We performed conventional two-dimensional and Doppler echocardiography in for one hour. 78 consecutive patients with prolactinoma (mean age 47G1.4 years, 26% male, 1) Pregnant rats exhibited a lack of decrease in the nocturnal food intake after icv 33% macroprolactinoma) treated with dopamine agonists for at least 1 year (mean leptin treatment. 8G0.6 years) and 78 control subjects (matched for age, gender, body surface, and 2) Pregnant rats presented higher levels of NPY and AgRP in the hypothalamus, left ventricular systolic function). Patients were classified according to treatment: but we could not demonstrate a decrease in their levels after leptin treatment. patients treated with ergot-derived dopamine agonists (cabergoline, bromocrip- 3) Administration of leptin iv and icv showed a clear increase in the levels of tine, and terguride) (group 1: nZ57), and patients treated with non-ergot derived p-STAT3 in control rats but not in pregnant rats. dopamine agonist (quinagolide) or other treatment modalities than dopamine All this indicates that a reduction in leptin signalling in the hyphothalamus likely agonists (group 2: nZ21). contributes to the leptin resistance mechanism during pregnancy. Results Clinically relevant valvular heart disease was present in 12% (9 of 78) of patients vs. 17% (13 of 78) of controls (PZ0.141), and in 14% (8 of 57) of patients treated with ergot-derived dopamine agonists vs. 5% (1 of 21) of patients treated with non-ergot derived dopamine agonists or no dopamine agonist (PZ0.483). Mild P444 regurgitation of the tricuspid valve was significantly more present in patients compared to controls (41% vs. 26%, PZ0.042). Effects of intranasal atrial natriutetic peptide (ANP) and insulin on Conclusion sleep-associated pituitary–adrenal inhibition in elderly humans Long-term dopamine agonist therapy in patients with prolactinoma is not 1 1 2 Manfred Hallschmid , Christian Bendict , Sophie Spielmann , associated with increased prevalence of clinically relevant valvular heart disease. Rick Schicke2, Werner Kern2, Jan Born1 & Hendrik Lehnert2
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P446 threshold of 7.5 ng/dl; none of the controls showed a GH peak less than 7.5 ng/dl. IGF-1 was significantly lower in the HIV-infected patients with a GH peak Expansion of grey and white matter volumes and increased white ! O matter gliosis in acromegaly: a clinicoradiological study of 43 patients 7.5 ng/dl than in patients with a GH peak 7.5 ng/dl and healthy females. 1 ¨ 1 1 1 Total lean body mass was the most significant predictive factor for GH peak after Caroline Sievers , Philipp Samann , Tatjana Dose , Michael Czisch , C 2Z 1 1 ¨ 2 GHRH Arg (r 0.13), followed by age in the HIV-infected females, while age Christina Dimopoulou , Harald Schneider , Josefine Rommler , 2Z Jochen Schopohl2 &Gu¨nter Karl Stalla1 was the only predictive factor (r 0.46) in the controls. 1Max-Planck-Institute of Psychiatry, Munich, Germany; 2Department of Conclusions Medicine (Innenstadt), Ludwig-Maximilians-University, Munich, Germany. The study suggests that relative GH deficiency is common among females with HARS if compared with matched controls, even when the most restrictive thresholds are used. The lack of correlations among GH peak, parameters of fat Background distribution and low serum IGF-1 in HIV patients suggests that impaired GH In acromegaly, few in vivo data exist on changes of the brain parenchyma as a secretion may be not related to fat redistribution. Anyhow, these results do not pathology caused by systemically elevated levels of GH and IGF-1. This is in permit to establish definitively whether females with HARS and with impaired contrast to neuropsychiatric symptoms such as depression, cognitive impairment, GH response to GHRHCArg are truly or functionally GH deficient. personality changes and pain syndromes that accompany the condition. We aimed at measuring brain tissue volumes and white matter pathology in acromegaly. Methods Forty-three patients (age 54G14 years, 54% female, age at diagnosis 46.9G14 years) and age/gender matched, neuropsychiatrically healthy controls (medical comorbidities tolerated) underwent high resolution clinical MRI. Total volumes of grey matter (GM), white matter (WM) and cerebrospinal fluid (CSF) were calculated using SPM5. Raw volumes and volumes normalized to total inracranial P448 volume were compared. Focal white matter lesions (WMLs, mainly reflecting Glucose infusion affects memory function but not ACTH concentrations gliosis) were rated on fluid attenuated inversion recovery (FLAIR) and in patients with Addison’s disease T2-weighted images, employing a classification into grades 0: no WMLs, I: Johanna Kuehn1, Christian Hubold1, Cecilia Loeck1, Kerstin M Oltmanns2 O 1–5, II: 6–20, III: 21–40, IV: 40 WMLs. & Achim Peters1 Results 1Department of Internal Medicine I, Luebeck, Germany; 2Department of G G Z Patients showed larger absolute (627 79 vs. 604 85 ml, P 0.076) and Psychiatry and Psychotherapy, Luebeck, Germany. normalized GM volumes (42.1G2.9% vs. 41.5G3.1%, PZ0.099) and WM volumes (460G64 vs. 435G61 ml, PZ0.090), and 30.8G29.8%, PZ0.043). Absolute and relative CSF was decreased in patients (403G74 vs. 416G70 ml, Background PZ0.029; 27.1G4.2% vs. 28.7G4.5%, PZ0.018). The proportion of patients Sucrose intake has been shown to normalize the disturbed neuroendocrine stress with intact WM was lower (18.6% vs. 39.5%, PZ0.028) with most prominent response in adrenalectomized rats. These previous data indicate a compensatory shifts to WML grade I changes (44.2% vs. 30.2%). effect of energy supply on altered parameters in chronic cortisol deficiency. Thus, Discussion we hypothesized that glucose infusion may have similar beneficial effects in We provide evidence of increased GM and WM volumes at the expense of CSF in patients with Addison’s disease. acromegaly. These changes may relate to the chronic exposure to GH and IGF-1 Methods and its trophic effects. The reported WM pathology likely reflects the increased We examined 10 patients with primary adrenal insufficiency who discontinued prevalence of vascular and metabolic comorbidities. These changes might their hydrocortisone substitution and 10 matched healthy controls in two contribute to an altered pattern of neuropsychiatric comorbidities in this patient randomized conditions. Subjects received either an intravenous glucose group. application (0.75 g glucose/kg for 2.5 h) or a sodium chloride infusion. We assessed parameters of cognitive function (short-term memory, selective attention) as well as symptom scores and measured concentrations of the relevant hormones in this context (ACTH, cortisol, catecholamines, GH, glucagon). Results In the Addison group, recall of emotional words was enhanced by glucose infusion, whereas recall of neutral words was impaired. Glucose infusion did not influence word recall in the control group. Selective attention and symptom scores P447 were not affected by glucose infusion as compared to placebo, but selective C attention was generally lower in patients than in controls under both conditions. GH response to GH-releasing hormone–arginine (GHRH Arg) is Concentrations of ACTH, cortisol, GH, and glucagon showed no significant impaired in women affected by human immunodeficiency virus (HIV)- difference between conditions in both groups. related lipodystrophy Conclusion Vincenzo Rochira1, Lucia Zirilli1, Gabriella Orlando2, Sara Scaltriti1, 2 1 2 1 Our data do not confirm a compensating effect of glucose infusion on Nicola Squillace , Chiara Diazzi , Roberto Esposito , Cesare Carani neuroendocrine parameters in chronic cortisol deficiency in humans. However, & Giovanni Guaraldi1 1 glucose affected short-term memory in a differential way with improvements in Chair of Endocrinology, Integrated Department of Medicine, Endo- the emotional task while neutral memory was impaired. Since emotional memory crinology, Metabolism and Geriatrics, University of Modena and Reggio 2 is primarily amygdala-dependent while neutral memory processing is rather Emilia, Modena, Italy; Clinics of Infective Diseases, Department of assigned to the hippocampus, one could speculate that glucose application may Medicine and Medical Specialties, University of Modena and Reggio cause differential effects on these brain areas in patients with Addison’s disease. Emilia, Modena, Italy.
Context Lipodystrophic HIV patients frequently display impaired pituitary GH response. Objective. To investigate the GH response to GHRHCArg in women with HIV- related lipodystrophy (HARS) compared with healthy females. To identify possible predictive factors for such a GH response in these patients. P449 Patients Prevalence of metabolic syndrome in adult hypopituitaric patients with Forty-nine female patients with HARS were compared with 10 healthy women GH deficiency (GHD) matched for age and BMI. Carolina Di Somma, Francesca Rota, Antonella Tufano, Francesca Rota, Methods C Dario Nicola Di Minno, Marianna D’Andrea & Gaetano Lombardi Patients and controls underwent a standard GHRH Arg test; demographics, Department of Molecular and Clinical Endocrinology and Oncology, anthropometric, metabolic and hormonal variables were evaluated. Basal serum Naples, Italy. GH, IGF-1, IGFBP-3, glycaemic-lipid profile, GH after GHRHCArg and HIV disease characteristics were assessed. Body composition was evaluated by DXA in patients and controls, abdominal CT scan being performed only in the HIV The prevalence of the metabolic syndrome is increasing worldwide. The untreated patients. metabolic syndrome places individuals at risk both for diabetes and Results cardiovascular disease. Adult GH deficiency syndrome present some of the 5 Using cut-offs of 4.2 and 5 ng/ml, 6.12% of the HIV-infected patients failed to features of the metabolic syndrome, abdominal obesity, high triglycerides, low reach GH peaks above these values, the percentage increasing to 22.44% with a HDL-cholesterol, elevations of blood glucose, hypertension and a 2-fold higher
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 risk of death for CD compared with controls. The aim of this study was to University Medical Faculty, Kahramanmaras, Turkey; 3Department of determine the prevalence of metabolic syndrome among adult hypopituitaric Cardiology, Sutcu Imam University Medical Faculty, Kahramanmaras, patients with GHD. Follow-up was undertaken of 100 GHD hypopituitaric adult Turkey. patients. Testing included fasting insulin, glucose, lipids and GHRHCARG test and IGF-I. The results were compared with population norms from 1990–2000 of Osservatorio Epidemiologico Cardiovascolare (OEC) data. The patient and Introduction control age range was 35–74 years. The prevalence of metabolic syndrome was Hemochromatosis is an iron storage disease characterized by iron deposition in significantly higher in patients than in population controls (35% vs. 23%, c2Z parenchymal cells due to increased intestinal iron absorption. Iron overload leads 7.35; PZ0.007). In particular hypertension was found in 41% of patients and in to tissue damage and dysfunction particularly in the liver, pancreas, heart, joints, 32% of controls (P!0.05), hyperglycaemia in 14% of patients and 7.5% of and pituitary gland. Panhypopituitarism is a clinical condition in which the controls (PZ0.02) and hypertrygliceridemia in 52% of patients and 23.6% of anterior pituitary gland hormones are deficient. Herein we report a very rare case controls (PZ0.000). of panhypopituitarism due to hemochromatosis. In conclusion, adult GHD hypopituitaryc patients have a higher prevalence of Case metabolic syndrome when compared to normal populations. Thus, these patients Sixty-two year old woman was admitted to a medical center because of should be carefully monitored for cardiovascular and diabetes risk profiles. hematemesis 6 years ago. An upper gastrointestinal Endoscopy revealed the Whether GH replacement therapy could reduce this risk remains to be established. presence of esophageal varices. Laboratory findings showed positive antibodies to HCV. 1.5 years ago performed liver biopsy established the presence of micronodular cirrhosis with accumulation of hemosiderin. Laboratory findings were as follows iron binding capacity: 120 mg/dl; Fe: 127 mg/dl; Ferritin: 581 ng/ml. Abdominal ultrasonography showed chronic liver parenchymal disease, splenomegaly (15.5 cm) and cholelitiazis. She hospitalized to the intensive care unit with the diagnosis of chronical liver parenchymal disease and P450 hepatic encephalopathy, and therapy started. Her thyroidal function tests were as follows f-T4: 0.396 pg/ml, f-T3: !1 pg/ml, TSH: 0.795 IU/ml. We analysed The benefit of long-term growth hormone replacement therapy in other hypophysary hormon tests because we thought hypophysary involvement adults, results of the German KIMS database due to hemochromatosis. The values were LH: 1.12 IU/ml, FSH: 2.77 IU/ml, GH: Christin Albrecht1, Michael Buchfelder2, Walter Faßbender3, !0.05 ng/ml, prolactin: 0.657 ng/ml, cortisol: 3.54 mg/dl. We performed ACTH Michael Faust4, Peter Kann5, Ilonka Kreitschmann-Andermahr6, stimulation test for hypophysary insufficiency (Synacten 1 mg IV). In 0 min Thomas Kohlmann7, Maria Kołtowska-Ha¨ggstro¨m8 & Henri Wallaschofski9 cortisol level was 3.54 mg/dl, 30 min 20 mg/dl and 1 h 10 mg/dl. Therefore, we 1Department of Gastroenterology, University of Greifswald, Endocrinology excluded primary adrenal insufficiency. The contrast hypophysary computerized and Nutrition, Greifswald, Germany; 2Department of Neurosurgery, tomography was normal. So we diagnosed the patient as panhypopituitarism. We University of Erlangen, Erlangen, Germany; 3Department of Internal administered prednisolon 40 mg initially and levothyroxin on the fifth day. She Medicine, Kempten, Germany; 4Department of Endocrinology, University recovered with this therapy and discharged with prednisolone 7.5 mg/d. and of Ko¨ln, Ko¨ln, Germany; 5Department of Endocrinology, University of levothyroxin 0.1 mg/d. Marburg, Marburg, Germany; 6Department of Neurosurgery, University of Discussion Aachen, Aachen, Germany; 7Community Medicine, University of Hemochromatosis may rarely cause panhypopituitarism by accumulation of Greifswald, Greifswald, Germany; 8KIMS Medical Outcomes, Pfizer hemosiderin. The clinician must be careful when a problem about conscious Endocrine Care, Department of Pharmacy, Uppsala University, Sollentuna, occurs in patients with cirrhosis due to hemochromatosis. Hepatic encephalo- Uppsala, Sweden; 9Department of Gastroenterology, Endocrinology and pathy may confuse with panhypopituitarism. The differential diagnosis should be Nutrition, University of Greifswald, Greifswald, Germany. made otherwise the treatment might be delayed. In conclusion, the patients with hemochromatosis who have cirrhosis should be assessed about pituitary Objective involvement. The German KIMS Database is a national surveillance study for evaluation of efficacy and safety of growth hormone (GH) replacement therapy in adults with GH deficiency (GHD) in clinical practice. Patients The analysis was performed using data of 1425 consecutively documented adult patients (777 men, 648 women) with GHD enrolled in KIMS Germany. The P452 present report examined baseline and long term data (O48 months, range: 48–161 Pituitary autoantibodies in patients with central diabetes insipidus and month) from a subset of 780 of these patients (420 men, 360 women) with GH polydipsia: evidence of autoimmune pituitary involvement in both deficiency aged 20–75 (median 44) years. Patients have been assigned to sex and states age-related groups (20–39, 40–59 and 60–79 years). Patients were examined for Ekaterina Pigarova, Ludmila Rozhinskaya, Larisa Dzeranova, Yulia Keda, serum IGF-1, blood glucose and lipid profile at baseline and at last visit. Maria Morozova & Yurii Pankov Furthermore QoL-AGHDA score has been determined for quality of live Research Centre for Endocrinology, Moscow, Russian Federation. assessment. Most of the patients required additional pituitary replacement and were on optimal doses at recruitment. Results A role of autoimmune aggression is postulated in the pathogenesis of different The IGF-1 and IGF-1 SDS-levels increased in all groups significantly (P!0.001). diseases in endocrinology. Forty to sixty percent of cases of central diabetes After GH therapy serum total cholesterol and low-density lipoprotein (LDL) insipidus (CDI) are considered to be idiopathic. Primary polydipsy is a diagnosis decreased in males (D K0.2 mg/dl, P!0.005) and females (D K0.2 mg/dl, of an exclusion of diabetes insipidus on the basis of water deprivation test, but P!0.005) significantly. Blood glucose increased from 4.7 to 4.9 mmol/l sometimes it precedes the overt CDI. Thus the aim of this study was to define the (P!0.01) and in 15 patients the development of diabetes has been observed. prevalence of pituitary autoantibodies in patients with CDI and primary The QoL-AGHDA score improved from 8 to 3 (P!0.001) in all groups polydipsia. significantly. Moreover we detected no influence of seasons on quality of live We studied serum samples from 110 individuals: 61 – with CDI, 16 – with assessment. During the treatment recurrences of pituitary tumors nZ44 (5.6%) or primary polydipsia, as defined by water deprivation test and 32 from control further neoplasia nZ23 (2.9%) have been observed. group matched by sex and age. Among patients with CDI: 36 had idiopathic form Conclusion of the disease, 10 – postoperative, 8 – had tumors of the sellar region, 3 – head Therefore, these observational data showed significant long-term efficacy of adult trauma, 2 – postinfectious, and 2 – due to hystiocytosis X. GH replacement therapy on IGF-1, lipid profile as well as quality of life. We used solid-phase immunoenzyme assay and human hypophyses for evaluation of autoantibodies (membrane and cytosol fraction). Results showed high prevalence of pituitary autoantibodies in the group of CDI (50.8%) In subgroups being: idiopathic – 61.1% (22), postoperative – 20% (4), tumors – 25% (2), trauma – 2 patients, hystiocytosis – 1 patient, postinfectious – none. Prevalence of pituitary autoantibodies in group of polydipsia was 37.5% (6) Control group P451 revealed 9.3% (3). Panhypopituitarism due to hemochromatosis: a case report Data shown confirms the endowment of autoimmunity in development CDI with Mesut Ozkaya1, Kadir Gisi1, Ali Cetinkaya2, Bulent Kantarceken2, its significant role in idiopathic form of the disease. Our results also indicate Mustafa Cerit1, Murat Sahin2 & Sedat Koroglu3 surprisingly high prevalence of pituitary autoantibodies in group of patients with 1Department of Endocrinology, Sutcu Imam University Medical Faculty, primary polydipsia which may represent the early phase of autoimmune CDI. Kahramanmaras, Turkey; 2Department of Gastroenterology, Sutcu Imam
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P453 moderate overexpression (mainly non-secreting and somatotropinomas) and mut Endocrinopathies with langerhans cell histiocytosis (LCH): nine cases 10% with underexpression, including the 3 AIP cases. AIP protein was Sema Yarman, Meral Mert, Serpil Salman, Refik Tanakol & Faruk Alagol detected in most PA (49/56), with immunostaining generally less intense than in NP (P!0.001). The strongest immunostaining was observed in Department of Internal, Istanbul Faculty of Medicine, Istanbul University, mut Istanbul, Turkey. somatotropinomas, though AIP somatotropinomas had a lower AIP score than other somatotrotropinomas (PZ0.023). Only 2/9 PA from AIPmut patients (1 GH-, 1-PRL-secreting) showed a complete loss of immuno- LCH is a rare proliferative histiocytic disorder, and it can infiltrate virtually staining. any site in the body. Diabetes incipidus (DI) is the most common Conclusion abnormality when there is involvement of the hypothalamic-pituitary axis AIP down-regulation is frequently observed in PA, mostly at a protein level. (HPA). We have evaluated the anterior pituitary function and their responses AIPmut somatotropinomas show AIP down-regulation at both mRNA and to treatment in 9 patients (5M/4F; range 19–60 years) with proven LCH and protein levels, but AIP immunostaining is totally abolished in only a DI. Endocrine evaluations consisted of clinical history, basal (GH, IGF-1, minority of cases. Though promising, further experience is needed to fT4, TSH, PRL, cortisol, LH, FSH, E2, and testosteron levels) and dynamic integrate IHC as a pre-screening tool for AIP mutational studies in patients pituitary function tests, plasma and urine osmolalities/water deprivation test with PA. at the time of diagnosis of DI and thereafter. The mean age at onset of DI was 28 years (15–60). Radiological evaluation included MRI of the HPA region. Three patients with infundibular and one patient with thalamic involvement were treated with local radiotherapy (RT). Chemotherapy and local (bone) RT combination had been given to 3 patients with bone lesions, and another 2 had been treated with chemotherapy alone. Median follow-up period was 74 month (2–300). On admission, single-organ involvement in one of the patients, and multisystem involvement in the remaining 6 patients were found. In addition to DI, diagnosis of secondary hypogonadism was P455 established in only one patient who had no signs of puberty but normal PRL Systemic comorbidities induce early vascular alterations in patients level. Another one had also secondary hypothyroidism, hypocortisolism, and with active acromegaly hypogonadism with thalamic involvement. The other 2 patients did not Francesco Ferrau`, Giovanni Romanello, Stefano Squadrito, Scipione Carerj, suffer from any additional abnormalities concomittant with the initial DI. Carmelo Nipote, Raffaella Iudicello, Francesco Trimarchi & Hyperprolactinemia was found in 3 patients (43%). MRIs showed Salvatore Cannavo` infundibular enlargement (89%), thalamic mass (11%), and the absence of University of Messina, Messina, Italy. the bright spot (100%) on the T1-weighted sequences. One patient had an additional mass in the pons with partially empty sella. Two patients who had received local RT to the pituitary stalk achieved complete radiological Mortality risk is increased in acromegalics, due to cerebrovascular and responses, and gonadotropin deficiency also recovered in one of them. One cardiovascular events. These events are namely related to atherosclerotic vascular patient with pons and another with thalamic involvement died after therapy. alterations, both at coronary and peripheral level. Systemic comorbidities Until now, GH deficiency developed in 5 patients and partial gonadotrophin increase the risk of atherosclerosis, but the role of GH and IGF-1 excess is still deficiency in another patient. Seven patients are currently under regular debated. To evaluate the relationship between GH/IGF-1 excess, systemic follow-up with stable disease, but DI persisted in all patients. As a result, atherogenic complications and vascular alterations we investigated stiffness index DI in LCH was the earliest hormonal deficiency. Localized RT can be (b), pulse wave velocity (PWV) and intima-media thickness (IMT) of right and successfully applied as a single treatment for infundibuler involvement or left common carotids in 11 patients (9F:2M, mean age 52.8G4.2) with active in combination with chemotherapy leads to high remission and local acromegaly complicated by systemic comorbidities (hyperlipidemia, blood control rates. hypertension and/or diabetes mellitus), in 8 healthy subject (HS, 6F:2M, mean age 48.8G3.2) and in 11 non acromegalic patients matched for comorbidities (NP, 7F:4M, mean age 55.7G3.3). To exclude the role of aging in atherosclerosis, patients and healthy subjects were younger than 60 years of age. Acromegalics showed higher b, PWV and IMT than HS (b: 9.2G1.8 vs 5.3G1.7, P 0.0004; PWV: 7.0G0.8 vs 4.8G1.0, P 0.0004; IMT: 0.9G0.2 vs 0.4G0.1, P 0.0001) but not than NP. The b (8.6G1.3 vs 13.1G1.4, P 0.005) and PWN (7.0G1.0 vs 8.5G P454 0.5, P 0.005), but not IMT, were significantly increased in patients with longer duration of acromegaly (%10 years vs O10 years). Serum GH and IGF-1 S.D. Aryl hydrocarbon receptor interacting protein (AIP) expression in values did not correlated with b, PWV and IMT in acromegalics and no human pituitary adenomas differences in these index were found on the basis of number of comorbidities 1 1 3 Marie-Lise Jaffrain-Rea , Cristina Spilioti , Jean-Franc¸ois Vanbellinghen , (acromegalics with 1 comorbidity vs acromegalics with 2 or more comorbities). 4 1 1 Adrian Daly , Donatella Gargano , Emanuela D’Innocenzo , In conclusion, 40–60 years old acromegalic patients are at risk for early 2 4 2 Felice Giangaspero , Maria Tichomirowa , Vincenzo Esposito , atherosclerotic vascular abnormalities more than healthy subjects and systemic 5 6 1 4 Luca Ventura , Luciana Naves , Edoardo Alesse & Albert Beckers comorbidities play a critical role on these alterations. Despite the increase of 1 Department of Experimental Medicine, University of L’Aquila, L’Aquila, atherosclerotic index is not correlated with GH and/or IGF-1 concentrations, early 2 3 Italy; Neuromed Institute, IRCCS, Pozzilli, Italy; Genetics, University of vascular abnormalities are increased in patients with longer duration of the 4 Lie`ge, Lie`ge, Belgium; Endocrinology, University of Lie`ge, Lie`ge, disease. Belgium; 5Pathology, S. Salvatore Hospital, L’Aquila, Italy; 6Endo- crinology, University of Brasilia, Brasilia, Brazil.
Background Germline AIP mutations confer a predisposition to pituitary adenomas (PA), usually in the setting of familial isolated pituitary adenomas (FIPA); AIP mutations account for 50% of familial acromegaly. AIP-related PA are GH, PRL- secreting or non-secreting. Little is known about AIP expression in PA. Although P456 the prevalence is low, identifying AIP mutations in apparently sporadic PA is important for studying at-risk relatives. Pre-screening criteria would help select Use of videocapsule endoscopy (VCE) for the detection of small bowel patients for mutational analysis. tumors in patients with acromegaly Material and methods Francesca Coletti1, Cristina Lucia Ronchi3, Laura Montefusco1, AIP expression was studied by Real Time RT-PCR in 45 PA, including 3 FIPA Edoardo Fesce2, Cristina Ogliari2, Emanuele Ferrante3, Paolo Epaminonda1, acromegaly cases with AIP mutations (AIPmut), and by immunohistochemistry Alessia Dolci1, Guido Adda1, Paolo Beck-Peccoz3 & Maura Arosio1 (IHC) in 56 PA, including 9 AIPmut cases (7 GH, 1 PRL and 1 non-secreting PA). 1Endocrine and Diabetic Unit, Department of Medical Sciences, San AIP immunostaining was scored semi-quantitatively. All PA phenotypes were Giuseppe-MilanoCuore Hospital, University of Milan, Milan, Italy; represented and normal pituitaries (NP) were used as controls. 2Gastroenterology Unit, San Giuseppe-MilanoCuore Hospital, AFaR, Results Milan, Italy; 3Endocrine and Diabetic Unit, Department of Medical AIP transcripts were detected in all cases. Mean transcript levels in PA were Sciences, Fondazione Policlinico, Mangiagalli and Regina Elena Hospital, similar those observed in NP, but variations were observed, with 20% with University of Milan, IRCCS, Milan, Italy.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
A high risk for small bowel (SB) tumors in acromegalic population has been 1Department of Endocrinology, University of Genova, Genova, Italy; reported in a cohort study (Baris D, 2002). SB lesions may be easily 2Division of Cardiology, Department of Internal Medicine, Genova, Italy. investigated by the recently developed videocapsule endoscopy (VCE). Aim of the study was to assess the prevalence of SB neoplasms by VCE in 14 GH deficiency (GHD) negatively influences cardiovascular function directly by acromegalic patients (Ac) in respect to 30 sex and age-matched control impairing cardiac filling, performance, and contractility and indirectly by subjects and to correlate it with cancer risk factors and acromegaly-related inducing atherosclerotic changes, hypercoagulability, abdominal obesity, insulin parameters. Local Ethical committee approved the study. The Ac group (5M resistance, dislipidemia, endothelial dysfunction, etc. This accounts for the and 9F, ageGS.D.: 52G11 years), included 4 patients cured by surgery and 10 reduced life expectancy and increased risk of death for vascular disease in these medically treated (9 by somatostatin and 1 by dopamine agonists, 7 of whom patients. with controlled disease). Cancer risk factors were similar in Ac and controls. CFR represents the capacity of the coronary circulation to dilate following an History of the disease, GH and IGF-I levels, IGF-II and IGF-BP3 levels and increase in myocardial metabolic demands and is considered an endothelial metabolic parameters such as glucose tolerance, insulin resistance and insulin function index. secretion were in addition investigated in Ac. Four gastrointestinal stromal We investigated the cardiac and endothelial function and evaluated coronary nodular tumors (GIST) and 1 polyp of SB were detected in 16% of controls microvascular circulation in a group of adult onset GHD patients during the first and in 29% of Ac (2 GISTs and 2 SB polyps, P: NS). In Ac the calculated year of GH replacement therapy. relative risk for overall SB neoplasms was 1.74 (95% CI: 0.5418–5.424, P: We studied 13 (7 males, 6 females aged 56.43G4.49 years) patients (all NS), and for SB adenomas was 4.28 (95% CI: 0.4230–43.422, P: NS). Ac nonsmokers, non diabetics, without hypertension or vascular disease) with adult- with positive VCE had a significantly longer duration of active disease onset hypopituitarism and GHD before and after 1 year of GH therapy. In these (128.5G107.5 vs 45.0G44.6 months, P!0.05) than Ac with negative VCE, patients CFR, echocardiographic analysis (cardiac mass, systolic and diastolic in spite of a younger age (48G4vs54G13 years, P: NS). No correlation function), IGF-I plasma levels, lipid profile, HbA1c, blood pressure and with control of the disease, the presence of colon cancer and any other anthropometric data were recorded before GH therapy and after 12 months of investigated parameters was found. In conclusions, these preliminary results continuous therapy (mean starting dose 1.2G0.19 mg/week adjusted every 8–10 show that acromegalic patients, mostly those with a long duration of active weeks on the basis of IGF-I response). disease, might have a high risk also for SB tumours development, even if After GH administration a significant improvement of cardiac mass (P!0.02) larger case studies are needed. VCE is a useful adjunctive diagnostic tool in and CFR (from 2.35G0.24 to 2.88G0.25; P!0.02) has been observed; systolic acromegaly. blood pressure decreased significantly (from 135.38G3.51 mmHg to 125.77G 4.04 mmHg; P!0.02) as well as LDL Cholesterol (from 143.25G7.16 mg/dl to 124.51G5.99 mg/dl; P!0.05). Improvement in diastolic filling was also observed. In conclusion these data show that GH therapy improves endothelial and cardiac performance and, therefore, can prevent the progression of the atherosclerotic processes in GHD by reducing these cardiovascular risk P457 factors. Fatigue in breast cancer patients during chemotherapy: correlation with neuromuscular dysfunction and IGF-1 plasma levels Roberto Baldelli1, Alberto Pietrangeli2, Giovanni Cigliana3, Alessandra Fabi4, Francesco Cognetti4, Patrizia Pugliese5 & Marialuisa Appetecchia1 1Unit of Endocrinology, Rome, Italy; 2Division of Neurology, Rome, Italy; 3Laboratory of Clinical Pathology, Rome, Italy; 4Division of Medical Oncology, Rome, Italy; 5Unit of Psychology, Regina Elena Cancer Institute, Rome, Italy. P459 Effect of cholescytokinin (CCK) on food intake and brainstem and hypothalamic neuronal activation and its modulation by glucocorticoid Introduction Henrique Sabino, Ernani Uchoˆa, Rodrigo Rorato, Jose´ Antunes-Rodrigues Adult growth hormone deficiency is associated with fatigue, tiredness and & Lucila Elias myalgias. The same clinical pattern can often be present in oncological patients School of Medicine of Ribeirao Preto-University of Sao Paulo, Ribeirao during chemotherapy and follow up. Preto, Sao Paulo, Brazil. Aim of the study To conduct an extensive neuromuscular investigation of patients with breast cancer (BC), treated with taxol, in an attempt to explain their neuromuscular symptoms, CCK, secreted from duodenal cells in response to nutrients is involved in eleven pre-menopausal patients with BC underwent a prospective protocol, the satiety mechanisms, via activation of nucleus tractus solitarius (NTS). including hormonal examination and a neurophysiological study that comprised The arcuate (ARC) and paraventricular nuclei (PVN), which receives electromyogram (EMG) of sural nerve. All patients were even evaluated for IGF-I projections from NTS, integrate the circuitry that controls food intake. plasma levels at the time of diagnosis of BC and during follow up. Corticotrophin releasing factor (CRF) participates in the energy homeostasis, Results decreasing food intake. Sensory neuromuscular examination showed a progressive derangement of EMG To evaluate the effect of glucocorticoid on feeding and neuronal activation suggestive for a neurogenic demage. A reduction of IGF-1 plasma levels was after CCK treatment, Wistar rats were subjected to Sham surgery, observed from baseline to follow up (P!0.05) where a direct positive correlation adrenalectomy without (ADX) or with corticosterone replacement (ADXC with IGF-I plasma levels was also found (P!0.05). B). Animals fasted (day 6) for 16 h received ip injection of CCK 3.5 mg/kg Conclusion or vehicle for determination of food intake and CRF and Fos The neurophysiological study confirmed the presence of sensory neuropathy of imunohistochemistry. sural nerve that can be a cause of fatigue in our series of patients; the presence of Lower food intake was observed in Sham and ADXCBratsafterCCK, low plasma levels of IGF-1 at follow up and a direct correlation of these data with compared to the respective vehicle-treated groups. However, this hipophagic EMG was suggestive for a possible direct involvement of somatotrope axis in response induced by CCK was not observed in ADX rats. CCK increased explaining, in part, the presence of fatigue in breast cancer patients. FosexpressionintheNTSinSham,ADXandADXCB animals, with no difference among the three CCK-treated groups. We observed a higher number of Fos imunorreactive neurons in the ARC and Fos/CRF neurons in the PVN in ADX group, compared to Sham group, both after vehicle and CCK (P!0.05). We demonstrated that ADX abolishes the hypophagic response induced by CCK, however, NTS neuronal activation was not altered by glucocorticoid deficiency. P458 These data suggest that in the absence of glucocorticoids, other factors Effect of GH replacement on coronary flow reserve (CFR) and on some besides CCK participate in the satiety mechanisms, leading to a decrease of cardiovascular risk factors in adult GHD patients food intake. The increased activation of hypothalamic anorexigenic Mara Boschetti1, Sergio Agosti2, Valeria Albanese1, Laura Casalino2, pathways during fasting, may contribute to the lower food intake observed Lara Vera1, Umberto Goglia1, Gian Paolo Bezante2, Diego Ferone1 with glucocorticoid deficiency. & Francesco Minuto1
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P460 found between patients d3K and d3C. Overall a positive correlation between log Intrasellar and parasellar tumors – concomitant symptoms and clinical GH and IGF-I levels was found, but the relationship was similar in patients syndromes carrying or not carrying copies of the d3 allele. Body mass index (BMI) was significantly lower in d3C than in d3-patients (25.8G2.1 vs 28.1G4.8 kg/m2, Maria Kurowska, Joanna Malicka, Jerzy S Tarach, Agnieszka Zwolak, G Z Marta Dudzinska & Mariusz Kowalczyk mean S.D., P 0.011). In addition, serum glucose and insulin concentrations Department of Endocrinology, Lublin, Poland. measured 2 h after OGTT in a subgroup of patients were also significantly lower in d3C. Finally, a linear regression analysis showed d3-GHR allele to be a significant negative predictor of HbA1c levels (BZK0.8G0.3, PZ0.025). Introduction Conclusions Pituitary gland, sella turcica and parasellar region can be involved by wide variety of This study supports the hypothesis that the d3 polymorphic variant of the GHR is lesions. Diagnosis of this pathology demands a multidisciplinary effort, especially functionally different from the full length variant mostly for the effects on glucose endocrinological, ophthalmologic and neurological procedures. Each of these metabolism and body weight regulation. entities has unique diagnostic and treatment considerations. Aim Review of clinical symptoms related to sellar–parasellar region tumors and documentation of heterogeneity of clinical syndromes accompanying their diagnosis in own material. Material 105 pts (63F; 42M) aged 18–83, observed in 2000–2007 in our department. Method P462 Analysis of clinical picture, hormonal and visual studies. Correlation of IGF-1 and IGFBP-3 levels with liver function in patients Results following traumatic brain injury or subarachnoidal haemorrhage Intrasellar pituitary adenomas composed 85% (89 pts) of the whole group, including Alexandra Mu¨ller-O¨ ffner1, Bodo Gutt1, Martin Bidlingmaier2, 73 macroadenomas (with 1 Nelsons’ syndrome and 3 corticothroph tumors) and 16 Thomas Knittel3, Thorsten Siegmund1 & Petra-Maria Schumm-Draeger1 microadenomas (1 TSH-oma). Among intrasellar tumors of extrapituitary origin 2 1Sta¨dtisches Klinikum Mu¨nchen GmbH, Klinikum Bogenhausen, Klinik fu¨r chordomas and 1 meningioma have been found. Extrasellar tumors comprised Endokrinologie, Diabetologie und Angiologie, Munich, Germany; 2Kli- 14.3% (15 pts) of cases, with 3 craniopharyngiomas, 2 meningiomas, 2 cysts, 1 nikum Innenstadt der Ludwig-Maximilian-Universita¨t, Munich, Germany; germinoma and 3 extremely rare: involving the sella brown tumor, pituitary stalk 3NovoNordisk Pharma GmbH, Mainz, Germany. granular cell tumor and located in sphenoid sinus somatotroph adenoma among them. In four remaining patients pituitary metastases of breast (2 pts), lung (1) and prostate (1) carcinomas have been recognized. In the group of hormonal active The prevalence of growth hormone deficiency (GHD) following traumatic brain pituitary adenomas we found: acromegaly in 21 subjects, prolactinoma in 10, injury (TBI) based on IGF-1 testing differs in literature between 10 and 40%. In Cushing disease in 8 and secondary hyperthyroidism in 1 patient. Among pituitary our cohort the frequency of IGF-1 values !1 S.D. was 25%. If our patients had a adenomas 51.5% were hormonally inactive. Parasellar tumor invasion (cavernous minimal hepatocellular damage, the IGF-1 value could be !1 S.D. We evaluated sinus, suprasellar region, sphenoid sinus) was observed in 78.1%. At least one of the the effects of BMI and liver function on IGF-1 and IGFBP-3 values in patients mass effects (headache, cranial nerves paralysis, epilepsy, deafness, visual defects, following TBI or subarachnoidal haemorrhage (SAH). anosmia, hyperprolactinemia and diabetes insipidus) or pituitary anterior lobe Fifty-eight consecutive patients (27 female, 29 men) of our centre (age 19–78 insufficiency have been found in 40 pts. Clinically evident pituitary apoplexy has years; mean 49 years) following TBI (nZ33) or SAH (nZ23) underwent baseline appeared in 9 subjects. testing for pituitary dysfunction including IGF-1. Liver function tests included Conclusion serum bilirubin (bili), g-glutamyl transpetidase (GGT), aspertat aminotransferase Abundant symptomatology and disturbed pituitary functions caused by sellar– (GOT), alanine aminotransferase (GPT), high sensitive C-reactive protein parasellar tumors require broad knowledge of several allied medical domains. (hsCRP), tumor necrosis factor (TNF) and retinol binding protein (RBP). The level of the main intravascular store of IGF-1, IGFBP-3 was assessed in a reference laboratory. Eight of 58 patients showed IGF-1 !1 S.D. and 8/58 IGFBP-3 !95% reference range. The expected positive correlation of IGF-1 and IGFBP-3 (P!0.0001) was confirmed. HsCRP was significantly negative correlated to IGF-1 (PZ0.0173) and IGFBP-3 (PZ0.0184). Patients with elevated hsCRP levels showed P461 significant lower values of IGF-1 and IGFBP-3. GGT was significantly negative correlated to IGF-1 (PZ0.0372) and RBP was significantly positive correlated to d3-growth hormone receptor polymorphism (d3-GHR) is associated IGFBP-3 (PZ0.0188). Interestingly no correlation of the BMI with IGF-1 with low BMI and better glucose metabolism in acromegaly (PZ0.2152) or IGFBP-3 (PZ0.3476) was detected. Maura Arosio1, Marcello Filopanti2, Laura Montefusco1, Luca Olgiati2, 2 3 2 1 According to our results the liver function influenced secretion of IGF1 and Cristina Lucia Ronchi , Marco Losa , Carmen La Porta , Francesca Coletti , IGFBP-3. Evaluations of IGF-1 levels !1 S.D. as baseline screening for GHD Andrea Lania2, Paolo Beck-Peccoz2 & Anna Spada2 1 had to consider the liver function tests (GGT, RBP and hsCRP) irrespective of Endocrine and Diabetes Unit, Department of Medical Sciences, San the BMI. Giuseppe-Milanocuore Hospital, University of Milan, AFaR, Milan, Italy; 2Endocrine and Diabetes Unit, Department of Medical Sciences, University of Milan, Fondazione Ospedale Maggiore Policlinico, Mangiagalli and Regina Elena, IRCCS, Milan, Italy; 3Neurosurgery Unit, San Raffaele Hospital, Milan, Italy. P463 Identification and molecular characterization of new somatostatin Background receptor subtype 5 truncated isoforms in rodents The d3-growth hormone receptor (GHR) polymorphism is a common variant Jose Cordoba-Chacon1, Raul M Luque1, Manuel D Gahete1, Mario Duran- characterized by genomic deletion of exon 3 (d3) of the GHR gene. It could be Prado1, Francisco Gracia-Navarro1, Rhonda D Kineman2, Maria linked to a better growth response to GH, but the findings are controversial. Due M Malagon1 & Justo P Castan˜o1 to the lack of IGF-I feedback on the tumoral GH secretion, acromegaly seems to 1Department of Cell Biology, Physiology and Immunology, Instituto de be a good model to study functional characteristics of this polymorphism. Aim of Salud Carlos III, University of Co´rdoba; and CIBER Fisiopatologia the study was to investigate possible influences of d3-GHR on GH and IGF-I Obesidad y Nutricion (CB06/03), Cordoba, Spain; 2Department of relationship and on metabolic parameters in acromegaly. Medicine, University of Illinois at Chicago, Chicago, Illinois, USA. Methods A retrospective study was conducted on 76 acromegalic patients Genotype analysis was carried out on blood leukocyte DNA by multiplex PCR assay. The neuropeptide somatostatin (SRIF) exerts a wide variety of actions through Clinical, hormonal and biochemical parameters were considered at diagnosis and five SRIF receptors (sst1-5). However, not all SRIF actions can be explained by taken from medical records of the patients. activation of the known sst. In this context, our research group has identified two Results novel isoforms of sst subtype 5 (sst5A) named sst5B and sst5C expressed in Forty-one patients (54%) were homozygotes for the full length GHR (d3K), human and pig. These isoforms are generated by splicing of cryptic introns within while 35 patients (d3C) carried one (fl/d3 GHR, nZ28, 36.8%) or two (d3/d3, the coding sequence, which alters the open reading frame, and results in new, nZ7, 9.2%) copies of the d3 allele variant. No significant differences in sex, age, truncated receptors with different size and sequence as compared to sst5A. Given tumor size, GH and IGF-I levels, fasting serum glucose and insulin levels were that rodents are widely used to study the physiological importance of gene
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 products because of the ability to generate genetically modified mice over- or Prospective non-comparable randomized clinical investigation of GH/IGH-1 under-expressing the product of interest, the current study was focused on the control and tumor growth reduction in active acromegalic patients on identification of new murine sst5 isoforms. Use of molecular biology techniques Octreotide-LAR is presented. Fifty patients (pts) with newly diagnosed to search for partial sequences of truncated sst5 isoforms in rodents led to the acromegaly (primary teratment, group 1; mean age 47.8G13.9 years old) identification of one sequence in rat, and two in mouse, one of which showed high and 39 pts after previous surgical and/or radiological treatment (secondary interspecific nucleotide and amino acid sequence identity. Conversely, these treatment, group 2; mean age 48.1G12.2 years old) were treated with truncated murine sst5 were not homologues to the human and porcine sst5 Ocrteotide LAR 20–40 mg every 4 weeks, duration of treatment was 24 isoforms identified originally. Undergoing studies indicate that these sst5 months. isoforms display differential tissue expression patterns. Use of mice models Initial hormonal levels were [median (25%O75%)]: group 1- GH 25 under different physiological conditions (i.e. fasting, obesity, SRIF-knockout) has (12.9O55) ng/ml; IGF-1 685 ng/ml (578O843); group 2: GH 14 (6.6O39.5) revealed that these isoforms are also differentially regulated in both pituitary and ng/ml; IGF-1 574 (443O755) ng/ml. Clinical improvement and hormonal hypothalamus. Taken together, the differential pattern of expression and response (more then 30% decrease of the GH and/or IGF-1 levels) were regulation of the sst5 isoforms, coupled to the fact that these isoforms are highly observed in 44 (88%) pts from group 1 and 35 (95%) pts from group 2. conserved in rodents suggests that these new truncated receptors may be of Significant IGF-1 levels decrease without any changes of GH levels were physiological relevance. Future experiments will focus on the study of the observed in 3 (6%) pts from group 1 and 3 (7.7%) pts from group 2; potential involvement of these new sst isoforms in mediating the unique SRIF markable GH levels decrease without changes of IGF-1 levels – in 7 (14%) actions that can not be explained with the known sst identified to date. pts from group 1 and 2 (5%) pts from group 2. Tachyphylaxis phenomenon Support was noted in 4 (8%) pts from group 1: both [GHCIGF-1] after 6–12 months CVI-139 and CTS-1705-J Andalucia; BFU2004-03883 and BFU2007-60180- of treatment in 3 pts, only IGF-1 after 3 months of treatment in 1 patient. MEC/FEDER-Spain. In group 1 GH/IGF-1 levels after 12 months of treatment were 4.3 (1.9O13.9) ng/ml and 453 (215O568) ng/ml; after 24 months – 7.1 (1.3O 10.8) ng/ml and 469 (395O670) ng/ml respectively. In group 2 GH/IGF-1 levels after 12 months of treatment were 3.7 (1.2O5.1) and 220 (174O330) ng/ml and after 24 months 5.8 (1.5O10.2) and 328 (180O476) ng/ml respectively. P464 Shrinkage of the pituitary tumor were observed in 58.4% of pts from group 1; degree of shrinkage was 13–99% from the initial tumor volume. Posttraumatic hypopituitarism is associated with an unfavorable body Thus, Octreotide LAR is an effective treatment of 88% of de novo patients composition and lipid profile, and decreased quality of life 12 months with active acromegaly, and 95% of patients with previous surgical and/or after injury radiological treatment. In our hogort of patients hormonal control was more 1 1 2 Marianne Klose , Torquil Watt , Jannick Brennum & Ulla Feldt- effective in group with secondary medical therapy compared with newly 1 Rasmussen diagnosed acromegalic patients. However, tumor shrinkage was more 1 Department of Endocrinology, Rigshospitalet, Copenhagen, Denmark; obvious in patients with primary medical treatment. 2Department of Neurosurgery, KAS Glostrup, Copengagen, Denmark.
Objective To describe body-composition, lipid profile, and health-related quality of life (HRQL) in patients with traumatic brain injury (TBI) in relation to the development of posttraumatic hypopituitarism. Design P466 Cross-sectional with a nested prospective sub-study. Effects of growth hormone replacement in 28 patients with growth Patients hormone deficiency The cross-sectional cohort included 104 hospitalized patients with TBI (26F/78M; Virginia Martı´n-Borge, Cristina Alvarez Escola´, Beatriz Lecumberri age: median 41 years (range 18–64); BMI: 25 kg/m2 (17–39); severity: mild Santamarı´a, Marı´a Garcı´a Dominguez, Elisa Moya Chimenti & Luis (Glasgow Coma Scale score (GCS) 13–15) nZ44, moderate (GCS 9–12) nZ20, Felipe Pallardo Sa´nchez severe (GCS!9) nZ40). A nested cohort of 46 patients was followed Servicio de Endocrinologı´a, Hospital La Paz, Madrid, Spain. prospectively. The study was approved by the local Ethical Committee. Measurements Body mass index (BMI), waist circumference, lipid profile, total- and regional- fat Aim mass was assessed 3 and 12 months (prospective) or only 12 months (cross- To evaluate the response to growth hormone (GH) replacement in patients sectional) post-traumatically. HRQL questionnaires (NHP, EQ-5D and the GH with growth hormone deficiency (GHD) after 1 year of treatment in terms of deficiency specific instrument – QoL-AGHDA) were completed ‘pre-traumati- body composition, carbohydrate metabolism, lipid metabolism and quality cally’, 3 and 12 months (prospective) or only 12 months (cross-sectional) of life. post-traumatically. Method and patients Results Twenty-eight patients with GHD with the following characteristics: 16 males, Patients with posttraumatic hypopituitarism had higher age-, gender- and BMI- 10 with radiotherapy and 18 with panhypopituitarism, were included in our adjusted 12 months LDL-cholesterol, waist circumference, and total fat mass study. Body mass index (BMI) and waist hip ratio (WHR) were determined as (P!0.05 in all cases), and a higher increase in total cholesterol (PZ0.01) during body composition parameters. The assessment of carbohydrate metabolism was follow-up compared with sufficient patients. These findings were unrelated to 12 made by measuring fasting plasma glucose and glycated hemoglobin. Total months IGF-I and IGF-I SD-scores. cholesterol, serum high density lipoprotein-cholesterol (HDL-c), serum low Hypopituitary patients also had worse age-, BMI- and TBI severity- adjusted density lipoprotein-cholesterol (LDL-c) and triglycerides were evaluated as overall EQ-5D VAS (PZ0.03) and QoL-AGHDA (PZ0.01) scores, and worse serum lipid markers. Quality of life was assessed by Nottinghan scale. NHP dimension scores of sleep (PZ0.03), energy (PZ0.02), and social isolation Results G G (PZ0.04), compared to patients with an intact pituitary function. The mean IGF-I level increased from 63.8 48.6 at baseline to 192.3 ! Conclusion 102.5 ng/ml, P 0.001. There were no significant changes in BMI and WHR (28.1G6.5 vs 28.1G7.0 kg/m2 and 0.84G0.08 vs 0.84G0.06). Fasting plasma Posttraumatic hypopituitarism was an independent predictor of the classical G G phenotypic features of hypopituitarism including an unfavorable lipid and body- glucose and glycated hemoglobin did not alter significantly (86 10 vs 88 G G composition profile, as well as worsened HRQL. 9mg/dland5.3 0.4 vs 5.4 0.4%). All serum lipid markers experimented an improvement (total cholesterol, LDL-c and triglycerides decreased and HDL-c increased compared to baseline levels; 212G52 vs 202G39 mg/dl, 133G41 vs 126G28 mg/dl, 129G81 vs 126G60 mg/dl and 53G16 vs 54G20 mg/dl, respectively) but these differences were not statistically significant. Quality of life assessed by Nottinghan scale improved significantly (12G10 vs 8G8, ! P465 P 0.05). Conclusion Gh/Igf-1 control and tumor growth reduction in active acromegalic According to our data we can conclude that GH replacement in patients with patients on Octreotide LAR GHD improves their quality of life and does not impair carbohydrate Irena Ilovayskaya, Natalia Molitvoslovova, Olga Egorova, metabolism. Despite the data on literature, we have not proved a significant Larisa Dzeranova, Svetlana Arapova & Evgenya Marova improvement on lipid profile. Research Centre for Endocrinology, Moscow, Russian Federation.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P467 (GH 50.8% (15.5–67.5, PZ0.0029), IGF-I 22.2% (3.1–57.9 PZ0.07)). In the Starting dose of 10 mg Octreotide-LAR appears ineffective for SSA group there was no effect of prior surgery on %GH or IGF-I decrease, PZ0.63 and 0.78, respectively. Prior RT did not have an effect on decrease in GH biochemical control in the majority of acromegalic patients: interim Z Z analysis from the OASIS trial (P 0.77) but it lead to a lower IGF-I% reduction (P 0.045). The role of Stephan Petersenn1, Alexander Tarasov2, Feng Gu3, Sungwoon Kim4, pituitary hormone deficiency in the response was assessed; no differences were Moises Mercado5, Amelia Rogozinski6, Hakim Bouterfa7, Kristin David8, found if there was ACTH or TSH deficiency. However in the DA group, 7 9 gonadotrophin deficiency was associated with less marked decrease in IGF-I% Antonio Silva & Yona Greenman K Z 1Division of Endocrinology, Medical Center, University of Duisburg-Essen, (4.5 ( 0.36–11.52) vs 25 (9.4–40.4), (P 0.04)). The efficacy of DA in patients Essen, Germany; 2Regional Endocrinology Center, Ekaterinburg, Russian with acromegaly is irrespective of basal prolactin levels. Prior surgery and Federation; 3Peking Union Medical College Hospital, Beijing, China; radiotherapy are associated with differences in GH and IGF-I response to DA and 4Kyung Hee University, Seoul, Korea; 5Endocrinology Service, Centro SSA. However ACTH and TSH deficiency did not have an influence in the Medico Nacional Siglo XXI, Hospital de Especialidades, IMSS, Mexico response. City, Mexico; 6Hospital Ramos Mejı´a, Buenos Aires, Argentina; 7Novartis Pharma AG, Basel, Switzerland; 8ProSanos Corporation, Harrisburg, Pennsylvania, USA; 9Tel Aviv Medical Center, Tel Aviv, Israel. P469 Octreotide LAR (SMS-LAR) is available in 10, 20 and 30 mg dosing. The relation-ship between SMS-LAR starting dose and GH, IGF-I and symptoms was Diagnosis of SIAD: Fractional urate excretion closes the diagnostic gap in hyponatremic patients on diuretics exam-ined. The Observational Acromegaly Study on Impact of Sandostatin LAR 1,2,3 1,2,3 1,2,3 (OASIS) collects data on GH, IGF-I, symptoms, safety and tolerability in recently Wiebke Fenske , Stefan Sto¨rk , Anne Blechschmidt & Bruno Allolio1,2,3 diagnosed acromegalic patients. Data are collected under normal practice 1 conditions over 12 mos. Eight hundred and sixty patients from 138 centers in Department of Endocrinology and Diabetes, Medical University Hospital, Wuerzburg, Germany; 2Department of Cardiology, Medical University 23 countries are enrolled; 353 patients have data available for analysis. One 3 hundred and fifty patients (mean age 48 years, 75.3% with a macro-adenoma) Hospital, Wuerzburg, Germany; Department of Endocrinology and started the study with SMS-LAR treatment. Eighty-three percentage started with Diabetes, Medical University Hospital, Wuerzburg, Germany. 20 mg SMS-LAR, 10% (nZ15 pts) with 10 mg, 7% with 30 mg and one patient with 40 mg. Patients with 30 mg starting dose had the highest GH and IGF-I Background levels at treatment start, patients with 10 mg had the lowest (Table). GH mean The syndrome of inappropriate antidiuresis (SIAD) is the most frequent cause of ! levels were significantly different for the 10 mg and 20 mg groups (P 0.01) and hyponatremia. Its diagnosis requires a decreased serum osmolality, urinary Z tended to be different for IGF-I (P 0.06). IGF-I levels were significantly osmolality O200 mosm/kg, clinical euvolemia, and urinary sodium (UNa) Z different for the 20 mg and 30 mg groups (P 0.01). Twelve of the 10 mg starting O30 mmol/l. The natriuretic effect of diuretics impairs the diagnostic accuracy of dose patients had efficacy information at 3 month evaluation, of those 82% were UNa and thus, limits the diagnostic and therapeutic decision in hyponatremic not biochemically controlled. Only half of those uncontrolled were up-titrated to patients substantially. We therefore examined the accuracy to predict SIAD of 20 mg. Prevalence of any symptoms at treat-ment start was highest in the 30 mg alternative markers, thought not to interact with diuretics. Z group (90%) followed by 20 mg (83.7%) and 10 mg (80%) (P 0.88). In Methods conclusion, higher starting doses of SMS-LAR are asso-ciated with higher GH In a prospective study 86 consecutive hyponatremic patients (serum sodium and IGF-I levels, suggesting that biochemical parameters, drive the choice of !130 mmol/l) were classified according to their history, clinical evaluation, and SMS-LAR starting dose. Starting dose of 10 mg appears ineffective for saline response (isotonic saline) into a SIAD and a non-SIAD group. In both biochemical control in the majority of acromegalic patients. groups the following biochemical parameters were tested in a diuretic collective (DC) and in a non-diuretic collective (NDC): UNa, serum uric acid concentration, fractional excretion of sodium, urea, and uric acid (FEUA). The parameters
SMS-LAR start dose (mgs) Mean GHGS.D. (ng/ml) Mean IGF-IGS.D. (ng/ml) accuracy to predict SIAD was assessed with a receiver-operating-charcateristic curve analysis. 10 10.3G9.5 583G313 Results G G 20 22.4 37.0 800 398 31 patients were diagnosed SIAD (36%), 53 patients were classified non-SIAD 30 23.7G20.2 1149G525 (64%), the mean age was 66G15 years, 57 patients were on diuretics (68%). In NDC, UNa was the most accurate test parameter to predict SIAD (AUC 0.96), however, showed a significant loss of accuracy in DC (AUC 0.80; P!0.01 vs NDC). In DC, FEUA had a significant better performance, compared with all of the alternative parameters (AUC 0.96; all P!0.01) and showed a positive predictive value of 100% choosing a cutoff value of 12%. Conclusion P468 In patients not taking diuretics, UNa is a sufficient test parameter to predict SIAD. Factors associated with response to medical therapy in patients with In patients on diuretics, FEUA is the most accurate predictor of SIAD and shows a Acromegaly discriminative quality, similar to UNa, in patients not taking diuretics. Eva Fernandez-Rodriguez1, Mark Sherlock1, Aurora Aragon Alonso1, John Ayuk1, Richard N Clayton2, Michael C Sheppard1, Andy Bates3 & Paul M Stewart1 1Division of Medical Sciences, Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Birmingham, UK; 2Department of Postgraduate Medicine, University of Keele, Stoke-on-Trent, UK; 3Birmingham Heartlands and Solihull NHS Trust, Birmingham, UK. P470 Circulating visfatin and adiponectin levels are reduced in women after long-term remission of Cushing’s syndrome Acromegaly is associated with increased morbidity and mortality. Surgery, Maria-Jose Barahona1, Nuria Sucunza1, Eugenia Resmini1, Wifredo Ricart2, radiotherapy (RT) and medical therapy are the treatment options to decrease GH Jose-Manuel Fernandez-Real2, Jose Rodriguez-Espinosa1 & Susan and IGF-I concentrations to levels associated with cure or normalisation of M Webb1 mortality. We examined the response to dopamine agonists (DA) and 1Endocrinology Department and Center for Biomedical Research on Rare somatostatin analogues (SSA) in 276 patients with acromegaly who received Diseases (CIBERER Unit 747), Hospital Sant Pau, Autonomous University medical therapy during follow up (198 DA, 143 SSA). One hundred and seventy of Barcelona, Barcelona, Spain; 2Endocrinology Department, Hospital J two had surgery and 73 RT prior to medical therapy. GH and IGF-I values before Trueta, Girona, Spain. and 12 months after initiation of therapy were analysed. In the DA group basal prolactin levels did not predict response to therapy (median GH% reduction): hyperprolactinaemia 26.7% (10.4–48) vs normal prolactin 34.8% (0.2–53.2), Metabolic syndrome and insulin resistance persist 5 years after remission of PZ0.58. Prior surgery was associated with a less marked GH% (PZ0.026) and Cushing’s syndrome (CS). Adiponectin and visfatin are two adipokines highly IGF-I% reduction (PZ0.0043): surgery group 23.9% (K9.9–48.5) and 9.2% expressed in adipose tissue. Adiponectin is reduced in obesity and insulin- (K1.0–26.6), no surgery group 40.5% (15–71) and 40% (15.4–88.2). Prior RT resistant states; visfatin has been shown in some studies to be reduced in obesity. was associated with an enhanced GH% reduction but no significant effect on IGF- The aim was to evaluate visfatin and adiponectin levels, body composition, I% reduction: no RT (GH 20.5% (K9.9–39.1), IGF-I 9.4% (K16.2–28.7)) vs RT insulin resistance and prevalence of metabolic syndrome in a cohort of women
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 with long-term remission of CS, and compare it with that of controls matched for translocated to the nucleus where it stimulates a number of genes that modulate sex, age and BMI. proliferation and differentiation upon binding to TCF/LEF-1. We have previously Methods shown that Wnt/ß-catenin pathway is dysregulated in adrenocorticotropin We report 37 women in long-term remission of CS and 72 controls, in whom body (ACTH)-secreting pituitary adenomas. The therapeutic options for this tumor composition was measured by dual-energy X-ray absorptiometry scanning. entity are limited. In this context, SRIF has been proposed as a therapeutic agent Circulating adiponectin, visfatin, insulin and lipid profile were measured. Insulin in the treatment of ACTH-secreting pituitary adenomas. The mechanisms remain resistance was calculated using the formula of the homeostasis model assessment largely unclear. The aim of the present study was to investigate the effect of SRIF (HOMA). Metabolic syndrome was evaluated using the NCEP ATP III criteria. on the Wnt/ß-catenin pathway in ACTH-secreting pituitary cells. Results Methods Patients had been cured of hypercortisolism for 11G6 years and their current age The ACTH secreting mouse pituitary cell line AtT-20 was treated with SRIF-14 was 50G14 years. When compared with the controls, cured CS patients had more and its effect on the expression of ß-catenin, GSK-3ß, TCF-4 and Cyclin D1 was total fat mass (39.7G7.4 vs 35.7G6.5, P!0.05) and trunk fat mass percentage analyzed both at the RNA and protein levels by RT-PCR and Western blotting, (40.8G9 vs 34.3G8.3, P!0.05) and less visfatin (15.57 (8.5–24.5) vs 19.9 respectively. Additionally, the relative values of phospho-ß-catenin to total (11.2–59.3) mg/ml, P!0.05) and adiponectin levels (12.48 (5.02–32.4) vs 18.1 ß-catenin and phospho-GSK-3ß to total GSK-3ß were studied under the effects of (4.5–56.5) mg/ml, P!0.05). There were no differences in insulin, HOMA-IR and SRIF-14 and forskolin (activator of cyclic AMP). prevalence of metabolic syndrome (9%) between both groups. Visfatin negatively Results correlated with fat mass. No correlation between adiponectin and body In the ACTH-secreting pituitary cell line AtT-20 treatment with SRIF-14 rapidly composition were found. decreased ß-catenin, TCF-4 and cyclin D1 mRNA expression at 4–6 h and caused Conclusions a potent and long-lasting decrease also at the protein level. The downregulation of Despite long-term control of hypercortisolism, patients who have suffered CS ß-catenin was blocked by forskolin. Furthermore, the phospho-ß-catenin/total have a persistent increase in total and trunk fat mass and a reduction in circulating ß-catenin ratio was higher in SRIF treated cells as compared to untreated controls visfatin and adiponectin levels, which may contribute to their increased and also to forskolin stimulated cells. These findings correlated well with the cardiovascular risk. These alterations are not related to metabolic syndrome or values of phospho-GSK-3ß, an inactive form of GSK-3ß, which was higher in insulin resistance. untreated controls and forskolin treated cells comparative to SRIF treated cells. Conclusions Our data indicate that SRIF downregulates the Wnt/ß-catenin pathway and this effect can be blocked by the activation of adenylate-cyclase pathway in ACTH- secreting pituitary cell line AtT-20. Inhibition of Wnt/ß-catenin pathway by SRIF P471 or its analogs might exert beneficial effects on corticotrope dysfunction in Cushing’s disease. The impact of conventional radiotherapy on Wisconsin card sorting test performance in acromegalic patients treated with transsphenoidal surgery Beatriz Lecumberri1, Javier Estrada2, Jose´ Garcı´a-Urı´a2, Julia´n Alcan˜iz2, Luis Felipe Pallardo1 & Toma´s Lucas2 1La Paz University Hospital, Madrid, Spain; 2Puerta de Hierro University P473 Hospital, Madrid, Spain. Identification of ACTH-secreting adenomas in Cushing’s disease using intraoperative high-frequency direct contact ultrasound. Preleminary Neurocognitive dysfunction has been described in patients following pituitary results radiotherapy. However, the relative contributions of other variables such as Ulrich Knappe1, Kornelia Konz2, Robert Schoenmayr3, Alexander Mann4 hormone-deficiency states and surgery is still unknown. Our aim was to compare & Martin Engelbach1 the results of an examination of executive function in acromegalic patients treated 1Department of Neurosurgery, Johannes Wesling Klinikum, Minden, with transsphenoidal surgery (TS) alone to those obtained from patients treated Germany; 2Department of Endocrinology, Deutsche Klinik fuer Diagnostik, with TS followed by conventional radiotherapy (CR) using a two-field technique. Wiesbaden, Germany; 3Department of Neurosurgery, Dr. Horst Schmidt We retrospectively compared these two outcome groups and carried out a Klinik, Wiesbaden, Germany; 4Endokrinologikum Frankfurt, Frankfurt, Wisconsin Card Sorting Test (WCST). Sixty-six patients, 26 men and 40 women, Germany; 5Endokrinologische Gemeinschaftspraxis, Frankfurt, Germany. aged 55.2G12.4 years, with an average duration of symptoms before diagnosis of 5.1G3.7 years, were included in this study. Forty-two patients were treated only by TS and 24 received additional CR. There were no significant differences Introduction between groups in sex, age, average duration of symptoms before diagnosis, and Up to 40% of cases with endocrinologically and surgically proven Cushing’s disease (CD) are MRI-negative1. With intraoperative transsphenoidal ultrasound mean GH and IGF-1 levels before TS (18.1 and 21.1 mg/l for GH, and 820.1 and 2 889 mg/l for IGF-1, respectively in both radiated and not radiated groups). 72% of microadenomas in CD were identified as hyperechogenic structure .We Although there were more pituitary deficits in the radiated group when their report on the first 9 cases with intraoperative use of direct contact high-frequency executive functioning was assessed, the prevalence of growth hormone deficiency ultrasound (hf-us) in patients with CD. was similar in both groups, as well as the percentage of patients that achieved Patients criteria for cure. The CR group performed significantly worse than the TS group, All 9 cases (all female, age 31–71 years) revealed typical symptoms of CD, 2 with mean centiles based on age-adjusted normative data of 10.5 vs 27.9 for were recurrencies. perseverative answers (PZ0.007) and 11.7 vs 28.5, for perseverative errors in Technique each group (PZ0.012). The CR group committed also more total errors and During direct transnasal microsurgical operations the sellar compartment was required more trials to achieve the first category but these differences were not investigated in axial and sagittal direction at 12 and 13 MHz through the pituitary statistically significant. In our study, postoperative CR in patients with capsule after drilling of the bony floor by use of a digital ultrasound probe (B- acromegaly is associated with a poorer performance on the WCST when mode frequency 7.5–13 MHz, wide of field 5 mm, penetration 20 mm). compared to TS alone, documenting specific problems in conceptual flexibility. Results In all 4 cases with negative preoperative MRI intraoperative hf-us correctly localized micoadenomas. In 2 out of 5 cases with positive MRI hf-us identified a hyperechogenic structure at the site expected (positive control). In 2 other cases with micoadenomas MRI correctly predicted the site of the tumor, but no identification was possible by hf-us. In the only case with a macroadenoma, P472 identification of the border between tumor and anterior pituitary gland was not Somatotropin release inhibiting factor (SRIF) downregulates Wnt/ß- possible by use of hf-us. Out of 8 cases with microadenomas, in 6 the tumor was catenin pathway in ACTH-secreting pituitary cell line AtT-20. identified by hf-us (75%). Early postoperative decline of serum cortisol to subnormal levels on the first postoperative morning revealed surgically induced Muhammad Nasir Khan Khattak, Natalia Kremenevskaya 1 & Michael Buchfelder remission of hypercortisolism in all 9 cases . University Erlangen-Nuremberg, Erlangen, Germany. Conclusion Intraoperative, direct contact hf-us may enable the surgeon to identify small pituitary adenomas even in cases of negative preoperative MRI, thus preventing Introduction these patients from extensive pituitary exploration. The involvement of the Wnt/ß-catenin pathway is apparent different epithelial 1. Knappe UJ & Lu¨decke DK. Neurosurgery 39 1996 484–493. human cancers. Wnt stabilizes ß-catenin (free ß-catenin) by preventing its 2. Ram Z et al. JNS 83 1995 225–230. phosphorylation which targets ß-catenin for degradation. Free ß-catenin is
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P474 The diagnosis of a prolactinoma is confirmed by MRI: 35.8% of cases with Macroprolactinaemia: a clinical problem microadenoma, 32.6% macroadenoma, 1% empty sella syndrome, 30.6% have normal MRI. Aldona Kowalska, Danuta Gasior-Perczak, Iwona Palyga & Anna Sluszniak G Holycross Cancer Centre, Kielce, Poland. The mean value of PRL at the moment of diagnosis was 238 257 ng/ml (NZ1.9–25). Treatment Introduction Prolactin microadenomas were treated with dopamine agonist drug. About 36.7% Prolactin is a hormone which is characterized with a high structural and functional were treated with Bromocriptine and 40.8% with Cabergoline. polymorphism. Macroprolactin is one of the form of prolactin - it is a complex of The mean PRL values before treatment with Cabergoline was 196G16.1 ng/ml, monomeric prolactin and immunoglobulin. Macroprolactin is characterized with after it 36.9G53 ng/ml. The mean PRL values before treatment with immunoreactivity and probably the lack of biological activity. Bromocriptine was 115.8G10.8 ng/ml, after it 51G66 ng/ml. Purpose About 87.5% of macroadenomas underwent surgery due to the complication of The main purpose of our study was to estimate the frequency of macroprolactin pituitary mass. PRL values before surgery was 232G154 ng/ml, after it 162G appearance among the patients with hyperpronactinaemia but also analysis of 168 ng/ml. clinical and biochemiacal symptoms of hyperprolactinaemia. Because of the still high values of PRL after surgery, drug therapy was used in Material 59% of them. The study involved 125 patients diagnosed of hyperprolactinaemia in term from Conclusion January to December 2006. The high percentage of macroadenomas is due to the late diagnosis of the cases. Method All the affected men present pituitary macroadenomas. Drug therapy is more The concentration of total prolactin, macroprolactin (using the method of effective than surgery alternative, but treatment should be prolonged. polyethylene glycol- PEG- precipitation) and recovery test of prolactin was marked to all patients. Macroprolactinaemia was diagnosed in case of recovery test below 40%. The frequency of clinical symptoms were evaluated in the patients. Results Among 125 patients with hyperprolactinaemia–macroprolactinaemia was diagnosed in 43 (34.4%). P476 Prospective comparison of the glucagon stimulation test (GST) with the Number Clinical Oligo] insulin tolerance test (ITT) in patients following pituitary surgery of Total PRL Free PRL symp- menor- Galactor- Amenorrhea/ Christian Berg, Timo Meinel, Ali Yuece, Harald Lahner, Klaus Mann patients mIU/l mIU/ml MRI toms rhea rhea galactorrhea & Stephan Petersenn 43 (34.4%) 1658 348 Yes/no 11 (25.5%) 6 2 3 University of Duisburg-Essen, Essen, Germany. 657–5900 116–2514 35/8 2 tumors Objective Among patients with clinical symptoms diagnosis of The ITT is the gold-standard for assessment of GH and ACTH reserve but – PCOS was established in 5 of 6 with oligomenorrhea (with free prolactin has certain contraindications. GH and cortisol responses of !3 ng/ml and concentration- 245,142, 163, 157, 207 mIU/l respectively) !500 nmol/l, respectively, have been defined as evidence of severe deficiency. – hypergonadotropic hypogonadism in 1 of 6 with oligomenorrhea (free The GST like the ITT stimulates both the ACTH and GH secretion and is PRL-260) suggested to be a good alternative in terms of efficiacy. However, there are limited – selective galactorrhea in 2 patients with galactorrhea (free PRL- 597, 643) prospective data with modern assays on sensitivity and specificity for the GST in – hipogonadotropic hypogonadism in 3 patients with galactorrhea–amenorrhea comparison to the ITT. Aim of this study was an evaluation of the diagnostic with free PRL concentration of 2514, 1062, 928 mIU/l respectively. utility of the GST in patients with hypothalamo–hypopituitary disease following Conclusion pituitary surgery. 1. Among patients with hyperprolactinaemia macroprolactinaemia is accounted Design and patients for 34.4%. ITT and GST were performed within 7 days in 22 patients (14 men, age 28–61) at 2. Clinical symptoms do not appear in case of macroprolactinaemia. least 3 months after transsphenoidal surgery. Serum GH and cortisol were 3. Irregular menstruations and galactorrhea are results of coincidence of measured by Immulite 2000 assay (Siemens AG). ROC analysis was performed to monomeric hyperprolactinaemia or other endocrine disorders (PCOS, premature identify optimal thresholds for GST; for cortisol deficiency analysis was adjusted ovarian failure) to achieve a sensitivity R95%. 4. Macroprolactin level measurement should be taken in every case of Results hyperprolactinaemia. Regarding GHD, 11/22 cases were classified as insufficient by ITT. For GST, ROC analysis revealed a cut-off of 3.1 ng/ml with 100% sensitivity and 81.9% specificity. Only 2/22 (9%) cases showed conflicting results compared to ITT in relation to this cut-off and were discordant in terms of defining GHD. Regarding cortisol deficiency, 6/22 cases were classified by ITT as cortisol insufficient. For GST, ROC analysis revealed a cut-off of 654 nmol/l with 100% sensitivity and poor 33.3% specificity. Using this cut-off, 10/22 (45%) cases showed conflicting results compared to ITT and were discordant in defining cortisol deficiency. P475 Conclusion In our prospective series of patients with pituitary disease, the GST is a good Prolaktinoma and hyperprolactinemia in Albania alternative test for assessment of GH reserve, but poor for ACTH reserve, as 1,2 1,2 1,2 1,2 Agron Ylli , Zamira Ylli , Malo Minga , Thanas Fureraj , demonstrated by comparison with the ITT. Test-specific cut-offs should be 1,2 1,2 1,2 1,2 Gerond Husi , Arian Xhumari , Gentian Kaloshi , Merita Alushani , applied to avoid misinterpretation. Entela Lamcaj1,2 & Blertina Olldashi1,2 1Endocrine Center Neo-Style, Tirana, Albania; 2UHC Mother Teresa, Tirana, Albania.
Background Prolactin hyper secretion is the most common endocrine abnormality due to hypothalamic–pituitary disorders. PRL is the hormone most commonly secreted P477 in excess by pituitary adenomas. Expression of ghrelin and opioid mRNAs in the hypothalamo– Materials and methods pituitary–adrenal axis after immune system activation A retrospective study was performed during the period 1998–2007. The diagnose Krystyna Pierzchala-Koziec & Joanna Zubel are based on objective examination, hormonal dosage, MRI. Agricultural University, Krakow, Poland. Results During these time were diagnosed 98 cases with hyperprolactinemia; 90.8% are females and 9.02% are males. Female/male ratio is 9.8:1.The mean age of The activity of the hypothalamo–pituitary–adrenal axis (HPA) is under control of diagnosis is 31.8G10.5 years olds. endocrine, nervous and immune systems, in which opioids and recently
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 discovered ghrelin play important role. Mannan polysaccharide is often used as an 1Department of Endocrinology, Hospital Universitario La Ribera, Alzira, alternatives to antibiotics, however, its role in the stimulation of the immune Valencia, Spain; 2Department of Endocrinology, CHU Lie`ge, Lie`ge system is still uncertain. As a part of study dealing with the interaction of different University, Lie`ge, Belgium; 3Department of Endocrinology, Hospital factors during the growth and development the experiment was carried out in Universitario La Fe, Valencia, Spain; 4Department of Neurosurgery, order to estimate the effect of prolonged treatment of mannan on the HPA Hospital Universitario La Ribera, Alzira. Valencia, Spain. synthesis of proghrelin and proenkephalin. Animal study were performed on the 30-days-old female lambs fed with standard food or with addition of prebiotic – mannan polysaccharide, isolated from the cell wall of Saccharomyces cerevisiae. Familial acromegaly (FA) is a rare disease with less than 150 cases published. For During 30 days of experiment lambs were i.v. injected with saline (control) or its diagnosis (FA), two or more cases of acromegaly in the same family and the naltrexone (3 mg/kg b.w.) five times every 7 days. Fragments of hypothalami, absence of MEN1 and/or Carney syndrome are required. FA is in the familial pituitaries and adrenals were taken out, frozen and directed to measurement of the isolated pituitary adenomas (FIPA) group although its genetic condition is still expression of mRNAs for proghrelin and proenkephalin by the in situ under investigation. hybridization method. Prolonged treatment with mannan significantly affected The index case is an asymptomatic 43-year-old woman with a 4mm pituitary the expression of mRNAs for proghrelin and proenkephalin in the hypothalamus micro-adenoma. There were not acromegaly signs/symptoms, IGF-1 and pituitary. Unexpectedly, naltrexone, an opioid receptor antagonist, decreased 849.84 ng/ml and a glucose tolerance test with GH values: 21.4, 6.97, 2.11, the expression of mRNA coding for proenkephalin and increased for proghrelin in 0.96, 0.47 ng/ml. Other hypophysis functions were normal. Genetic study for mannan fed animals. MEN1 was negative. She was operated in 2004 with an inmuno-hystologic study In contrast, the response of both mRNAs in adrenals to polysaccharide treatment positive for GH, ACTH y PRL. She is still disease-free at the present time. Her ! was very weak. Thus, the obtained results showed the interaction of father was diagnosed of a pituitary GH-secreting macro-adenoma (20 22 mm) hypothalamo–pituitary–adrenal opioids and ghrelin in the response to activated in 1995. He had acromegalic phenotypic changes, basal GH: 20 ng/ml and post- immune system. glucose load GH level, 21 ng/ml. He died of a cerebrovascular accident before other diagnostic or therapeutic interventions were performed. Index case took part in the FIPA International Multicentre Study. The aryl hydrocarbon receptor interacting protein (AIP) gen mutations were negative for the more than 10 described mutations (also negative in 50% of FA and 85% in FIPA). It was also negative for the other 34 relatives (1st, 2nd, 3rd and 4th degree relatives in four different generations). All signed the informed consent form. A family tree was done of the three previous generations and, demographic and anthropometric P478 data, GH and IGF-1 levels and a clinical symptoms questionnaire were collected. Several asymptomatic relatives with abnormal basal GH and IGF-1 values or Cyclical Cushing’s syndrome: prevalence in patients with Cushing’s height above 97% CI are still in the study. We describe a new family that meets disease the criteria of familial acromegaly in the FIPA group. FIPA would reach in the Krystallenia I Alexandraki, Gregory A Kaltsas, Andrea M Isidori, Scott future a new clinical entity in the endocrine tumours classification. However, a A Akker, William M Drake, Shern L Chew, John P Monson, more characteristic genetic pattern needs to be identified to be used as screening G Michael Besser & Ashley B Grossman tool in potential FA. Department of Endocrinology, St Bartholomew’s Hospital, London, UK.
Background Cyclical Cushing’s syndrome has been considered to be a rare clinical entity, characterised by periodic increases in cortisol levels followed by regression of the P480 Cushing’s syndrome. The cycles of hypercortisolism may occur before the Hypopituitarism following traumatism brain injury in the West Indies: establishment of the diagnosis, rendering actual diagnosis difficult, or may occur a pilot study between July 2005 and July 2006 after inadequate or ineffective treatment and affect disease management. The aim Sabine Morineaux, Laurent Do, Maurice Simonetti, Jacques Salin, of this study was to investigate the prevalence of cyclicity of clinical symptoms Patrick Foucan, Jean-Paul Donnet & Marie-Laure Lalanne-Mistrih and signs in patients with Cushing’s disease, and to identify the characteristic CHU de Pointe-a`-Pitre, Guadeloupe, France. features of this idiosyncratic population. Methods Two hundred and two patients with biochemically confirmed Cushing’s disease, Sixty patients with traumatic brain injury are newly diagnosed every year in admitted from 1946 until 2001, were subjected to a retrospective case-note study. our island, particularly in patients with addictive behaviours. In France, it is Cyclical disease was defined by the presence 1) intermittent signs and symptoms the 4th rank of health expenses, as a major issue of public health care. In of Cushing’s syndrome with or without biochemical confirmation prior to order to perform a first endocrine assessment, we performed a pilot study to presentation; and 2) variability in signs, symptoms and biochemical findings diagnose traumatic brain injury induced hypopituitarism, assessed at least 6 during their follow up. months after injury, in moderate to severe traumatic brain injuries patients, Results hospitalized in our institution, from July 2005 to July 2006. It was a Fifty-eight (24%) patients had evidence of cyclical disease. The patients transversal study, approved by the Ethics Committee System of Bordeaux. were diagnosed at a mean age of 37.5 (median: 36; range: 7–95) years and All patients gave their informed consent after oral and written information. were followed-up for a mean period of 14.5 (median: 14; range: 0–52) Over 65 medical files, 36 met our criteria: 12 patients died (6 in intensive years. Evidence of cyclic disease before diagnosis was present in 28 (45%) care unit and 6 after their discharge); 14 out of 24 survivors were excluded and after diagnosis in 32 (55%) of patients. Before diagnosis the first after the first appointment (7 patients declined; 7 were lost for follow up). evidence of cyclicity was present at a mean period of 5.58 (median: 5; Of the 10 remaining patients, 6 showed traumatic brain injury hypopituitar- range: 0–23) years before the established diagnosis. In the female population ism: 3 isolated growth hormone deficiencies (2 severe, 1 partial), 2 cyclical disease was present in 27% (41/154) and in the male population in adrenocorticotropic hormone deficiencies associated with 1 partial and 1 35% (17/48). About 16 (8%) patients were under 18 years old at severe growth hormone deficiency and 1 isolated thyroid stimulating presentation and cyclic disease was present in 2 (12.5%). hormone deficiency. This study pointed out the different difficulties we Conclusions also met. This pilot study will lead to a further multicentric long-term study, The findings in this large population study reveal that cyclic disease is not a rare in order to perform statistical analysis and to compare our results to those of presentation of Cushing’s disease, and the physician should be alert to this the literature. possibility in making the diagnosis as well as after treatment in the follow-up period.
P481 Hypopituitarism after traumatic brain injury and its possible relation P479 with neurocognitive and psychiatric disturbances Familial acromegaly: family screening and assessment in the familial Ana I Castro, Mary Lage, Roberto Peino, Monica Lorenzo isolated pituitary adenoma (FIPA) & Felipe Casanueva Carmen Fajardo1, Adrian Daly2, Carlos Trescoli1, Rosa Camara3, Hospital de Conxo.Complejo Hospitalario Universitario de Santiago. Pedro Riesgo4, Jose Gomez1 & Albert Beckers2 Santiago de Compostela University, Santiago de Compostela, Spain.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Introduction P483 Recent advances in medicine have allowed a considerably decrease in mTOR inhibitors rapamycin and RAD001 (Everolimus) induce mortality after traumatic brain injury (TBI) with the consequent increment antiproliferative effects in GH3 cell line and human pituitary adenomas in the number of subjects with physical, psychological and cognitive Hadara Rubinfeld1, Alexander Gorshtein2, Efrat Kendler1, Moshe Hadani3 sequelas which means an important worsening of quality of life as well as & Ilan Shimon1 difficulties in social and labour integration. Considering that many of the 1Institute of Endocrinology and Felsenstein Medical Research Centre, Rabin symptoms classically attributed to the TBI (memory impairment, concen- Medical Centre, Petach Tikva, Israel; 2Department of Internal Medicine, tration impairment, fatigue, social isolation etc.) are also associated with Meir Hospital, Kfar Saba, Israel; 3Department of Neurosurgery, Sheba pituitary hormones deficiency, especially growth hormone deficiency, we Medical Center, Tel-Hasomer, Tel Aviv University, Tel Aviv, Israel. thought about the possibility of studying if the presence of GH deficiency could be related with psychological and neurocognitive sequelas in TBI patients, and if a hormonal replacement treatment could be an adequate The effect of mTOR inhibitors on pituitary tumors is unknown. Akt over- complement in the rehabilitation process. expression was demonstrated in pituitary adenomas, which may render them Material and methods sensitive to the antiproliferative effects of these drugs. Eighty-three patients were studied, 65 men and 18 women, with a mean age of To evaluate the in vitro effects of mTOR inhibitor rapamycin, and its orally- 43.9G1.9 years; age at TBI of 38.7G1.9 years and body mass index (BMI bioavailable analog RAD001 on pituitary cells, GH3 cells, a mammosomatotroph kg/m2)of27.1G0.4. The severity of injury was assessed by the glasgow coma rat pituitary tumor cell line, and human GH-secreting and non-functioning scale (GCS) score; 57 patients had suffered a mild TBI, 10 patients a moderate pituitary adenoma (NFPA) cells were used. TBI and 14 patients a severe TBI. All patients underwent: 1) A Basal Hormonal Treatment of GH3 cells, cultured GH-secreting adenomas and NFPAs with Study: ACTH, fT3, fT4, TSH, IGF-1, FSH, LH, testosterone (male) and rapamycin or RAD001 induced a significant dose- and time-dependent inhibition oestradiol (women), PRL and ADH. To assess GH secretion the GHRHC of cell viability. The inhibition of GH3 cell viability involved G0/G1 cell cycle GHRP-6 test was performed. 2) Psychiatric and neurocognitive evaluation: arrest associated with cyclin D3 suppression. Expression of phosphorylated- cognitive function by using Rey-Osterrieth Complex Figure y Digit Letter p70S6K in GH3 cells, GH-secreting adenoma and NFPA cells was significantly Substitution Test, and presence of psycho-psychiatric symptomatology by reduced by rapamycin and RAD001. mTOR phosphorylation was significantly means of Beck’s Depression Index and SCL-90 questionnaire decreased by rapamycin and RAD001 in GH3 cells, while Akt phosphorylation Results was unchanged. In our patients neurocognitive assessment revealed a significant correlation of Our results showed that mTOR inhibitors potently inhibit pituitary cell peak GH levels after stimulation with spatial construction, planning ability proliferation suggesting that mTOR inhibition may be a promising antiprolifera- (PZ0.02) and with visual short memory (PZ0.003). A significant correlation of tive therapy for pituitary adenomas. This therapeutic manipulation may have GH peak with DLST scoring, which is a measure of attention, perceptual speed, beneficial effects particularly for patients harboring invasive pituitary tumors motor speed, visual scanning and memory was also observed (P!0.0001). unresponsive to current treatments. Psycho-psychiatric evaluation revealed a significant correlation of peak GH levels with PSDI (positive symptom distress index; (P!0.0072). Conclusion It is important to establish the neurocognitive an psychiatric aspects potentially affected by hormonal deficiencies, especially GH deficiency, to assess the efficacy of hormone replacement therapy on neurocognitive and psychiatric alterations in TBI patients.
Obesity P482 P484 Endoscopic pituitary surgery as the primary treatment for acromegaly: The influence of low calorie-high dietary fibres diet on the change of a prospective study in a specialised centre parameters of the metabolic syndrome Marco Faustini-Fustini, Satima Magrini, Mascia Anagni, Diego Mazzatenta, Snezana Polovina, Koviljka Milenkovic & Mile Novkovic Ernesto Pasquini & Giorgio Frank 1General Hospital Subotica, Subotica, USA; 2General Hospital Cacak, Department of Neurological Sciences, Centre for Surgery of Pituitary Cacak, USA; 3General Hospital Vrbas, Vrbas, USA. Tumours, Bellaria Hospital, Bologna, Italy. Metabolic syndrome is risk factor for cardiovascular event. According The main aims of treatment of acromegaly are reversing symptoms and signs, recommendation of NCEP ATP III, the major component of metabolic removing the tumour, preventing disease recurrence, and improving survival. syndrome is waist circumference up to 94 cm in male and 80 cm in female, Increased mortality associated with acromegaly can be diminished if treatment is and two of following disturbances: fasting glucose up to 5.6 mmol/l, HDL successful in reducing GH !2–2.5 ng/ml. We carried out a prospective study to below 0.9 in male and 1.3 in female, triglycerides up to 1.7 mmol/l and BP assess whether recent advances in surgical technique (namely the endoscopic up to 135/80 mmHg. approach in a specialised centre encompassing specialist pituitary surgeons We have analyzed the influence of low calorie diet (1200–1500 kcal/day) working in team with endocrinologists, pathologists, and neuroradiologists) could with increased dietary fibers of 25–40 g/day and the macronutrients ratio: obtain remission and stable disease control in the majority of acromegalic fats 22–23%, proteins 15–18% and carbohydrates 55–65%. 95 subjects patients. Between 1998 and 2007, 152 consecutive acromegalic patients (65 men; divided into two groups took part in this investigation. Examined group was 48 microadenomas; median age, 46 years, range 13–78) underwent pituitary treated with recommended diet and control group was treated with standard surgery. Of these, 26 (17%) were operated for a residual tumour, while the low calorie diet with dietary fibers of 10–15 g/day, carbohydrates 35–45%, remainder (83%) had had no previous intervention for their pituitary adenoma. On fats 20–30% and proteins 20–25%. the basis of tumour extension, the pituitary adenomas were classified into grade 0 After 6 months waist circumference decrease significantly (PZ0.001) in (18.4%), grade I (9.6%), grade II (57.5%), grade III (13.2%), and grade IV (1.3%). examined group, and non significantly increased in control group (PZ0.17). Surgery led to partial hypopituitarism in 2.6% and permanent diabetes insipidus Fasting glucose decreased high significantly in examined group, and there in 1.3%. Based on biochemical criteria evaluated 3–6 months after surgery (mean was no changes in control group. HDL in examined group significantly GH !2.5 ng/ml, nadir GH on 75-g OGTT !1 ng/ml, and IGF-I in the normal increased (P!0.05) while in control group there was no changes (PO0.05). age- and sex-related range), the overall remission rate was 68%, despite the lack Triglycerides and systolic blood pressure decreases significantly in examined of a residual tumour on MRI in 76%. A partial surgical success was achieved in group (PZ0.001), but control group had more significant decrease of 21% of cases (clinically relevant improvement with or without a residual tumour). diastolic blood pressure (P!0.05). The remainder 11% showed an active disease with a residual tumour on MRI. Our These results suggest positive effect of low calorie diet on the parameters of prospective study has showed that recent technical advances in surgical approach the metabolic syndrome. The reductions of total and saturated fats, balanced to the sella coupled with expertise surgeons working in team can obtain remission protein and carbohydrates intake and increased intake of dietary fibers have of the disease in about two thirds of cases, even though 17% of patients in our positive influence on the lipid profile and improve glycemic regulation in series had had a previous intervention. obese people with metabolic syndrome.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P485 P487 Estradiol reverts the impairment of the natriuretic peptide system in a Bariatric surgery for patients whit morbid obesity: a cohort study menopause-associated obesity model Sandra Herranz Antolı´n, Miriam Pe´rez Pelayo, Toma´s Gonza´lez Losada, Najara Belo1, Adelina Reis2 & Malur Sairam3 Luis Mun˜oz de Dios, Sergio Fuentes Tudanca, Dolores del Olmo Garcı´a& 1Federal University of Bahia, Bahia, Brazil; 2Federal University of Minas Jaime Va´zquez Echarri Gerais, Minas Gerais, Brazil; 3Clinical Research Institute of Montreal, Severo Ochoa Hospital, Legane´s, Madrid, Spain. Montreal, Quebec, Canada. Objectives The follicle-stimulating hormone receptor knockout (FORKO) female mouse Analyze the evolution of body mass index (BMI) and percentage of excess weight provides a useful model to examine the role that lack of estrogen plays in loss (PEWL) after bariatric surgery; compare adjustable gastric banding (LABG) the development of obesity and hypertension in postmenopausal women. vs laparoscopic gastric bypass (LGB). Estrogen increases circulating levels of atrial natriuretic peptide (ANP), a Methods hormone with renal and cardiovascular effects. It has been shown that atrial Cohort study. Inclusion criteria: all cases underwent laparoscopic bariatric surgery; natriuretic peptide (ANP) is a potent stimulator of fat cell lipolysis in nZ89; 9 patients were excluded for incomplete follow up. Differences between the 2 addition of its well established effect in the blood pressure. The aim of this groups were evaluated using the Student t-test; P!0.05 was considered significant. study was to determine the status of natriuretic peptide system in female Results follitropin-receptor knockout mice (FORKO) that could be associated with nZ80 (35 LABG/45 LBG). obesity and hypertension observed in these mutants. FORKO and wild-type (WT) mice received daily injections of 17b-estradiol (E2)orvehicle,for Table 1 Baseline characteristics. 4 days. In the 5th day, blood was collected for determination of plasma ANP levels and some tissues were removed for determination of ANP, Sex (male/female) Age (years) Hospital stay (days) BMI (kg/m2) natriuretic peptide receptor type-A (NPr-A) and type-C (NPr-C) gene LABG 8.6/91.4 (%) 40G12.7 6.3G3.2 43.7G6.6 expression by RT-PCR. FORKO mice, that are obese, have lower circulating LBG 28.9/71.1 (%) 41.7G10.7 16.4G11.4 50.8G7.9 ANP levels and atria ANP gene expression and higher renal and adipocyte NPr-C gene expression than WT. E2 treatment induced a significant reduction of body weight and mesenteric adipose tissue weight only in Table 2 Evolution of BMI and percentage of excess weight loss. Stadistic FORKO. This reduction was accompanied by an increase of plasma ANP results. and atrial ANP gene expression in FORKO compared to WT. E2 treatment also induced a decrease of renal and adipocyte NPr-C gene expression in N (LABG/LBG) LABG LBG P
FORKO. In summary, this study shows that FORKO have an impaired 3 months 35/45 BMI (kg/m2) 37.4G5.5 39.4G5.8 – natriuretic peptide system and that E2 treatment improved this condition by PEWL 30.1G10.7 39.4G9.7 0.001 increasing atrial ANP synthesis as well as by decreasing ANP clearance 6 months 33/45 BMI (kg/m2) 35.7G5.2 35.2G6.3 – PEWL 37.9G14.6 56.9G12.1 0.001 receptors, resulting in enhancement of circulating ANP level. Thus, estrogen 12 months 27/43 BMI (kg/m2) 34.6G4.8 31.5G5.6 – regulated ANP system could have multiple roles in modulating obesity and PEWL 46.8G18.1 69G17.3 0.001 hypertension. 24 months 17/24 BMI (kg/m2) 34.9G4.4 32.4G5.8 – PEWL 41.6G19.8 66.1G20.5 0.001
Conclusions Bariatric surgery is a successful treatment to obtain an adecuate weight loss. The best results are observed during the first year. LBG had better results.
P486 The effect of various dyslipidemia management guidelines on the assessment of LDL-C goal attainment in population-based studies Pendar Farahani McMaster University, Hamilton, ON, Canada. P488 Overweight and obesity in Iranian adolescents Morteza Abdollahi, Mitra Abtahi & Anahita HoushiarRad Drug therapies are effective for improving lipid profiles. However, a large National Nutrition and Food Technology Research Institute, Tehran, Islamic proportion of patients and specifically high-risk patients appear unable to achieve Republic of Iran. the recommended goals for LDL-C level. Furthermore, the proportions of patients, who lack the targeted LDL-C goal, are inconsistent among different studies. Introduction Objectives The problem of increasing prevalence of overweight and obesity as a consequence To explore if application of different guidelines for the management of of new life styles is worrying the scientists and health officers in less developed dyslipidemia can influence the proportion of LDL-C target level achievement countries. In Iran that is experiencing an accelerated nutrition transition in a population level. overweight has turned into a major public health problem. Methods Objective To assess the attainment of LDL-C goal, data from a Canadian community- To determine overweight and obesity prevalence in Iranian adults. based (CCB) study (Clin Invest Med 2007 30 E63–E69) were evaluated Material and methods against three guidelines: the 2003 Canadian guideline for management of We have used data on 35 924 individuals (17 996 male) from the National Food dyslipidemia, the NCEP-APT guideline and AFSSAPS guideline. These Consumption Survey. This survey recruited 7158 households from urban and result were also compared with goal attainment observed in other studies, rural regions of all the 28 provinces of the country. Age was confirmed by including CALIPSO (Canada), L-TAP (USA), EUROASPIRE (Europe), observing the ID, weight and height were measured due to standard protocols and OLYMPIC (Greece), REALITY-PHARMO (The Netherlands), BKL-Thales BMI was calculated. Pre-obesity was defined as BMI R25 and obesity as BMI (France). R30. Overweight was defined as the sum of the pre-obesity and obesity. Results Findings Using the Canadian guideline, only 73% of patients in CCB study achieved the The average BMI was 25.5 among women and 26.4 among men. The prevalence goal for LDL-C level. About 96% of low risk and 62% of high risk patients of overweight was %42.4 among men and %56.5 among women. Obesity achieved the LDL-C goal. Similar results were obtained when data from the prevalence was %10 among men and %24 among women (P!0.001). Prevalence CALIPSO study were used. Conversely, the CCB study demonstrated a of pre-obesity and obesity among rural individuals is higher than their urban significantly different attainment of LDL-C targets compared with the studies counterparts (P!0.001). from Europe and the United States that used the NCEP-APT guideline or Conclusion AFSSAPS guideline to set the LDL-C target levels. Our data show that the prevalence of overweight and obesity in Iran especially Conclusion among rural women can be considered as a public health problem. After Several factors may contribute to the observed inter- country differences in goal conducting analytic studies to determine the determinants and risk factors of attainment, including different patient populations, different clinical practice overweight in different social layers, proper and feasible action plans are needed guidelines and different time frame when the results were obtained. to slow down the accelerated trend of obesity.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P489 P491 Obesity and it’s hormonal profile in saudi population Iranian overweight children and adolescents: who are seeking weight Adil Bahathiq, Afaf Alharthy, Ebtehaj Assery & Hind Nafady loss treatment? Um-Alqura University, Makkah, Saudi Arabia. Mohsen Maddah Guilan University of Medical Sciences, Rasht/Guilan, Islamic Republic of Iran. Objective To evaluate and to study obesity in Saudi female population represente by Makkah community. This study aims to investigate obesity, by detecting leptin Objective concentration and to take other parameters like body mass index (BMI) and waist This study described overweight/obese children and adolescents seeking weight circumference (WC) in assessing obesity. loss treatment regarding their age, gender, severity of obesity and maternal Methods education in Rasht City, northern Iran. Two-hundred forty women (nZ240) between the ages 18 and 65 participate in Design this study. Volunteers were divided into three groups. The first group was the A descriptive study on overweight children and adolescents setting: the main normal or control group with (BMI) range from 18 to 29.9, the second group were clinic of obesity management in Rasht, northern Iran. the obese and characterise with (BMI) R30 and finally obese diabetic group with Subjects body mass index (BMI) R30 and suffer from diabetes mellitus. Items collected Data on 1465 overweight/obese children and adolescents aged 2–18 years included height, weight, waist circumference and blood sample. Blood samples engaged in weight loss program were analyzed in this study. These data included were later thawed and serum leptin levels were detected with ELISA. age, sex, weight, height; self reported parental weight and height, history of Result dieting, and mother’s level of education. Leptin was measured in all the groups and their means found to be (8.4G1.4) in Results normal, (56.3G18.8) in obese and (42G19.3) in diabetic obese group. Leptin Overweight/obese girls engaged in weight loss program more than overweight/- levels were directly associated with BMI (rZ0.152, PZ0.178) in normal group, obese boys (71.2% vs 28.8% P! 0.0001). Only 3.2% of the children were in age and strong positive correlation in obese group and diabetic obese as the follow: group 2–6 years. These data showed that 18.2% of the overweight/obese children (rZ0.350, PZ0.001), (rZ0.355, PZ0.001). Also, leptin concentrations were and adolescents were from families with low maternal education and the positively correlated with WC in obese and diabetic obese. remainders were from families with high maternal education. Mean excess body Conclusion weight was not different across educational levels although the boys were heavier Leptin concentrations were found to be high in both obese and diabetic obese than girls at. These findings showed that the maternal body weight was related to group and showed a directly positive relation with BMI and waist circumference. the child’s excess weight (rZ0.26 P!0.0001). Understanding that leptin hormone influencing appetite and body weight that Conclusion cause obesity. However, serum leptin concentration changes in response to many These data suggest that parents of overweight/obese children and adolescents features like fasting, hypertension, practice physical activity, smoking or follow from low social level, boys and young children across all maternal educational special diet. levels should be warned against risk of their children’s accelerated growth.
P490 P492 Metabolic and hormonal patterns in men under the age 40 years with Adiponectin induces CXCL8 in primary human hepatocytes via the obesity and metabolic syndrome adiponectin receptor 1 Nikolai Goncharov, Gulinara Katsya & Nina Chagina Josef Wanninger1, Markus Neumeier1, Johanna Weigert1, Thomas Weiss2, Endocrinology Research Center, Moscow, Russian Federation. Cornelius Bollheimer1, Roland Buettner1, Andreas Scha¨ffler1, Ju¨rgen Scho¨lmerich1 & Christa Buechler1 1 2 Internal Medicine I, Regensburg, Germany; Department of Surgery, Objectives Regensburg, Germany. To assess the androgens profile (total testosterone (TT),free testosterone (fT), SHBG, and DHEA-sulphate), cortisol, aldosterone, insulin, and leptin in patients with obesity (OB), metabolic syndrome (MS) and healthy men (HM). Background Subjects and methods Adiponectin was suggested to exert hepatoprotective effects in animal models of Group 1: 26 men with obesity, age 30G6 years. BMI 27–35 kg/m2. Group 2: tetrachlorcarbonate-, endotoxin- and alcohol-induced liver injury. Further, in 34 men with MS, age 31G6 yrs. BMI 30–36 kg/m2. Group 3: 20 healthy men, age patients with non-alcoholic fatty liver disease (NAFLD) low adiponectin levels 28G5 yrs, BMI 20–24 kg/m2. All antropometrical parameters such WC,HC, and were found to be associated with more severe steatosis and hepatic inflammation. WC/HC ratio were determined. Additionaly we used MRT. All biochemical Methods variables (glucose, spectrum of lipids) were measured by standard methods. The To investigate the molecular basis of the hepatoprotective effects of levels of TT, DHEA-S, SHBG, insulin and leptin were measured in serum the adiponectin primary human hepatocytes were incubated with recombinant using validated direct immunoassay method. Aldosterone was measured by RIA. adiponectin for 24 h. GeneChip analysis was performed and CXCL8 mRNA Results was found induced. Significant association between antropometric, metabolic and hormonal Results parameters was found. There was a progressive decline of plasma TT with Adiponectin upregulated CXCL8 mRNA and induced CXCL8 secretion in increasing obesity, particularly in men with MS. There were no differences in primary human hepatocytes. Elevated CXCL8 in the supernatants was cortisol levels between the groups. measured as early as 3 h after the addition of adiponectin to the hepatocytes. Adiponectin receptor 1 and 2 are expressed in hepatocytes and knock-down of AdipoR1, but not AdipoR2, by siRNA abrogated adiponectin induced CXCL8 release. The p38 MAPK inhibitor SB203580 did not significantly Indices (Me) Ms Obesity Healthy diminish adiponectin-mediated release of CXCL8. Electrophoretic mobility shift assays (EMSAs) revealed that adiponectin activated NFkBinprimary TT nmol/l 11.2 14.8 21.9 fT pmol/l 258 280 372 hepatocytes but not in HepG2 cells. The hepatocytic cell lines HepG2, SHBG nmol/l 24 35 40 Hep3B and PLC were also incubated with adiponectin but CXCL8 release Insulin mIU/ml 14 7 4 was not significantly induced in these cell lines. Leptin ng/ml 26 14 5 Conclusions DHEA-S nmol/l 2841 3925 4617 The current experiments revealed that adiponectin activated NFkappaB and Aldosterone pmol/l 459 335 244 induced CXCL8 in primary human hepatocytes whereas hepatocytic cell lines were resistant to the effects of adiponectin. So far the role of CXCL8 Conclusion in hepatic injury is not clearly established. Whereas CXCL8-mediated Multivariate regression analyses shows that many predictive factors of variability recruitment of neutrophils may be harmful to the liver, CXCL8 was also in plasma TT levels are directly or indirectly related to SHBG in patients with described to protect the liver against galactosamine/endotoxin and T-cell MS. If plasma TT levels were included in the classification of diagnostic ATP III mediated apoptosis. criteria, it would improve identification of MS from 79 to 85% among patients with obesity. Changes in aldosterone levels go in parallel with increasing insulin
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 and decreasing testosterone levels. Possible mechanisms of the above associations Conclusion will be discussed. The prediction of susceptibility to diet-induced obesity is possible using simple auxologic parameters. Individual differences in skeletal muscle gene expression could contribute to the development of the DIO/DR-phenotype.
P493 Prevalence of overweight in comparison to wasting, among Iranian P495 under 5 year-old children in urban and rural A pharmacologic sympathectomy prevents the development of obesity Mitra Abtahi, Anahita Houshiarrad, Morteza Abdollahi & and insulin resistance in the high fat fed rat Behnoush Mohammadpour Ahranjani Cornelius Bollheimer, Peter Ha¨rle, Andreas Scha¨ffler, Christa Bu¨chler, National Nutrition and Food Technology Research Institute, Tehran, Islamic Christian Wrede, Rainer Straub, Ju¨rgen Scho¨lmerich & Roland Bu¨ttner Republic of Iran. University of Regensburg, Regensburg, Germany.
Introduction and aim Background Beside protein–energy malnutrition among children, high prevalence of over- Obese patients show an increased activity of the sympathetic nervous system, but weight is also a public health problem and a major nutritional challenge in most the causality of the relationship is not known. Here, we examine whether a developing countries. The aim of this research was to determine and compare the pharmacologic sympathectomy influences diet-induced obesity and insulin prevalence of wasting, overweight and obesity among Iranian urban and rural resistance in the high fat fed rat model. under 5 year -old children. Methods Subjects and methods Wistar-Rats were fed ad libitum with a high fat diet (HF, 40 energy% of fat, based This study was based on national comprehensive study on household food on lard) for 12 weeks. A pharmacologic sympathectomy was performed by a) consumption pattern and nutritional status (2001–2003). Seven thousand and one weekly intraperitoneal applications of 6-hydroxydopamine (S1, nZ6) or b) a hundred and fifty eight households in rural and urban areas were selected single application of a saporin-bound dopamine-b-hydroxylase-antibody (S2, randomly. Weight and height of 2562 children (! 5 years) were measured and nZ6) and verified by spleen immunohistochemistry. Insulin sensitivity was recorded using the standard protocol. Wasting was defined based on NCHS/WHO assessed by insulin tolerance tests and measurement of fasting glucose and insulin cutoffs (weight for age %2SD Z-scores, respectively) and overweight defined as levels. weight for age R2SD. Data were analyzed using MS Access, and SPSS 11.0 Results softwares. Sympathectomy was successful in both experimental groups. Weight gain was Results reduced by 25% (S1, P%0.05) and 30% (S2, P%0.05), respectively, when Children under five years old were 7% of total population. The Prevalence of compared to untreated controls. Fasting glucose did not differ significantly wasting among children was 10% (2–26%). The Prevalence in rural areas was 4% between the S1/S2 groups and the controls. Serum fasting insulin was reduced by higher than urban areas (14% vs 10%, P!0.01).The prevalence of overweight 70% in S1 (P%0.05) and by 75% in S2 (P%0.05), respectively. Consistently, the were 3% (1–6%) and in urban and rural areas were similar (4% vs 4.5%). in vivo insulin tolerance tests revealed an improved glucose disposal in the S1 and Discussion S2 animals when compared to the controls. Evidence suggests that the prevalence of wasting among Iranian children Conclusions especially among rural area is a major nutritional problem. A pharmacologic sympathectomy can impede the development of obesity and According to high prevalence of overweight and obesity among this age group, insulin resistance in the high fat diet animal model. This effect could be used for there is a need to implement nutritional strategies at micro and macro levels for the generation of new therapeutic strategies against the metabolic syndrome. preventing and controlling malnutrition.
P496 P494 Lipid-loaded hepatocytes release soluble factors that activate hepatic Gene expression profiling in skeletal muscle from diet-induced obesity stellate cells: a new in vitro model to study fibrogenesis in NASH susceptible rats Hella Wobser, Christoph Dorn, Thomas Weiss, Ju¨rgen Scho¨lmerich & Roland Bu¨ttner, Andreas Scha¨ffler, Christa Bu¨chler, Christian Wrede, Claus Hellerbrand Ju¨rgen Scho¨lmerich & Cornelius Bollheimer University Clinic, Regensburg, Germany. University of Regensburg, Regensburg, Germany. Background Background Non-alcoholic steatohepatitis (NASH) can progress to hepatic fibrosis and end- The variablity of the individual susceptibility to diet-induced obesity and insulin stage liver disease. Hepatic stellate cells (HSC) are the central mediators of liver resistance is well known, but so far insufficiently explained. As skeletal muscle fibrosis. The molecular mechanisms linking hepatic steatosis to activation of metabolism and insulin sensitivity are important pathophysiologic features of HSC, thereby promoting inflammation and fibrosis, are mainly unknown. Here, obesity-asscociated metabolic perturbations, we tried to identify differences we demonstrate a novel in vitro model to study the effect of hepatic lipid in muscular gene expression profiles between high fat fed rats prone to accumulation on HSC. develop obesity (diet-induced obesity, DIO) and those which remained lean Methods and results (diet-resistant, DR). After exposure of human hepatocytes to the saturated fatty acid palmitate (PA), Methods significant intracellular lipid accumulation was documented morphologically and Wistar-Rats were fed ad libitum with a high fat diet (HF, 40 energy% of fat) for 12 by colorimetric assays. Subsequently, conditioned-media (CM) from PA-treated weeks. Weight changes and food intake as well as serum and cerebral spinal fluid hepatocytes were used for stimulation of HSC, leading to enhanced proliferation (CSF) glucose, insulin, leptin and adiponectin were monitored during the diet and induction of the activation process of HSC. Furthermore, CM from phase. Using these parameters, a model for the identification of DIO rats was PA-treated cells significantly induced a pro-inflammatory (MCP-1) and established. Next, gene expression profiles were obtained using Affymetrix fibrogenic gene expression (Collagen I, TGF-beta, TIMP-1/-2, MMP-2) in GeneChips from the M. gastrocnemius of DIO and DR rats after one week of HF HSC. Flow cytometric analysis revealed a significant apoptosis resistance of HSC diet, i.e. before induction of obesity. after stimulation with CM from steatotic hepatocytes. Results Summary and conclusion No clear association between the animals’ weight curves and any serum or CSF Lipid accumulation in hepatocytes causes the secretion of soluble mediators that parameter was noticed, whereas the ratio between the absolute weight gain after stimulate activation and proliferation of HSC as well as the expression of pro- one week and the rats’ initial weight (weight gain index, WGI) was significantly inflammatory and fibrogenic genes in HSC. These findings demonstrate a correlated with the final weight and could therefore be used to predict obesity potential mechanism how hepatic steatosis contributes to the progression of susceptibility. In skeletal muscle of DIO rats we detetected a striking inflammation and fibrosis in NAFLD. Furthermore, this study provides an transcriptional upregulation of genes from the MAP (mitogen acivated protein)- attractive in vitro model to identify innovative anti-fibrotic strategies for the kinase pathway, intracellular calcium-sensing, pyruvate metabolism and of Rab- therapy of NAFLD/NASH. asscociated proteins participating in vesicle transport and GLUT4 translocation.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P497 1Institute of Experimental Pediatric Endocrinology, Charite´ University 2 Insulin resistance, atherogenic dyslipidemia and other atherogenic Children’s Hospital, Berlin, Germany; Institute of Neuropathology, Charite´ factors in simple obesity and obesity with Acanthosis nigricans (an) in University Hospital, Berlin, Germany. childhood Istvan Ilyes1, Eniko¨ Felszeghy1, Zita Va´radi2, Ildiko´ Seres2 & 2 The highly conserved Leptin-Melanocortin signaling pathway plays a central role Gyo¨rgy Paragh in the regulation of body weight and energy expenditure. Mutations in POMC and 1Pediatric Department, Medical and Health Science Center, University of 2 MC-4R lead to dosage dependent monogenetic obesity. However, several Debrecen, Debrecen, Hungary; 1st Deprtment of Internal Medicine, evidences suggest an epigenetic impact on the regulation of body weight. Medical and Health Science Center, University of Debrecen, Debrecen, Moreover it has been shown recently that variants of the FTO gene, which affects Hungary. ss DNA methylation in the arcuate nucleus, correlate with increased body weight in children and adults. We therefore investigated the epigenetic state of the MC- The aim of the study was to investigate insulin resistance, dyslipidemia and 4R and POMC gene in different, obese and normal individuals, in different tissues atherogenic factors influencing HDL functions in symple obesity (SO) and and in different species. We analysed the DNA methylation pattern of the POMC obesity with acanthosis nigricans (OAN). Althogether 37 children with obesity, and MC-4R gene with bisulfite cloning technique in human peripheral blood cells, 17 girls and 20 boys, 19 with SO and 18 with OAN, were included into the study. microdissected human ß-MSH expressing cells in the arcuate nucleus and in mice Their age was 14.2G1.8 years and BMI was 35.9G6.1 kg/m2. peripheral blood cells. Promoter activity has been analysed with Luciferase- Fasting glucose (FG), insulin (INS) were measured and HOMA-IR was Reporter-Gene-Assays. Comparing DNA from non-expressing peripheral blood calculated. Total cholesterol (T-C), LDL-C, HDL-C, triglycerid (Tg), apoproteins cells and expressing arcuate neurons we observed a non-tissue specific POMC (Ap-AI and AP-B100), lipoprotein a) /Lp(a)/were measured, and paraoxonase DNA methylation pattern, which was also conserved in mouse peripheral blood (PON-1), arylesterase (ARYL), lecitin cholesterol acyltransferase (LCAT), cells. We obtained a significant over-all hypermethylation in one CpG island of cholesterol-ester transfer protein (CEPT) activities, intracellular adhesion the POMC gene in peripheral blood cells in obese compared to normal weight molecule-1 (ICAM-1) and vascular adhesion molecule (VCAM) concentrations individuals. In in vitro studies we could demonstrate that expression of the MC- were determined. 4R gene was decreased after methylation of the promoter fragment. This study FG was normal in all obese patients, hyperinsulinemia was detected in 27, insulin reveals a distinct evolutionary conserved DNA methylation pattern of the POMC resistance in 31 cases of 37 children. Increased T-C and LDL-C in 5–5, increased Tg and MC-4R gene, suggesting a functional role of methylation in melanocortin in 6 and decreased HDL-C in 9 patients were found, abnormal Ap-AI in 13, Ap-B100 gene function. In aggreement with that the MC-4R promoter can be silenced by in 5, Lp(a) in 11 cases were detected. Frequencies of abnormal INS, Tg and HDL-C DNA methylation in vitro. In obese individuals we observed significant values were higher in OAN than in SO. PON1, ARYL, LCAT and CEPT activities as differences in the DNA methylation pattern of the POMC gene, which might well as ICAM-1 and VICAM-1 did not differ. ICAM-1 levels were higher in patients lead to altered gene function and might contribute as an epigenetic alteration to with low HDL-C than in cases with normal HDL-C, and a significant negative the onset of obesity. correlation was found between PON-1 and ICAM-1. These results demonstrate that insulin resistance and atherogenic dyslipidemia are more frequent in OAN than SO, and they also suggest that atherogenic dyslipidemia in childhood obesity has a complex influence to the parameters related to HDL P500 function. Retinol-binding protein 4 (RBP-4) levels do not change after oral glucose tolerance test in obese and overweight individuals, but correlate with some indices of insulin resistance Krzysztof C Lewandowski1, Magdalena Basinska-Lewandowska2, P498 Malgorzata Bienkiewicz3, Harpal S Randeva4 & Andrzej Lewinski1 1 Tribbles pseudokinases and adipose tissue biology Department of Endocrinology and Metabolic Diseases, Medical University of Lodz, Lodz, Poland; 2Department of Family Medicine, The Medical Anke Ostertag & Stephan Herzig 3 German Cancer Research Center, Heidelberg, Germany. University of Lodz, Lodz, Poland; Department of Quality Control and Radiological Protection, The Medical University of Lodz, Lodz, Poland; 4Department of Biological Sciences, The University of Warwick, Obesity, insulin resistance and high cholesterol levels are hallmarks of the Coventry, UK. metabolic syndrome. The molecular players involved in the onset of the metabolic syndrome are mostly unknown. In this context the three pseudokinases of the tribbles family have emerged as potential candidates. Among them, TRB3 has Background been described as a negative regulator of Akt, a key player in insulin signal Secretory products from adipocytes may contribute to increased insulin resistance transduction. However, the biological functions of TRB family members remain (IR). Retinol-binding protein-4 (RBP-4) may increase IR in mice, with elevated largely unknown. Therefore, the aim of this study was to learn more about the levels in insulin resistant mice and humans with obesity and type 2 diabetes. metabolic role of the three tribbles orthologs. Mechanisms regulating RBP-4 synthesis remain not fully understood. It is not Analysis of tribbles mRNA expression in wt C57Bl/6J, db/db and ob/ob mice under clear whether short-term hyperglycaemia alters RBP-4 levels in humans. In order fasting and refed conditions revealed that in both diabetic animal models the to investigate this, we measured serum RBP-4 concentrations during 75 gram oral expression of TRB1 is significantly upregulated in adipose tissue. The expression of glucose tolerance test (OGTT). TRB3 is upregulated due to fasting conditions only in wt and db/db and the Subjects and methods The study included 24 subjects (5 males), age 38.7G15.1 years, BMI 34.4G8.3 expression of TRB2 was not altered under any condition. Furthermore, in adipose 2 tissue of C57Bl/6J mice treated with either dexamethasone for three weeks or with kg/m . Glucose, insulin and RBP-4 were measured at 0, 60 and 120 min of OGTT. ! LPSfor eight hours an upregulation of TRB1 and a downregulationof TRB3 could be IR was assessed by HOMA (calculated as fasting insulin (mU/ml) fasting observed compared to control animals, pointing to a role of TRB1 in the control of glucose (mmol/l)/22.5) and by Insulin Resistance Index (IRI) that takes into adipose tissue metabolism. To test for the cell autonomy of these effects, 3T3-L1 account glucose and insulin levels during OGTT. IRI is calculated through the ! C adipocytes were treated with different stimuli and analyzed for TRB expression formula: 2/(1/(INSp GLYp)) 1, where INSp and GLYp are the measured patterns. Whereas, TRB1 expression was found to be upregulated due to insulin, insulin and glycaemic areas. dexamethasone, and LPS, TRB3 expression was downregulated. Results The opposite regulation of TRB1 and TRB3 might be indicative of a role for these Glucose administration resulted in significant increases in insulin and glucose ! G pseudokinases in the control of adipose tissue biology. Therefore, future experiments (P 0.0001). There was, however, no change in RBP-4 concentrations (124.1 G G will address TRB-dependent signalling pathways in these cells and investigate their 32 mg/ml at 0 min, 123 35 mg/ml at 60 min and 126.5 37.5 mg/ml at 120 min of Z Z impact on the obesity phenotype. OGTT, P ns). RBP-4 correlated moderately with fasting insulin (r 0.40, PZ0.025), fasting glucose (rZ0.41, PZ0.02) and HOMA (rZ0.43, PZ0.015), but not with IRI (rZ0.19, PZ0.31). There was, however, only a moderate correlation between HOMA and IRI (r2Z0.24; PZ0.006) (Spearman rank correlation), while the best correlation was obtained between the product of glucose and insulin levels at 60 min of OGTT and IRI in a non-linear model (r2Z P499 0.88; P!0.00001). Differences in the POMC methylation pattern in normal weight and Conclusions obese individuals and regulation of MC-4R promoter activity by DNA RBP-4 levels do not change during oral glucose tolerance test, so it is unlikely that methylation RBP-4 is involved in short-term regulation of glucose homeostasis. Moderate Peter Kuehnen1, van Landeghem Frank2, Grueters Annette1 & Krude Heiko1 correlation between RBP-4 and HOMA suggests, however, that RBP-4 may be
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 one of many factors that influence insulin sensitivity in humans. Lack of the physical activity programs should be considered. In addition, the educational correlation between RBP-4 and IRI may be a consequence of a limited correlation program to improve nutritional knowledge of this population is essential. between static (HOMA) and dynamic indices of insulin resistance (IRI).
P503 Expression of the different components of the endocannabinoid system P501 (ECs) in morbid obesity Valentina Vicennati1, Uberto Pagotto1, Cristina Cervino1, Enrico Amenta2, Overweight adolescents, a group at risk for metabolic syndrome Stefano Cariani2 & Renato Pasquali1 (Tehran Adolescent Obesity Study) 1Endocrinology Unit, Bologna, Italy; 2General Surgery, Bologna, Italy. Heshmat Moayeri, Katayoon Bidad, Ali Rabbani & Zarrin Keihani doust Tehran University, Tehran, Islamic Republic of Iran. Visceral fat (VAT) may represent the more important site of endocannabinoid dysregulation in obesity. No data are available on the expression of the ECs Background in morbid obesity. Eleven morbidly obese women, who underwent bariatric Metabolic syndrome not only is a serious problem for adults, but is also afflicting surgery, were enrolled and paired samples of VAT and subcutaneous fat an increasing number of children and adolescents. This syndrome is a risk factor tissue (SAT) were obtained from each patient. Real-Time PCR for the gene for type 2 diabetes mellitus and cardiovascular diseases. The aim of this study was expression levels of cannabinoid type 1 (CB1) receptor, N-acyl-phosphatidil- to estimate the prevalence of metabolic syndrome in a sample of Iranian ethanolamine (NAPE), and fatty acid amide hydrolase (FAAH) which adolescents. respectively sinthesize and degradate anandamide (AEA) and, diacylglycerol Methods lipase (DAGL-b) and monoacylglycerol lipase (MAGL), which respectively A total of 554 overweight adolescents (aged 11–17 years) participated in a synthesize and degrade 2-arachidonoyl-glycerol (2-AG) was performed. After community-based cross sectional survey. Anthropometric examinations including extraction and after exclusion of genomic DNA contamination, 1 mg RNA height, weight, body mass index, and blood pressure were assessed. A fasting was reverse transcribed using oligodT primers. Real-time cDNA quantification blood sample was taken for measurement of glucose and lipid profile. Metabolic w was performed by a thermocycler. iCycler iQ (BioRad). CB1, FAAH, syndrome was determined by the definition released by the National Cholesterol w NAPE-PLD, DAGL-b and MAGL primers for SYBR Green analysis were Education Program Adult treatment Panel III, which was modified for age. w designed by ‘Beacon Designer ’ and synthesized by Invitrogen. Assays were Results performed in duplicate and a standard curve from consecutive 10-fold The overall prevalence of metabolic syndrome was 26.6%. There was no gender dilutions of a cDNA pool representative of all samples, was included for each difference in the distribution of metabolic syndrome. When stratified by body determination. Relative expression analysis was corrected for PCR efficiency mass index, 22.5% of the overweight (BMIR95th percentile) adolescents met the and normalized respect to reference gene b-actin. BMI was 46.3G1.38 kg/m2. criteria for MS, while 4.1% of the adolescents who were at risk for overweight Total cholesterol was 186G12.8 mg/dL, HDL-cholesterol 53.3G3.74 mg/dL (BMI between 85th and 95th percentile) had MS (P!0.001). Hypertriglycer- and triglycerides 118G16.3 mg/dL. CB1 mRNA was significantly higher in idemia was the most common and low high density lipoprotein (HDL) was the SAT than in VAT. VAT had a significantly higher expression of NAPE than least common constituent of metabolic syndrome. SAT. There was no difference in FAAH mRNA between SAT and VAT. SAT Conclusion displays a higher expression of MAGL than VAT, not reaching the statistical This study suggests a high prevalence of metabolic syndrome among overweight significance. DAGL-b was more significantly expressed in SAT than in VAT. Iranian adolescents. This poses a serious threat to the current and future health of These data, obtained in morbid obesity, suggest that the ECs plays a crucial Iranian youth. role not only in VAT but also in SAT, underlying the differences in the ECs dysregulation when morbid obesity without metabolic alterations is compared to abdominal obesity with metabolic alterations.
P502 The obesity, physical activity status and dietary pattern in 10–12 years old girls of a mountainous region in north of Iran Nahid Salarkia1 & Homeira Nasiri Reineh2 1National Nutrition and Food Technology Research Institute, Tehran, Iran, P504 Islamic Republic of Iran; 2Open University, Tonekabon, Iran, Islamic Plasma adrenomedullin positively correlates to body mass index, and Republic of Iran. significantly decreases after bariatric surgery Martin Clodi1, Greisa Vila1, Michaela Riedl1, Ammon Handisurya1, Christina Maier1, Nils G Morgenthaler2 & Anton Luger1 Background 1Division of Endocrinology and Metabolism, Department of Internal It has been shown that one of major causes of obesity in young people could be Medicine III, Medical University of Vienna, Vienna, Austria; 2Research explained by physical inactivity and fat intake. Department, BRAHMS AG, Biotechnology Centre, Hennigsdorf, Germany. Purpose This study was carried out to investigate the prevalence of obesity, dietary pattern and physical activity status in Tonekabon girls, a mountainous city in north of Adrenomedullin is a vasoactive peptide originally discovered in extracts of Iran. human pheochromocytoma. It is highly expressed in plasma and adipose tissue of Methods obese subjects and considered as a member of the adipokine family. In a cross-sectional study 311 girls aged 10–12 years old in Tonekabon were Adrenomedullin inhibits adipogenesis under the transcriptional control of insulin. studied. Weight, height, waist and hip circumferences of subjects were measured. We determined plasma adrenomedullin concentrations in a cohort of 360 healthy Body mass index (BMI) and WHR (waist-to-hip ratio) were calculated. Food subjects and found a very significant positive correlation to body mass index intake was assessed by using three 24-hour dietary recall and food frequency (BMI). In parallel, 28 morbidly obese patients were selected from the cohort questionnaire. Physical activity level was measured using the physical activity scheduled to undergo laparoscopic gastric bypass surgery, and studied at two time questionnaire. Subjects were classified based on the intensity of effort as having points: just before and one year after surgery. As expected, bariatric surgery light, moderate, heavy and very heavy levels of physical activity. induced significant decreases in body weight, BMI, insulin resistance, plasma Results leptin, total cholesterol, LDL-cholesterol and CRP. Plasma adrenomedullin levels The prevalence of overweight and obesity was 17 and 6%, respectively. 65% of decreased one year after bypass surgery in all the subjects studied: preoperative subjects had normal weight and 12% were underweight. In 30% of the adrenomedullin was 0.757G0.033 and postoperative values were 0.624G0.025 participants WHR was R0.85.The mean percentage values of energy intake (P!0.001). In obese subjects, basal plasma adrenomedullin significantly derived from carbohydrate, protein and fat were 60, 11 and 29%, respectively. correlated with leptin. Moreover, there was a positive association of surgery The physical activity level of subjects was 45, 43 and 12% that was light, induced changes in plasma adrenomedullin and leptin. In summary, we present moderate and heavy, respectively. here a positive significant correlation of adrenomedullin with BMI in healthy Conclusion patients. Weight loss after bariatric surgery is associated with a significant This study showed that overweight and obesity is common in this population. decrease in plasma adrenomedullin. Thus prevention of overweight and obesity through a healthy diet and increasing
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P505 months) admitted with fever R38 8C and nonspecific infection (upper respiratory tract Plasma osteopontin correlates with insulin resistance in obese subjects, infection, otitis, urine tract infections) symptoms were included. Their ideal body but increases following bariatric surgery parallel to other markers of weights (IBW) for height were within 100–110%. Venous blood samples were taken bone turnover from them both during the period of the fever at admission and three days later after the fever dropped (control) for analyzing serum AN levels and complete blood count Michaela Riedl1, Greisa Vila1, Christina Maier1, Ammon Handisurya1, 2 2 3 (CBC), erythrocyte sedimentation rate and CRP, Hs-CRP, fibrinogen, ferritin, glucose, Soheila Shakeri-Manesch , Gerhard Prager , Oswald Wagner , insulin, total cholesterol, triglyceride, LDL-C, HDL-C levels. Serum AN levels at the Alexandra Kautzky-Willer1, Martin Clodi1 & Anton Luger1 1 admission (8.8G1.7 mg/ml) were lower than at the control visit (12.04G Division of Endocrinology and Metabolism, Department of Internal ! 2 2.38 mg/ml)(P 0.0001). Serum AN levels were not correlated with the degree of Medicine III, Medical University of Vienna, Vienna, Austria; Division of fever, BW, IBW, body-mass index, homeostasis model assessment (HOMA-IR), and General Surgery, Department of Surgery, Medical University of Vienna, O 3 the all other parameters analyzed in the study (P 0.05) in both analysis except Vienna, Austria; Clinical Institute of Medical and Chemical Laboratory glucose/insulin ratio at the admission (rZ0.33, P!0.05). Serum glucose levels, Diagnostics, Medical University of Vienna, Vienna, Austria. glucose/insulin and HDL-C levels were higher (P!0.01, P!0.05 and P!0.001, respectively) and triglyceride and LDL-C levels were lower (P!0.001, P!0.01, Osteopontin (OPN) is a multifunctional glycoprotein implicated, among others, in respectively) at the admission than at the control. Lower serum AN levels were found in bone metabolism, cardiovascular disease, diabetes and obesity. It promotes children with fever during the acute phase of nonspecific infections. It is suggested that inflammation and insulin resistance. Osteopontin is elevated in the plasma and AN may have anti-inflammatory and acute phase reactant roles in infections. adipose tissue of obese subjects and decreases upon diet induced weight loss. Here we investigated the effect of bariatric surgery on plasma OPN concentrations in morbidly obese patients. 40 obese patients aged 43.1G1.8 years were recruited from the cohort scheduled to undergo bariatric surgery. Roux-en-Y gastric bypass (RYGB) was performed in 30 subjects (27 females, 3 males), and laparoscopically adjustable P508 gastric banding (LAGB) in 10 subjects (8 females, 2 males). All patients were studied NCEP-ATP-III defined metabolic syndrome, type 2 diabetes mellitus before and one year (10.3 to 14.8 months) after the surgical intervention. Prompted by and prevalence of hypogonadism in male patients with sexual the associations of OPN with both bone metabolism and metabolic diseases, we dysfunction explored the changes in metabolic, inflammatory and bone turnover parameters. Both Giovanni Corona1, Edoardo Mannucci2, Luisa Petrone1, bariatric procedures significantly reduced body weight, body mass index (BMI), 3 3 1 1 G Giancarlo Balercia , Federica Paggi , Alessandra Fisher , Francesco Lotti , insulin, leptin and CRP one year after surgery. Plasma OPN increased from 31.38 Valerio Chiarini4, Gianni Forti1 & Mario Maggi1,5 3.8 to 52.81G3.7 ng/ml after RYGB (P!0.001) and from 29.76G6.9 to 46.4G 1 2 Z Andrology Unit, University of Florence, Florence, Italy; Diabetes Section 10.6 ng/ml after LAGB (P 0.042). Preoperative OPN correlated with age, insulin, Geriatric Unit, University of Florence, Florence, Italy; 3Endocrinology Unit, HOMA insulin resistance index and postoperative OPN. Postoperative OPN Polytechnic University of Marche, Ancona, Italy; 4Endocrinology Unit, correlated with C-telopeptide and OC. In summary, plasma OPN levels significantly Maggiore-Bellaria Hospital, Bologna, Italy; 5Endocrinology Unit, rise and correlate with biomarkers of bone turnover one year after RYGB and LAGB. Unlike other pro-inflammatory cytokines, OPN does not normalize, but further University of Florence, Florence, Italy. increases after bariatric surgery. Objectives Type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) are characterized by insulin resistance and often associated with male hypogonadism. To discriminate the specific contribution of T2DM and MetS to male hypogonadism. P506 Design and methods G Cholinergic regulation of meal induced ghrelin and PYY release is A consecutive series of 1134 (mean age 52.1 13 years) male patients with sexual impaired in obesity dysfunction was studied. Several hormonal and biochemical parameters were studied Christina Maier1, Michaela Riedl1, Greisa Vila1, Michael Wolzt2, along with ANDROTEST, a 12-item validated structured interview, specifically 1 1 1 designed for the screening of hypogonadism (total testosterone TT, !10.4 nmol/l or Martin Clodi , Bernhard Ludvik & Anton Luger ! 1Division of Endocrinology and Metabolism, Department of Internal free-testosterone FT, 37 pmol/l) in a male population with sexual dysfunction. Medicine III, Medical University of Vienna, Vienna, Austria; 2Department Results of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria. Irrespective of the criteria used to define hypogonadism, MetS was associated with a significantly higher prevalence of the condition, both in subjects with and without T2DM (41 and 29% vs 13.2% and 77.1 and 58% vs 40.6%; respectively for Ghrelin and PYY are gastrointestinal peptides involved in appetite regulation. The TT and FT in patients with MetS and with or without T2DM, when compared with cholinergic part of the vagal nerve participate in the regulation of glucose and insulin subjects without MetS and T2DM; both P!0.0001). Conversely, T2DM was levels. We aimed to examine the effects of the cholinergic antagonist atropine on associated with a higher prevalence of hypogonadism in subjects with MetS but not ghrelin, PYY, glucose and insulin under basal conditions and after meal ingestion in in those without MetS. Patients with MetS, with or without T2DM, also showed a lean and obese subjects. Eight lean and eight obese subjects received in a higher ANDROTEST score when compared with patients without MetS. Logistic randomized, double-blind, placebo controlled crossover study design (1) placebo, multivariate regression analysis, incorporating the five components of MetS, (2) placeboCbreakfast, (3) atropine and (4) atropineCbreakfast. Plasma ghrelin, identified a significant association of elevated waist circumference and hyper- PYY, insulin and glucose were measured. Hunger and satiety feelings were rated on triglyceridaemia with hypogonadism both in patients, with or without T2DM. 10 cm visual analog scales. In lean individuals atropine led to a decrease in plasma Conclusions ghrelin and to a significant decrease in both basal and meal induced PYY Our study demonstrated that MetS and in particular visceral adiposity (as assessed concentrations. In obese subjects atropine did not significantly change ghrelin or by increased waistline and hypertriglyceridaemia) is specifically associated with PYY concentrations whereas it induced a comparable increase in heart rate and in hypogonadism in subjects consulting for sexual dysfunction. meal induced glucose concentrations in the two study groups. Only lean, but not obese subjects experienced sustained feelings of satiety after breakfast. We suggest that the impaired cholinergic regulation of the postprandial drop in ghrelin concentrations and rise in PYY concentrations might be part of the deregulated food intake in obese subjects. P509 Interleukin-1ß is a positive regulator of TIARP/STAMP2 in 3T3-L1 adipocytes Grit Sommer, Susan Kralisch, Sebastian Weise, Lossner Ulrike, Bluher Matthias, Stumvoll Michael & Fasshauer Mathias P507 University of Leipzig, Department of Internal Medicine III, Leipzig, Serum adiponectin levels in children with nonspecific infections: Germany. relations with fever and acute phase reactants Banu Aydin, Birgu¨l Kirel & Basar Sirmagu¨l Osmangazi University Faculty of Medicine, Eskisehir/Eskisehir, Turkey. Tumor necrosis factor alpha-induced adipose-related protein (TIARP)/six-trans- membrane protein of prostate 2 (STAMP2) has been characterized as an adipocyte- expressed protein which might play a crucial role in metabolic homeostasis and It has been shown that adiponectin (AN) has antidiabetic, antiatherosclerotic and inflammatory pathways. In the current study, the impact of insulin resistance-inducing antiinflammatory activities. We analyzed serum AN levels in children with nonspecific and proinflammatory interleukin (IL)-1ß on TIARP/STAMP2 gene expression was infections. Forty-two prepubertal children (18 boys, 24 girls, age range: 14–163 determined by quantitative real-time reverse transcription-polymerase chain reaction in
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
3T3-L1 adipocytes. Interestingly, TIARP/STAMP2 mRNA synthesis was significantly access to HF–LC. In conclusion, the weight loss observed on HF–LC diet with pair stimulated by IL-1ß in a dose-dependent fashion with 2.6-fold induction seen at IL-1ß feeding was not seen in an ad libitum setting, but changes in metabolic parameters concentrations as low as 0.02 ng/ml and maximal 9.2-fold upregulation found at 20 ng/ml and IGF-I seem to be similar. Also in humans reduced palatability and availability effector. Furthermore, induction of TIARP/STAMP2 mRNA by IL-1ß was time- of food items on HF–LC diets might lead to a reduced caloric intake and thus dependent with maximal 18.6-fold upregulation detectable after 8 h of IL-1ß treatment. explain the observed weight loss. Signaling studies suggested that janus kinase 2, nuclear factor k B, and p44/42 mitogen- activated protein kinase are involved in IL-1ß-induced TIARP/STAMP2 mRNA expression. Taken together, these results show that TIARP/STAMP2 is highly upregulated in fat cells by IL-1ß and might participate in proinflammatory and insulin resistance-inducing effects of this cytokine. P512 No feedback inhibition of obestatin during acylated ghrelin infusion in humans Barbara Lucatello, David H. St-Pierre, Fabio Settanni, Ilaria Olivetti, P510 Andrea Benso, Riccarda Granata, Ezio Ghigo & Fabio Broglio University of Turin, Turin, Italy. Daily and nightly urinary free cortisol ratio as a marker of the hypothalamic-pituitary-adrenal (HPA) axis activity in abdominal obesity Background 1 1 1 Romina Di Agostinio , Valentina Vicennati , Uberto Pagotto , Obestatin is a 27 aa peptide derived from the ghrelin gene. Obestatin was first 1 2 2 2 Silvia Genghini , Bruno Ambrosi , Mauro Maccario , Ettore Degli Uberti , described to exert anorexigenic effects by decreasing gastric motility in rodent 2 2 2 Marco Boscaro , Francesco Cavagnini , Franco Mantero , models, however these results have been debated and there is presently only small 2 2 2 1 Decio Armanini , Roberto Vettor , Mario Marugo & Renato Pasquali information regarding its activity and its regulation in humans. Furthermore, its 1 2 Endocrinology Unit, Bologna, Italy; ‘HPA axis and Obesity Group’, the interactions with acylated ghrelin (AG), derived from the same gene, have not been Italian Society of Endocrinology, Bologna, Italy. evaluated. Therefore, in these preliminary data, we sought to evaluate obestatin levels innormalsubjects submitted toa 2 h infusion with1 mg/kg per h AG orisotonic saline. Methods Abdominal obesity (AO) might have a hyperactivation of the HPA axis but previous Three normal subjects were included in the study. An isotonic saline infusion was studies are limited by the small and heterogeneous number of patients investigated. The maintained for 1 h and then, either AG (1 mg/kg per h) or isotonic saline was aim of this study was to evaluate urinary free cortisol (UFC) output during daily and K K nightly hours in a large cohort of AO women versus normal weight controls (CT). 107 AO continuously administrated iv for 2 h. Blood samples were collected at times 60, 30, women and 37 CT women were enrolled in this study; all subjects underwent a complete 0, 30, 60, 90 and 120 min. For each treatment, infusion, peak, nadir and AUC obestatin physical examination, an OGTT and biochemical determinations. Moreover, each subject values were evaluated. Glycemia and insulin levels were evaluated for each timepoints. collected daily (from 0800 am to 0800 pm, dUFC) and nightly (from 0800 pm to 0800 am Results G of the day after, nUFC) urine for UFC determinations. Baseline circulating obestatin concentrations were respectively 246 102 ng/ml and G Total cholesterol and triglycerides levels were significantly higher in the AO, whilst HDL 242 111 ng/ml for the 2 treatment groups (isotonic saline and AG infusions). were significantly lower than in CT. AO had significantly higher HOMA index than CT. Furthermore, obestatin levels were not significantly modulated by the administration There were no differences neither in dUFC nor in the nUFC between the groups but on the of either isotonic saline (mean valueZ267G56 ng/ml) or AG (mean valueZ270G contrary, AO had significantly lower dUFC/nUFC ratio than CT. There was a negative 81 ng/ml). These results suggest that both observed insulin and obestatin circulating and significant correlation between dUFC/nUFC and waist and BMI in all subjects. In the concentrations could be correlated (rZK0.60; PZ0.59). AO group, the correlation between dUFC/nUFC and anthropometric variables was still Conclusion present, moreover, the ratio was also positively correlated to HOMA index. This preliminary study suggests that obestatin levels are not regulated by a feedback In order to assess the linkage between HPA axis activity and metabolic syndrome, a multiple mechanism during an AG infusion in normal subjects. Meanwhile, the possibility of an regression was performed in AO. dUFC/nUFC was still negatively and significantly association between obestatin and insulin concentrations could be investigated in correlated to BMI, while the correlation with waist circumference was lost. Interestingly, further studies. dUFC/nUFC was still positively and significantly correlated to HOMA index and systolic blood pressure. On the contrary, a negative and significant correlation was found between dUFC/nUFC and both HDL and diastolic blood pressure. In conclusion, obesity by itself is characterized by high nightly UFC excretion. The HPA axis dysregulation is strictly associated to the abnormalities of the metabolic syndrome. P513 Prevalence and characterization of metabolic syndrome (MS) in different classes of obesity and related endocrine factors Silvia Genghini, Valentina Vicennati, Adria Zampighi, Stefania Corvaglia P511 & Renato Pasquali Endocrinology Unit, Bologna, Italy. Impact of dietary management and diet duration on body weight and metabolic and endocrine changes in rats fed a high fat/low carbohydrate diet The aim of study was to evaluate in a group of obese women the prevalence of the Maximilian Bielohuby, Samantha J Caton, Lothar J Spangler & metabolic syndrome, defined accordingly to the International Diabetes Federation, Martin Bidlingmaier of single factors of the syndrome and the correlations with endocrine factors. We Neuroendocrine Unit, Medizinische Klinik Innenstadt, Ludwig Maximilians evaluated 351 women, 262 overweight-obese and 89 normal weight controls, which University, Munich, Germany. underwent physical, biochemical and hormonal evaluation. The prevalence of MS in obese and overweight subjects was 62.3%; the prevalence increased significantly by increasing body mass index, ranging from 20.6% for overweight to 71.6% for class High-fat/low carbohydrate (HF–LC) diets in humans, such as the Atkin’s diet, are III obesity. The analysis of prevalence of single factors of MS showed that the claimed to work in an ad libitum setting. In a previous study, we had demonstrated prevalence of low HDL levels and high fasting glycaemia had an inverse trend, by reduced bodyweight (BW) gain in rats when pair-fed isocaloric amounts of a HF– increasing values from overweight to class II obesity but decreasing levels in class LC compared to normal chow (CH). However, rats on HF–LC also showed III obesity. In the normal-weight controls there is 12.5% prevalence of increased increased body fat and low serum IGF-I. We now compared BW development, waist circumference and 14.8% prevalence of hypertension. The analysis of the food intake and resting energy expenditure (EE) in an ad libitum setting in male prevalence of single factors showed that in overweight subjects the commonest Wistar rats fed a HF-LC or CH matched in protein content (nZ8 per group). After association was between waist circumference, high fasting glycaemia and 20 days (d) the HF–LC group had gained significantly more BW (HF-LC: 41.1G hypertension. In class I and II obesity, the most frequent association was between 7.1 g versus CH: 27.1G13.8 g; PZ0.02). BW-gain in the HF–LC group was metabolic parameters whereas in class III obesity, hypertension was the main significantly higher between d10 and d20 than between d1 and d10 (d1–10: 15.5G element. Urinary free cortisol and testosterone levels were significantly higher in 6.1 g; d10–20: 25.6G6.7 g; P!0.01) despite comparable caloric intake. CH fed subjects with MS. controls gained similar weight in both intervals (d1–10: 12.4G9.1 g; d10–20: In conclusion, the lower prevalence of metabolic alterations in massive obesity 14.7G10.4 g; PZ0.65). No differences in EE were observed between the groups. might be related to genetic factors or to a protective role of the large amount of EE did not change with duration of the diet, but the respiratory exchange ratio subcutaneous fat of these individuals. The presence of some elements of the MS also continuously decreased on HF–LC group. Daily energy excess was greater in the in normal weight controls indicate that even this group had a risk of development of HF–LC group (CH: 18.95G6.97 kcal; HF–LC; 39.71G7.6 kcal; P!0.01). HF–LC MS. Hormonal differences detected in women with MS might be due to the already fed rats have severely reduced daily faeces amounts (CH: 9.53G1.5 g versus HF– described different hypothalamic-pituitary-adrenal axis activity and/or to the effect LC: 2.92G0.3 g; P!0.001), remaining energy in the faeces is under investigation. of insulin resistance. Preliminary results indicate that IGF-I levels are also reduced with ad libitum
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P514 P516 Relationship among stress, weight gain and the activity of the Chronic central infusion of a ghrelin receptor (GHS-R1A) antagonist to hypothalamic-pituitary-adrenal (HPA) axis rats: impact on ICV ghrelin-induced food intake and altered body Valentina Marconi, Valentina Vicennati, Stefania Corvaglia, composition Adria Zampighi, Romina Di Agostino & Renato Pasquali N Salome´1, L Gustafsson1, M Taube1, C Hansson1, L Karlsson1, Endocrinology Unit, Bologna, Italy. JA Fehrentz2, J Martinez2, D Perrissoud3 & SL Dickson1 1Department of Physiology, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden; 2Institut des Biomole´cules Max Mous- The aim of this study was: 1) to determine whether there is a correlation between a seron, UMR 5247,CNRS, Univerity Montpellier I and II, Montpellier, stressful event, such as the mourning, the hyperactivity of HPA axis, and the fast France; 3Aeterna Zentaris, Frankfurt am Main, Germany. weight gain 2) to assess whether there is a specific parameter that can predict the susceptibility of individuals to develop metabolic syndrome following a stressful event. We investigated 80 obese women, aged between 23 and 67 years; each subject Central treatment with ghrelin increases body weight and fat accumulation. Here we underwent a clinical evaluation, an OGTT and biochemical, metabolic, hormonal explore the pharmacological effect of a combined central (ICV) infusion of ghrelin and inflammatory parameter determinations. To express the amount of time in which (0.3 nmol/day) and a recently developed ghrelin receptor (GHS-R1A) antagonist weight gain has happened, an arbitrary index called INCR (ratio between weight (JMV2959, 100 nmol/day) on food intake and body composition. The effect of ghrelin gain and interval time) was used. Subject were divided into two groups based on the infusion for 14 days to increase body weight (20.7G0.9% vs 34.3G3.1%, saline vs history of their weight increase: the first group, used as controls, included 61 women ghrelin, P!0.001) was blocked by co-infusion with JMV2959 (34.3G3.1% vs 24.8G become obese dynamically, after pregnancy; the second group, called Mourning, 2.5%, ghrelin vs JMV2959Cghrelin, P!0.05). The higher food intake (rat chow; however, included 19 women become obese after mourning. The parameter INCR 333.4G6.8 g vs 407.4G16.4 g, saline vs ghrelin, P!0.005) and the increase of food was significanthy different between two groups. There were no significant efficiency (17.9G0.5% vs 24G1.4%, saline vs ghrelin, P!0.05) in ghrelin treated rats differences between the groups neither in metabolic profile nor in insulin resistance was not suppressed by the antagonist (407.4G16.4 g vs 368.3G13.4 g and 24G1.4% indices. The Mourning group had significantly higher levels of 24hrs-FCU than the vs 19.8G1.6%. Body composition analysis (DEXA) showed that ghrelin treatment control group. The values of androstenedione were significantly higher in the increased delta lean mass (9.4G1.4% vs 12.9G1.2%, saline vs ghrelin) and delta fat Mourning group compared with controls. All other hormonal parameters were not mass (0.27G0.5% vs 2.6G0.6%, saline vs ghrelin, P!0.001) but only the latter was significantly different between two groups. This study confirm that women become blocked by JMV2959 (2.6G0.6% vs K2.1G0.3%, ghrelin vs ghrelinCJMV, obese following an acute stress showed an hyperactivation of the HPA axis as P!0.001). Ghrelin induced an increase in the weight of all dissected fat pads documented by higher 24 h-UFC and androstenedione levels, which support the (retroperinotenal, inguinal, reproductive and mesenteric as well as the intracapsular hypothesis that acute stress may be involved in fast weight increase. The lack of brown adipose (iBAT) tissue) but only the effects on retroperitoneal, inguinal and iBAT difference in metabolic parameters might be due or to the small time of observation depots were suppressed by the antagonist. or to the small number of subjects. However, 24 h-FCU and androstenedione Thus, the ghrelin antagonist JMV2959 suppresses the weight gain and fat accumulation levels might be considered as predictive parameters of future metabolic alterations. induced by central ghrelin administration. These antagonist effects are not mediated by changes in food intake and food efficiency and future studies will elucidate whether this is due to an influence on metabolic rate. Supported by EC 6th LSHM-CT-2003-503041.
P515 Glucose-dependent insulinotropic polypeptide (GIP) receptor knock- out prevents ovariectomy-induced obesity in mice P517 1 1 2 1 Frank Isken , Andreas FH Pfeiffer , Rube´n Nogueiras , Martin A Osterhoff , Increased unsaturated fatty acids biosynthesis when pyruvate Michael Ristow3, Bernard Thorens4, Matthias H Tscho¨p2 & Martin 1 carboxylase is suppressed in adipocytes O Weickert 1 2 3 1 1 Marc Slawik , Sarawut Jitrapakdee , Helen Atherton , Dirk Hadaschick , Charite´-University Medicine Berlin, Campus Benjamin Franklin, Depart- Wendy L Kimber1, Robert Considine4, John C Wallace5, Jaswinder ment of Endocrinology, Diabetes and Nutrition; and German Institute of 1 1 3 1 2 K Sethi , Stephen O’Rahilly , Julian L Griffin & Antonio Vidal-Puig Human Nutrition, Berlin and Potsdam-Rehbruecke, Germany; University 1 3 Department of Clinical Biochemistry, University of Cambridge, Adden- of Cincinnati Genome Research Institute, Cincinnati, USA; Institute of 2 4 brooke’s hospital, Cambridge, UK; Department of Biochemistry, Faculty Nutrition, University of Jena, Jena, Germany; Department of Pharma- of Science, Mahidol University, Bangkog, Thailand; 3Department of cology and Toxicology, University of Lausanne, Lausanne, Switzerland. Biochemistry, University of Cambridge, Cambridge, UK; 4Division of Endocrinology and Metabolism, Indiana University School of Medicine, 5 Objectives Indianapolis, USA; School of Molecular and Biomedical Science, Premature estrogen deficiency and menopause are associated with increases in University of Adelaide, Adelaide, Australia. body weight and fat mass. Ovariectomized (OVX) mice also show reduced locomotor activity. Because glucose-dependent-insulinotropic-polypeptide (GIP) To maintain a proper lipid composition of cellular membranes is fundamental for is known to play an important role both in fat metabolism and locomotor activity, cell viability and intracellular signalling. Therefore we hypothesised the existence of we hypothesized that effects of estrogen on the regulation of body weight, fat mass membrane quality control homeostatic mechanisms. Previously, we have shown that and spontaneous physical activity could be mediated in part by GIP signaling. Pyruvate Carboxylase (PC), an enzyme involved in de novo lipogenesis and fuel Methods partitioning, is a target of PPARg and that PC level is decreased in PPARg KO and K K C57BL/6 mice and GIP-receptor knock-out mice (Gipr / ) were exposed to obese insulin resistant mouse models. Here, we used RNAi knock-down of PC (PC- Z OVX or sham-operation (n 10 per group). Effects on body composition, energy KD) in 3T3-L1 preadipocytes to elucidate the metabolic consequences associated expenditure, locomotor activity, markers of insulin resistance, and expression of with the decreased levels of PC in vitro. Our results show that reduced mRNA hypothalamic anorexigenic and orexigenic factors were investigated over expression and protein levels of PC (by 90 – 95%) does not prevent fat accumulation 26-weeks in all four groups of mice. in 3T3-L1 adipocytes. However, using 13C-Nuclear Magnetic Resonance Results spectroscopy and Gas Chromatography-Mass Spectrometry we found that OVX wild-type mice developed obesity, increased fat mass, and elevated markers suppressed levels and activity of PC changes the composition of fatty acid acids of insulin resistance as expected. This was completely prevented in OVX GiprK being synthesised resulting in increased amount of unsaturated fatty acids (fatty /K animals, even though their spontaneous locomotor activity levels and energy acids with structure 16:1, 18:1, 20:1), and decreased levels of saturated fatty acids expenditure did not significantly differ from those of OVX wild-type mice. (fatty acids with structure 10:0, 14:0, 15:0, 16:0, 22:0, 24:0). This was associated Cumulative food intake in OVX GiprK/K animals was significantly reduced and with specific gene expression (qRT PCR) changes of elongase enzymes (Elovl). associated with significantly lower hypothalamic mRNA expression of the Moreover, we show that the same pattern of reduction in PC expression and orexigenic neuropeptide Y (NPY). Hypothalamic expression of cocaine and preferential accumulation of unsaturated fatty acids is also observed in adipose amphetamine related transcript (CART) or thyroid stimulating hormone releasing tissue of morbidly obese individuals compared to lean individuals (local ethical hormone (TRH) were not significantly different in OVX GiprK/K vs OVX wild- committee approval had been obtained). Therefore our results support the notion that type control mice. that under metabolic dysregulation such as seen in obesity and insulin resistance, Conclusions when there is decreased substrate flux for de novo lipid biosynthesis, adaptive GIP receptors appear to interact with estrogens in the hypothalamic regulation of mechanisms do occur to maintain the biosynthesis of unsaturated fatty acids. We food intake. Pharmacological inhibition of GIP receptors may carry promising speculate that this adaptation may ensure that enough unsaturated fatty acids are potential for the prevention of obesity in estrogen deficient states. available to maintain membrane lipid composition.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P518 96.3G0.7 cm). HOMA index was significantly greater in MSO than in MSL G G ! Glomerular filtration rates as a cardıometabolıc risk markers in obese (5.1 0.3 vs. 3.9 0.3, P 0.05), while all the other variables of the MS were similarly altered in the 2 groups. Both MSO and MSL displayed MSNA values women G G G ! Taner Bayraktaroglu1, Faruk Kutlutu¨rk2, Adil Dogan Azezli3 & greater than C (62.4 1.5 and 52.8 1.7 vs 39.7 1.2 bs/100 hb, P 0.05). Yusuf Orhan3 Compared to C, both the bradicardic and the tachycardic responses to vasoactive 1 drugs were impaired in MSL (K24.4G4 and K29.5G6%, P!0.05), a further Zonguldak Karaelmas University, Faculty of Medicine, Endocrinology and K G K G ! Metabolism, Zonguldak, Kozlu, Turkey; 2Gazi Osman Pasa University, impairment being detected in MSO ( 40.6 7 and 46.2 8%, P 0.05). This Faculty of Medicine, Endocrinology and Metabolism, Tokat, Turkey; was the case also for sympathoinhibitory and sympathoexcitatory responses to 3 baroreceptor manipulation (MSL K26.6G5 and K39.4G7%, MSO K39.8G8 Istanbul University, Istanbul Faculty of Medicine, Endocrinology and K G ! Metabolism, Istanbul, Fatih/Capa, Turkey. and 51.1 6%, P 0.05 for all). Conclusions These data provide evidence that the sympathetic activation and the baroreflex Introduction impairment characterizing the MS are independent on the presence of obesity. This study carried out relationship between glomerulary filtration rates (GFR) and They also show that the obese state exerts potentiating effects on the sympathetic various metabolic parameters in obese women. alterations seen in the MS, presumably because of the greater autonomic Materıals and methods (baroreflex impairment) and metabolic (insulin resistance) alterations seen when Selected subjects recruited retrospectively from outpatient clinic for this study the obese state and the MS are combined together. were 5115 overweight or obese women with mean GFR which was 93 ml/dk/1.73 m2 calculated by MDRD (modification of diet in renal disease). According to mean GFR, they divided group I (low GFR) having %92 ml/dk/1.73 m2 and group II (normal GFR) having O93 ml/dk/1.73 m2. Thereafter, we determined and compared body compositions (body mass index, abdominal fat mass), resting blood pressures, plasma lipoprotein levels, glucose homeostasis and other related biochemical parameters. P520 Results Changes of the testosterone levels in young males with obesity and Calculated GFR were 74.2G10.8 ml/dk/1.73 m2 in low GFR group (nZ2555, G 2 Z metabolic syndrome 49.9%) and 110.8 34.1 ml/dk/1.73 m in normal GFR group (n 2560, 50.1%). Ralitza Robeva, Georgi Kirilov, Analia Tomova & Philip Kumanov Mean age, BMI, body fat mass, systolic and diastolic blood pressures, fasting Clinical Center of Endocrinology, Sofia, Bulgaria. glucose, fasting insulin, HOMA values, total cholesterol, LDL-cholesterol, triglycerides, uric acid and high sensitive C-reactive protein levels, counts of leukocytes, liver transaminases except aspartate transaminases activity were Aim significantly higher in low GFR group than normal GFR group (P!0.05). But The present study aimed to compare the androgen levels in men with obesity, mean waist circumferences, abdomal fat mass and ferritin levels were not metabolic syndrome /MS/ and healthy normal – weight controls. different between groups (PO0.05; Table 1). Materials and methods Eighty-six males (mean age 29.65G8.57 /18–50/) were investigated. 31 of them Table 1 were healthy (mean BMI – 23.66G1.97); 22 were with simple obesity (mean BMI – 32.79G7.16) and 33 (mean BMI – 35.78G8.71) were with overt metabolic Low GFR group Normal GFR group syndrome /MS/ according to the IDF definition. The levels of the sex-hormone nZ nZ P ( 2560) ( 2555) values binding globulin /SHBG/, total /TT/ and free testosterone /FT/ were determined. Age (year) 43.47G11.93 37.31G11.63 !0.001 Results BMI (kg/m2) 36.42G6.93 35.74G6.90 !0.001 The mean levels of the TT were lowest in the group with metabolic syndrome Waist circumferences (cm) 100.68G13.55 100.32G19.50 NS G G HOMA 3.81G4.95 3.32G4.17 0.008 (16.34 7.36 nmol/l) and highest among healthy non-obese men (30.08 Total cholesterol (mg/dl) 213.79G45.49 197.55G39.70 !0.001 10.96 nmol/l). The mean androgen levels of the obese males (21.27G Triglycerides (mg/dl) 162.66G126.98 134.46G113.34 !0.001 6.89 nmol/l) were significantly higher than in the MS group but significantly lower than in the healthy controls. The concentrations of the FT in the groups with G G Discussion obesity (0.50 0.18 nmol/l) and MS (0.46 0.20 nmol/l) were not significantly In obese women, reduction in GFR was associated with metabolic, cardiovascular different. However, they both were lower in comparison to the levels in healthy men (0.69G0.27 nmol/l). The SHBG concentrations were lowest in the male with and renal end points. It should be careful during a slimming program with G G G included GFR in obese or overweight women. MS (20.74 12.94 nmol/l vs. 31.31 17.40 nmol/l in obese male and 36.84 16.25 nmol/l in controls). Conclusion In young males with obesity and MS the serum levels of androgens decrease. Probably, the reduction of the SHBG in patients with MS limits further decrease of the free testosterone, but it is also related to negative metabolic consequences. Further investigations are needed to clarify the possible mechanisms. P519 In the metabolic syndrome adrenergic overdrive is independent on the obese state Manuela Carla Colombo, Fosca Quarti-Trevano, Raffaella Dell’Oro, Pierluigi Gamba, Francesca Arenare, Rita Perego, Valeria Ilardo, Guido Grassi & Giuseppe Mancia P521 S. Gerardo Hospital, University of Milano-Bicocca, Monza, Italy. Expression of adrenergic receptors and atrial natriuretic peptide in human adipose tissue of severe obese women and Rosiglitazone action during differentiation of human pre-adipocytes Objective Gabriella Garruti1, Vittorio Giusti3, Jurg Nussberger3, Christian Darimont4, The metabolic syndrome (MS) is characterized by a marked sympathetic Aline Appert-Collin2, Sebastiano Perrini1, Monique NennigerTosato2, activation. Whether this adrenergic overdrive is mainly dependent on the obese Riccardo Giorgino1, Francesco Giorgino1 & Susanna Cotecchia2 state or it can be detected also in absence of obesity is unknown, however. 1Department of Emergency and Organ Transplantation- Section of Internal Design and Methods G G Medicine, Endocrinology and Metabolic Diseases, University Medical In 25 male patients (age 41.4 yrs., mean S.E.M.) with MS (ATP III criteria) and School, Bari, Italy; 2Department of Pharmacology and Toxicology, in 12 age-matched healthy male controls, we measured body mass index (BMI), University of Lausanne, Lausanne, Switzerland; 3Department of Internal waist circumference (WC), beat-to-beat arterial blood pressure (Finapres), heart Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; rate (EKG), HOMA index and efferent post-ganglionic muscle sympathetic nerve 4Nestle´ Research Center, Lausanne, Switzerland. traffic (microneurography, MSNA). Measurements were performed at rest and during arterial baroreceptor stimulation and deactivation via vasoactive drug infusion. Background Results The balance between Adrenergic Receptor (AR) subtypes and Atrial Natriuretic Patients with MS were classified as obese (MSO, nZ16, BMI 33.7G0.7 kg/m2 Peptide (ANP) is crucial for lipolysis. It was previously demonstrated that ANP is and WC 109.2G1.3 cm) and lean (MSL, nZ9, BMI 26.2G0.7 kg/m2 and WC strongly lipolytic and we recently demonstrated that ANP is expressed and
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 secreted by human pre-adipocytes. In previous studies, b-receptor density and Introduction lipolysis were higher in human visceral adipose tissue (HVAT) as compared with A retrospective study of the year 2003, of 1314 women with GDM, from 24 public human subcutaneous adipose tissue (HSAT). health Centres in Portugal, was performed. Aims and Methods Patients and methods The expression levels of ANP, AR subtypes and adipocyte differentiation markers Women were divided into two groups according to their pre-pregnancy BMI: (AdM) were analyzed by real-time RT-PCR in human subcutaneous (HSAT) and group Go – BMI R30 kg/m2 and group Gno BMI !30 kg/m2. The mean age of visceral (HVAT) fat biopsies from obese women and in a human pre-adipocytes these women was 32.9G5 years (18–45), the A1c was !6% in both groups. The cell line (ChubS7) during rosiglitazone-mediated differentiation. influence of the BMI in different variables was analysed: family history of DM, Results weight gain during pregnancy according to the recommendation of the Institute of The expression of a2A-AR and b2-AR were higher in HSAT than in HVAT; Medicine – Washington 1990, blood pressure, need of insulin therapy, gestation a1A-AR, b1-AR and ANP expression were comparable, and a1B-AR, a1D-AR age at the beginning of insulin therapy, time of delivery, type of delivery, new- and b3-AR were not measurable in HVAT and HSAT. In both rosiglitazone- and born weight and the re-evaluation post-partum. non-stimulated Chub-S7 all AR subtypes, except for b3-AR, as well as ANP were Results expressed from day 3 to 6 of differentiation. At day 17, in rosiglitazone-stimulated The mean BMI was 26.7G5.1 (16–49.7), 76.3% had BMI !30 and 23.8% Chub-S7, ANP was switched off, AdM and b3- AR were switched on, b2-AR had BMI R30. Patients with a family history of DM had higher mean BMI increased, b1-AR was constantly low and a2A-AR significantly decreased as (26.93 kg/m2), than those without family history (26.19 kg/m2)–PZ0.01. compared with basal. The weight gain during gestation was adequate in 41.4%, reduced in 29.9% Conclusions and excessive in 28.7% of the patients. The prevalence of normal arterial Data on HVAT and HSAT suggest that both the pro-lipolytic b2-AR and the blood pressure was 86.5%, hypertension worsened by pregnancy was 6.9% anti-lipolytic a2A-AR are involved in the balance between HVAT and HSAT and pregnancy induced hypertension was 6.6%, the mean BMI in these three accumulation. Data on ChubS7 demonstrate that b3-AR and AdM are groups were 26.1, 30.51 and 29.33, respectively (P!0.05). There was simultaneously switched on during adipocyte differentiation. We suggest that statistical significant difference (P!0.05) between the two groups in these at the end of the rosiglitazone-mediated differentiation, adipocytes require parameters: Insulin therapy 75.2% in Go vs 52.5% in Gno and its need b3-AR-activation whereas the a2A-AR anti-lipolytic and ANP-mediated effects was earlier in Go -28.83 wks vs Gno -30.97 wks; time of delivery 38.1 wks are decreased. in Go vs 38.4 wks in Gno; caesarean section 49.8% in Go vs 35% in Gno; new- born weight 3324.8 g in Go vs 3167.9 g in Gno; macrosomic babies 8.3% in Go vs 4.4% in Gno. In the re-evaluation post-partum we found that higher BMI were related with severe degrees of carbohydrate intolerance: the mean BMI in the DM group was 29.53, in the IGT was 28.16, in the IFG was 26.99 and in the NGT was 26.55, P!0.05. We didn’t find any difference in the re-evaluation between the women with adequate and P522 excessive weight gain. Conclusions Glucose-dependent insulinotropic polypeptide downregulates In GDM, obesity was found to be an increased risk for hypertension, earlier expression and enzyme activity of 11b-Hydroxysteroid Dehydrogenase insulin need, earlier delivery, caesarean delivery, high baby weight and type 1 macrosomic babies. Pre-pregnancy BMI has a positive correlation with the 1 ¨ 1 2 1 Janin Andres ,Ozlem Go¨gebakan , Knut Mai , Andreas Pfeiffer & development of carbohydrates intolerance. Thus we conclude that obesity in Joachim Spranger2 1 2 GDM is a risk factor for maternal and fetal outcomes, with the risk of early German Institute of Human Nutrition, Nuthetal, Germany; Charite- development in the mother of glucose intolerance. Campus Benjamin Franklin, Berlin, Germany.
Introduction 11b-hydroxysteroid dehydrogenase type 1 (11 b-HSD1) converts cortisone into its active metabolite, cortisol. Mechanisms regulating the promoter-activity of 11b-HSD1 are of considerable importance to understand the basics of intracellular cortisol, lipid and glucose metabolism. The incretine glucose- dependent insulinotropic polypeptide (GIP) has been suggested to affect insulin sensitivity. However, the mechanisms of this effect are unclear yet. Objectives and Settings We aimed to analyse the effect of GIP on 11b-HSD1 enzyme activity and P524 mRNA level in adipose tissue. Therefore fat biopsies of 10 healthy overweight Sleep loss and metabolic response to breakfast men (BMI: 28–40 kg/m2; age: 30–65 years) with a normal glucose tolerance Sebastian M Schmid1, Kamila Jauch-Chara2, Manfred Hallschmid3, were taken before and after a GIP or saline infusion over 4 h. Enzyme activity Britta Wilms1, Jan Born3 & Bernd Schultes1,4 of 11b-HSD1 was measured and qRT-PCR was performed to determine the 1Department of Internal Medicine I, University of Luebeck, Luebeck, gene expression level of 11b-HSD1. Effects of GIP on 11b-HSD1 promoter Germany; 2Department of Psychiatry and Psychotherapy, University of activity were analysed using 11b-HSD1-Luciferase promoter constructs in Luebeck, Luebeck, Germany; 3Department of Neuroendocrinology, 3T3-L1 cells. University of Luebeck, Luebeck, Germany; 4Interdisciplinary Obesity Results Centre, Kantonspital St Gallen, St Gallen, Switzerland. GIP reduced mRNA-expression and activity by approximately 30% (P!0.05). Comparably, the promoter activity of 11b-HSD1 as measured by Luciferase activity and the mRNA-expression of 11b-HSD1 was substantially reduced by Background GIP in differentiated 3T3-L1 cells. Sleep loss is increasingly common in the western world and has been shown to be Conclusion associated with an increased risk of diabetes mellitus and obesity. We demonstrated that GIP downregulates the expression and activity of Objective 11b-HSD1 in adipose tissue in vivo and in vitro. Thus, GIP might affect fat We hypothesised that short term sleep loss results in a diabetogenic metabolic metabolism via inhibition of 11b-HSD1. status during carbohydrate challenge at a breakfast buffet. Subjects and methods Fifteen healthy, normal-weight young men were studied in randomized balanced order on the subsequent morning after (i) two nights with 8 h sleep and (ii) after two nights with only 4 h sleep in the second half of the night. Blood glucose and relevant hormones (insulin, C-peptide, and glucagon) were measured after awakening and during a standardised breakfast buffet. The study was approved by the ethics committee of the University of Lu¨beck and all subjects gave written P523 informed consent. Obesity in GDM: a registry of GDM in Portugal Results Luisa Ruas1, Sandra Paiva1, Tiago Rocha2, Jorge Dores3 & Circulating morning concentrations of any parameter were comparable between Manuela Carvalheiro1 conditions (PO0.30 for all comparisons). There was no difference in 1Endocrinology Department, Huc, Coimbra, Portugal; 2Maternity Alfredo carbohydrate composition of ingested breakfast between conditions (PO0.35). Da Costa, Lisbon, Portugal; 3Endocrinology Department, Sto Anto´nio In response to breakfast blood glucose (P!0.001) as well as serum insulin Hospital, Oporto, Portugal. (PZ0.02) and C-peptide concentrations (PZ0.01) raised to distinctly higher
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 concentrations in the 4 h than in the 8 h sleep condition. Also, plasma glucagon Design levels increased rapidly in response to breakfast with concentrations being In a randomized crossover design ten healthy non-obese young males were constantly lower after 4 h than 8 h sleep (PZ0.03). examined postabsorptively (14 h-fast) and after 38 h of fasting (38 h-fast). Conclusion A bolus of GH was administered intravenously on each occasion followed by Data indicate that short-term sleep loss markedly reduces glucose tolerance infusion of [3-3H]glucose. Muscle- and fat biopsies were taken one hour later. 1 with the pattern of blood glucose and insulin response pointing to insulin A hyperinsulinaemic euglyceamic clamp was performed after 2 2⁄h. Intrahepatic resistance as the underlying mechanism. Thus results provide strong evidence lipid content (IHL) was assessed by 1H- MR spectroscopy. for a causal link between sleep loss and the development of type 2 diabetes Results 1 mellitus. Endogenous GH were higher during the 38 h-fast (P!0.00). Before and 2 2⁄h after the GH bolus, significantly higher levels of FFA (P!0.00 vs P!0.00), glycerol (PZ0.02 vs P!0.00) and 3-hydroxybutyrates (3-OHB) (P!0.00 vs P!0.00) were found after the 38 h-fast. The GH-induced increase in 3-OHB was significantly higher during the 38 h-fast (P!0.00). IHL increased significantly during fasting and correlated with circulating levels of ketone bodies. We found no significant difference between pSTAT5/STAT5 ratio (western blot), STAT5- DNA-complexes (EMSA), or IGF-I and SOCS3 mRNA levels when comparing P525 the 14 h-fast and 38 h-fast. Hepatic and peripheral insulin sensitivity was Abdominal fat and atheromatosis risk factors in non-obese healthy significantly decreased during the 38 h-fast. subjects Conclusion Grazyna Bednarek-Tupikowska1, Eliza Kubicka1, Urszula Tworowska- 1) Prolonged fasting is associated with elevated GH levels, increased lipolysis and Bardzinska1, Agnieszka Lenarcik1, Magdalena Matczak-Giemza1, IHL, and hepatic and peripheral insulin resistance, 2) We could not detect fasting- Andrzej Milewicz1, Barbara Krzyzanowska-Swiniarska2 & Barbara Katra3 induced alterations in GH signaling proteins in either muscle or fat, 3) The 1Department of Endocrinology, Diabetology and Isotope Treatment, molecular mechanisms underlying the changes in the actions of GH during fasting Medical University of Wroclaw, Wroclaw, Poland; 2Department of remain to be characterized. Endocrinology, Arterial HYpertension and Metabolic Diseases, Pomeranian Medical University, Szczecin, Poland; 3Department of Metabolic Diseases, Collegium Medicum, Jagiellonian University, Krakow, Poland.
In the 1980s the concept, that some individuals with normal weight (Metabolically Obese, Normal-Weight) have disturbances of metabolism, related to obesity was proposed. It is known, that obesity promotes atheromatosis by various mechanism, inter alia due to excess of inflammatory markers. This P527 problem however, was not investigated in non-obese subjects. Regulation of acylation stimulating protein by insulin in overweight and We analyzed anthropometric variables, body fat distribution by DXA obese postmenopausal women: a MONET study and serum CRP, Il-6 and Il-18 in 431 healthy, non-obese Polish subjects: David H St-Pierre1,4, Katherine Cianflone2,4, Jessica Smith2,4, Huiling Lu2,4, 232 women (age 32G5.5; BMI 21.3G2.7) and 199 men (age 30G6; BMI Lise Coderre1,4, Antony D Karelis3,4, Pascal Imbeault1,4, Jean- 24.9G2.9). Marc Lavoie1,4 &Re´mi Rabasa-Lhoret1,4 In our study abdominal fat volume was significantly correlated with CRP 1Universite´ de montre´al, Montre´al, Que´bec, Canada; 2Universite´ Laval, (rZ0.3; P!0.001) in women, but there were no significant correlations Que´bec, Canada; 3Universite´ du Que´bec a` Montre´al, Montre´al, Que´bec, between abdominal fat volume and serum Il-6 (rZ0.02; PZ0.7) or Il-18 Canada; 4University of Ottawa, Ottawa, Ontario, Canada. (rZ0.07; PZ0.3). We demonstrated strong correlations between WHR and CRP (rZ0.2; PZ0.004), and Il-18 (rZ0.16; PZ0.02), but not with Il-6 (rZ0.005; PZ0.9). Objective Similar significant correlation between abdominal fat volume and CRP (rZ Acylation Simulating Protein (ASP) has been shown to regulate lipid clearance 0.3; P!0.001) was noticed in men. In this group also Il-18 (rZ0.16; and glucose uptake in adipose tissue. In vitro studies demonstrate that insulin PZ0.03) was strongly correlated with abdominal fat. On the contrary, there stimulates ASP secretion from adipocytes. Individuals with obesity and/or were no significant correlations between abdominal fat depot and serum metabolic disturbances (insulin resistance and type 2 diabetes) have increased levels of Il-6 (rZK0.1; PZ0.16). Strong correlation between WHR and CRP plasma ASP, suggesting ASP resistance. Therefore, the present study evaluates (rZ0.2; PZ0.002), and Il-18 (rZ0.19; PZ0.02), but not Il-6 (rZK0.05; whether ASP levels are influenced by the metabolic profile of overweight and PZ0.5) was seen. obese postmenopausal women during a euglycemic/hyperinsulinemic clamp In conclusion, not only in obese, but also in non-obese young healthy (EHC). subjects visceral fat influences some inflammatory markers of atheromatosis: Materials and methods CRP in women, and CRP and Il-18 in men. The study population consisted of 76 overweight and obese sedentary postmenopausal women. We evaluated insulin sensitivity using the EHC, ASP levels, body composition (fat mass and visceral adipose tissue area), blood lipid profile, liver enzymes, maximal aerobic capacity (VO2peak), resting metabolic rate and total energy expenditure using doubly labeled water. Results We observed wide inter-individual variations of ASP levels during the EHC. Therefore, subjects were divided into two groups based on a O20% change P526 in ASP levels. Negative ASP Responders (NAR; nZ24) showed, at least, a K20% decrease in ASP levels while Positive ASP Responders (PAR; The effect of fasting on substrate metabolism and growth hormone Z C signaling n 42) displayed hormonal fluctuations superior to 20%. Ten subjects had Louise Moller1, Lisa Dalman1, Helene Norrelund2, Nils Billestrup3 & an ASP change of less then 20% and were excluded from the analysis. PAR Jens Otto Jorgensen1 women displayed a worse metabolic profile then NAR women: higher BMI, 1Medical Department M (Endocrinology and Diabetes), Aarhus University visceral adipose tissue, fasting insulin levels, lean body mass, and alanine Hospital, Aarhus, Denmark; 2Medical Department C, Aarhus University aminotransferase (ALT), a marker of impaired liver function. After Hospital, Aarhus, Denmark; 3Steno Diabetes Center, Gentofte, Denmark. adjustment for BMI, only ALT remained significantly different while lean body mass (PZ0.08) and visceral adipose tissue (PZ0.07) remained marginally higher. In PAR and NAR subjects, fasting ASP levels correlated Background positively with albumin and VO2peak and this association remained Fasting is associated with suppression of IGF-I production, which is likely to be significant after adjustments for the effect of BMI. In addition, the % the stimulator of GH secretion and the subsequent increase in lipolysis. The GH maximal change in ASP levels during the EHC was positively associated signalling events subserving this switch in the actions of GH have not been with aspartic acid aminotransferase (AST) and ALT. studied. Conclusion Aim Overall these results suggest that an elevated ASP response during the EHC is To assess whole body substrate metabolism and GH signalling proteins in skeletal associated with metabolic disturbances in overweight and obese postmeno- muscle and fat in healthy human subjects in the postabsorptive state and after 38 h pausal women. of fasting.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P528 Introduction Prevalence of obesity and overweight in Iranian middle aged adults Melatonin plays a key role in the circadian timing system. The question Anahita Houshiar Rad, Morteza Abdollahi & Mina Esmaeili remains whether changes in endogenous melatonin may be associated with National Nutrition and Food Technology Research Institute, Tehran, Islamic food intake. Orexin and ghrelin are involved in the regulation of energetic Republic of Iran. homeostasis. Therefore, we decided to obtain more detailed data on the circadian changes of orexin, ghrelin and melatonin for identification of the changes in these hormones to food intake and day-time, together with Introduction glycemic and C-peptide levels. High prevalence of obesity and overweight among middle aged adults is a major Methods health problem. It is related to high prevalence of many chronic degenerative Five women (mean age 31.6G2.8 years, mean BMI 23.2G2.3 kg/m2)in diseases in this high risk group. This study was conducted to determine the follicular phase of menstrual cycle was examined. The levels of orexin, ghrelin, prevalence of obesity and overweight among young and middle aged Iranian melatonin, C-peptide and glucose were studied during a daily regimen (16 h) adults. including standardized food intake. The diurnal profiles of the hormones and Methods serum glucose were evaluated using ANOVA with Period and Subject as This study was based on anthropometric data collected in the national household independent factors. The correlations between melatonin and the remaining food consumption and nutritional status survey (2001–2003). Seven thousand and parameters were assessed by Pearson’s correlations and using a multiple one fifty eight households were selected randomly. Height (to the nearest 0.1 cm) stepwise backward regression model consisting of the time factor as a and weight (to the nearest 100 g) of 15636 adults aged 20–65 years were polynomial, and serum C-peptide and glucose. The study was approved by measured according to the standard protocols. BMI (kg/m2) was calculated. local Ethical Committe. Obesity and overweight were defined as BMI R30 and BMI 25–29.9 kg/m2 Results respectively. The levels of blood glucose and C-peptide reflected periodic food intake Results being in a physiological range. A significant negative correlation between Mean (GS.D.) and median of weight and height of young and middle aged adults melatonin and C-peptide was found (Pearson’s correlation, rZK0.5525, were 67.1(G13.7), 66.0 kg and 162.6(G10), 162 cm and 68.5(G13.0), 68.0 kg P!0.0001, nZ50, partial correlation rZK0.3532, P!0.02, nZ50). A and 160.5(G9.4), 160 cm respectively. Median BMI for two groups was 24.8 and borderline significant relationship between melatonin and blood glucose was 26.2 kg/m2. Prevalence of obesity and overweight in young adults were (17%, detected (Pearson’s correlation, rZK0.4679, P!0.0006, nZ50). Ghrelin 31.6%) and middle aged were (22.9%, 37.5%) respectively. negatively correlated with C-peptide (rZK0.356, P!0.02). We found Conclusion positive correlation between melatonin and ghrelin (rZ0.453, P!0.003). Prevalence of obesity and overweight especially in middle aged Iranian adults is Our results showed no significant correlation between orexin levels and similar to developed countries such as Canada and England. Obesity and other measured variables. overweight must be considered as a major risk factor for high prevalence of Conclusions chronic diseases (coronary heart diseases, diabetes type 2) in Iranian middle aged The negative relationship between melatonin and C-peptide as well as relatively adults. rapid changes in melatonin levels permits speculation about food as one of the factors influencing daytime melatonin production. The study was supported by grant: NR9055-4 IGA MZCR and GAUK.
P529 Determination of dimerisation domains of the human melanocortin 4 receptor Jessica Genetzky, Patrick Tarnow, Anne Rediger, Annette Gru¨ters & Heike Biebermann P531 Charite´ Universita¨tsmedizin Berlin, Institute for Experimental Pediatric Endocrinology, Berlin, Germany. Metabolic syndrome and endothelial dysfunction in women with polycystic ovary syndrome – relationship with insulin sensitivity Irina Kowalska, Agnieszka Kozlowska, Marek Straczkowski, The melanocortin 4 receptor (MC4R), a G protein coupled receptor, has a Monika Karczewska-Kupczewska, Agnieszka Adamska, prominent role in hypothalamic weight regulation. The MC4R was recently Agnieszka Nikolajuk, Slawomir Wolczynski & Maria Gorska shown to form receptor dimers. The cannabinoid 1 receptor (CB1R) is the nearest Medical University of Bialystok, Bialystok, Poland. phylogenetic relative of MC4R but fails to interact with the MC4R in vitro. In this study we aim to investigate receptor domains that are necessary for MC4R interaction. Four different chimeric receptors of MC4R and CB1R were Polycystic ovary syndrome (PCOS) is a main cause of women infertility. constructed. The generated constructs were transfected into COS-7 cells. There are data suggesting an increased risk for cardiovascular disease in Functional characterization included the determination of total expression, cell PCOS. Insulin resistance might play a role in the pathogenesis of PCOS and surface expression and dimerisation studies by a sandwich-ELISA approach as its metabolic complications. The aim of the study was to asses the well as ligand binding and signal transduction properties. All constructs were prevalence of The National Cholesterol Education Program (NCEP)-defined investigated in comparison to MC4R homodimers. Exchanging of the metabolic syndrome (MS) in women with PCOS in relation to insulin transmembrane domain (TM) 1 and 2 (construct 1) or TM 4-7 (construct 2) resistance and endothelial dysfunction – soluble E-selectin (sE-selectin) and resulted in a complete loss of expression. Total expression of constructs where the soluble intercellular cell adhesion molecule-1 (sICAM-1).Euglycemic MC4R is exchanged with the following parts of the CB1R: TM4 alone (construct hyperinsulinemic clamp, serum sE-selectin, sICAM-1, and sex hormones 3) or TM 3 to TM 4 (construct 4) could be determined but cell surface expression were measured in 97 women with PCOS (33 lean and 64 overweight or was reduced compared to the MC4R (85 and 58% respectively). No ligand obese) and 33 healthy women (22 lean and 11 overweight or obese). MS was present in 21 PCOS patients (21.6%). Both the lean and obese women binding for constructs could be determined therefore these constructs resulted in a Z Z total loss of function indicating the involvement of TM 4 and possibly TM 3 in with PCOS had lower insulin sensitivity (P 0.03 and P 0.01). The PCOS group had significantly higher serum concentrations of sICAM-1 and ligand binding. Investigation of homodimerisation of construct 3 and 4 could Z Z demonstrate a strong interaction for construct 3 but no interaction of construct 4. E-selectin than control group (P 0.008 and P 0.01, respectively). The comparison of the subgroups of patients with PCOS according to the For construct 3 also interaction of the MC4R could be observed. These findings ! point to a crucial role of TM3 and intracellular loop 2 for dimerisation of the presence of the MS revealed the significantly higher sICAM-1 (P 0.001) and E-selectin (P!0.001) concentration, lower insulin sensitivity human MC4R. Ongoing studies will closer narrow the domains of amino acids ! Z involved in interaction. (P 0.001), SHBG (P 0.005) and higher free androgen index (FAI) (PZ0.018) in patients with PCOS and MS. Analysis of variance showed that together with the increase of the number of NCEP criteria in PCOS group, there was a significant decrease of insulin sensitivity, SHBG and an increase in sICAM-1 and E-selectin serum concentration and FAI (P!0.001). The significant inverse correlations between the insulin P530 sensitivity and sICAM-1 (rZK0.33, PZ0.002) and E selectin (rZK0.33, Fluctuation of orexin, ghrelin and melatonin levels during daytime P!0.0001) were observed. Our study indicates that in young PCOS women, Beata Racz, Michaela Duskova, Karel Vondra, Katerina Simunkova, insulin resistance is associated with both classical and non-classical risk Jara Nedvidkova, Dana Sedlackova, Martin Hill & Luboslav Starka factors for cardiovascular disease. Institute of Endocrinology, Prague, Czech Republic.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P532 RNA levels as dependent variable, LDL/HDL ratio and fibrinogen remained independently associated with VAT-PTX3 expression (b 0.521, P!0.01 and b Diabetogenic effects of a continuous infusion of acylated ghrelin in ! normal and type 2 diabetic patients 0.616, P 0.01). These associations were not seen within SAT. David H St-Pierre, Ilaria Olivetti, Elisa Pomero, Elena Gramaglia, Conclusions Fabrizio Riganti, Andrea Benso, Ezio Ghigo & Fabio Broglio Human adipose tissue expresses and releases PTX3 possibly under TNFa control. University of Turin, Torino, Italy. VAT production of PTX3 seems to contribute to the mechanisms underlying the development of atherosclerosis.
Background Previous studies have shown that acylated ghrelin (AG) modulates insulin secretion and glucose disposal in vitro and after acute administration in humans. The aim of the present study was to evaluate postprandial glucose and insulin P534 response following AG infusion in normal subjects and patients with type 2 diabetes. Insulin and glucose regulates omentin-1, a novel adipokine: relation to women with the polycyastic ovary synfrome Methods 1 1 1 2 Six normal subjects and 3 patients with type 2 diabetes were included in this Bee K Tan , Raghu Adya , S Farhatullah , KC Lewandowski , Paul O’Hare1, Hendrik Lehnert3 & Harpal S Randeva1 study. AG (1 mg/kg per h) or saline were continuously administrated iv for 5 h and 1 a standardized lunch of w920 Kcal (50% carbohydrates, 30% lipids and 20% Endocrinology and Metabolism Group, Warwick Medical School, Clinical Sciences Research Institute, University of Warwick, Coventry, UK; protein content) was served after 2 h of infusion. Blood samples were collected at 2 times 0, 15, 30, 45, 60, 90, 120, 150 and 180 min in order to assay insulin levels Department of Endocrinology and Metabolic Diseases, The Medical University of Lodz and Polish Mother’s Memorial Research Institute, Lodz, and glycemia. 3 Results Poland; 1st Medical Department, University of Lu¨beck Medical School, Before meal, insulin levels (saline: 12.7G3.3 mIU/ml; AG: 13.1G6.6 mIU/ml) Luebeck, Germany. and glycemia (saline: 70.8G6.8 mg/dl; AG: 75.3G9.1) were not significantly different for both treatments. In postprandial conditions, AG infusion upregulated Polycystic ovary syndrome (PCOS) is associated with insulin resistance and G G Z the glycemic peak value (153.2 22.6 mg/dl vs 110.0 9.3; P 0.03) while obesity. Recent studies have shown that plasma omentin-1 levels decrease G insulin concentrations were marginally increased (205.9 114.5 mIU/ml vs with obesity. Currently, no data exists on the relative expression and regulation of G O 96.3 17.2 mIU/ml; P 0.05) when compared with saline. Continuous AG omentin-1 in adipose tissue (AT) of PCOS women. G administration induced a significantly increased of glycemic AUC (22 041 Objectives G G 3758 mg/dl per min vs 15 273 834 mg/dl per min) while insulin AUC (24 959 To assess mRNA and protein levels of omentin-1 in omental (om) AT of PCOS G O 13 310 mIU/ml per min vs 10 027 1933 mIU/ml per min; P 0.05) tended to be women and matched controls, including circulating omentin-1. Ex vivo and elevated compared to the one observed during saline administration. In addition, in vivo regulation of AT omentin-1 was also studied. preliminary data suggest that AG infusion could also confer detrimental effects Research design and methods (increased insulin secretion and elevation of glycemia) in patients with early onset Real-time RT-PCR and western blotting were used to assess mRNA and protein of type 2 diabetes. expression of omentin-1. Plasma Omentin-1 was measured by ELISA. The effects Conclusion of D-glucose, insulin, gonadal and adrenal steroids on AT omentin-1 were The present study is the first to evaluate the influence of AG infusion in analysed ex vivo.Thein vivo effects of insulin (hyperinsulinemia) on omentin-1 postprandial conditions both in normal subjects and patients with type 2 diabetes. levels were also assessed by a prolonged insulin-glucose infusion. Finally, these results strongly suggest that continuous administration of AG Results induces diabetogenic effects. In addition to decreased plasma omentin-1 levels in PCOS women (P!0.05), compared to controls, there was significantly lower levels of omentin-1 mRNA (P!0.01) and protein (P!0.05) in om AT of PCOS women (P!0.01). Furthermore, in om AT explants, insulin and glucose significantly dose- dependently decreased omentin-1 mRNA expression, protein levels and secretion into conditioned media (P!0.05, P!0.01). Also, hyperinsulinemic induction in healthy subjects significantly reduced plasma omentin-1 levels (P!0.01). Conclusions P533 Our novel findings reveal that omentin-1 is down regulated by insulin and Pentraxin 3 production in human visceral adipose tissue is associated glucose. These may in part explain the decreased omentin-1 levels observed in our with cardiovascular risk factors overweight PCOS women. Luisella Alberti1, Luisa Gilardini1, Andrea Girola1, Giancarlo Micheletto2, Giuseppe Peri3, Andrea Doni3, Alberto Mantovani3 & Cecilia Invitti1 1Istituto Auxologico Italiano, Milan, Italy; 2University of Milan, Milan, Italy; 3Istituto Clinico Humanitas, Milan, Italy. P535 Pentraxin 3 (PTX3) is an acute phase protein expressed in the advanced Postnatal determination of ghrelin secretion levels and sexual atherosclerotic lesions and produced by endothelial cells, macrophages and, in dimorfism in the rat rodents also by adipocytes under tumour necrosis factor a (TNFa) exposure. Omar Al-Massadi1, Carmen Ruth Gonza´lez3, Marı´a Pardo2, We investigated if PTX3 is expressed in human adipose tissue and is associated Carlos Die´guez3, Felipe Casanueva1 & Luisa Marı´a Seoane4 with cardiometabolic risk factors. 1Endocrinologı´a Molecular, A´ rea de Investigacio´n, Complejo Hospitalario Methods Universitario de Santiago (CHUS) and Departamento de Medicina, Samples of subcutaneous (SAT) and omental visceral (VAT) adipose tissue Universidad de Santiago de Compostela and Ciber Fisiopatologı´a de, G 2 G were obtained from 21 obese (BMI 38.8 4.48 kg/m , 37.4 8.15 years) and 10 Santiago de Compostela, Spain; 2Departamento de Medicina, Universidad G 2 G normal weight subjects (BMI 23.8 1.69 kg/m , 43.7 11.07yr) who underwent ´ . de Santiago de Compostela and Ciber Fisiopatologıa de Obesidad y abdominal surgery and had normal leucocyte count Real-time PCR was used Nutricio´n (CB 06/03). ISCIII, Santiago de Compostela, Spain; 3Departa- to quantify specific mRNA for PTX3, CD68 (macrophage marker), TNFa and mento de Fisiologı´a, Universidad de Santiago de Compostela and Ciber adiponectin. Fresh adipose tissue was cultured and PTX3 measured in the medium. Fisiopatologı´a de Obesidad y Nutricio´n (CB 06/03). ISCIII, Santiago de Serum insulin, glucose, HDL and LDL cholesterol, triglycerides, C- reactive Compostela, Spain; 4Endocrinologı´a Molecular, A´ rea de Investigacio´n, protein (CRP), fibrinogen, adiponectin, TNFa and PTX3 were measured. Complejo Hospitalario Universitario de Santiago (CHUS) and Ciber Results Fisiopatologı´a de Obesidad y Nutricio´n (CB 06/03). ISCIII, Santiago de PTX3 was expressed by adipocytes at similar levels in obese and normal weight Compostela, Spain. subjects and in the two fat compartments. CD68 and PTX3 expression were correlated each other in SAT but not in VAT. In the whole group of subjects, after adjustment for age and sex, VAT PTX3 expression and release were correlated Ghrelin is a pleiotropic hormone characterized mainly by its strong orexigenic with VAT TNFa expression (r 0.537 and r 0.773, P!0.01 for both) and with action and its role as GH secretagogue. LDL/HDL ratio (r K0.471, P!0.01 and r 0.773, P!0.001). VAT-PTX3 Age-related level variation of this hormone has been previously shown in expression was also correlated with BMI (r 0.365, P!0.05), triglycerides different studies centred in mARN expression and in its plasma levels; however (r 0.420, P!0.05), CRP (r 0.475, P!0.05), fibrinogen (r 0.446, P!0.05) and there is no data about its secretion directly from the stomach although this is the adiponectin (r K0.390, P!0.05). In the multivariate analysis with VAT-PTX3 main ghrelin producing organ.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Objectives accompanied by insulin resistance. The crucial step in the development of insulin To determine the levels of ghrelin in the postnatal development and its possible resistance is an impaired increase in carbohydrate oxidation and decrease in lipid sexual dimorfism. oxidation in response to insulin. The aim of the present study was to estimate Methods carbohydrate and lipid oxidation in relation to serum adiponectin concentration in Real Time PCR, RIA, Organ culture, Surgery. women with AN. Experimental groups We examined 16 women with AN, 15 lean control women and 15 obese women. Male and female rats from 1 to 24 weeks. Euglycemic hyperinsulinemic clamp, indirect calorimetry in baseline state and Rats subjected to ovariectomy and orquidectomy. during the last 30 min of the clamp and the measurements of serum adiponectin Results concentration were performed. Our results showed a diminution of ghrelin plasma levels in the second week; Insulin sensitivity was decreased in obese women in comparison to AN levels were normalized in the following weeks. In relation to ghrelin secretion (PZ0.0045) and controls (PZ0.015), whereas it was not different between AN from the stomach, we found a great decrease of secretion in the fourth week and a and controls. Serum adiponectin was higher in AN women in comparison to other peak in the sixth week of development. groups (control, PZ0.015; obese, PZ0.038) and in control in comparison to the Gastric ghrelin mARN levels increased along time in a non significant manner. obese women (PZ0.047). Women with AN had preserved carbohydrate and Gonadectomy did not change plasma ghrelin levels although it did affect gastric lipid oxidation, and non-oxidative glucose metabolism during hyperinsulinemia. ghrelin levels. All these parameters were not significantly differ from control group, although Conclusions lipid oxidation in the hyperinsulinemic state tended to be lower in AN The weaning and the puberty in the rats regulate gastric ghrelin secretion during (PZ0.066). Obese women had lower carbohydrate oxidation during the clamp postnatal development. Sexual hormones can influence the secretion of ghrelin. in comparison to AN (PZ0.022) and controls (PZ0.01) and lower non-oxidative glucose metabolism and higher lipid oxidation during the clamp in comparison to AN (PZ0.016 and PZ0.038, respectively). Serum adiponectin was related to lipid oxidation during hyperinsulinemic state (rZK0.38, PZ0.039). Women with AN had normal insulin sensitivity due to the preserved response to P536 insulin of substrate oxidation and non-oxidative glucose metabolism. Adiponectin is related to insulin sensitivity through its association with the suppression of lipid The effect of polyunsaturated fatty acids enriched eggs on lipid profile oxidation during hyperinsulinemia. and inflammatory markers Dana Manda1, Mihaela Giurcaneanu1, Liliana Ionescu1, Rodica Criste2, Tatiana Panaite2, Suzana Vladoiu1, Carmina Busu1 & Olga Ianas1 1C.I. Parhon Institute of Endocrinology, Bucharest, Romania; 2National Research, Development for Biology and Animal Nutrition Institute, Bucharest, Romania. P538 Molecular insights in dysfunctions of the human melanocortin-4- The correction of a subtle nutritional deficiency that may reduce the risk of a receptor (MC4R) caused by mutations in the third transmembrane future chronic disease is indeed a challenge. One of the most intriguing current domain (TM3) and the second intracellular loop and future impacts on public health may come from a greater intake of omega-3 Patrick Tarnow1, Anne Rediger1, Kurt Widhalm2, Susann Friedel3, fatty acids such as a-linolenic acid (ALA). Gunnar Kleinau4, Hanno Bolz5, Thomas Bettecken3, Anke Hinney3, Objective Gerd Krause4, Annette Gru¨ters1 & Heike Biebermann1,6 We investigated the effect of an increased amount of dietary a-linolenic acid 1Charite´ Universita¨tsmedizin Berlin, Institute for Experimental Pediatric (ALA) from enriched eggs on the lipid profile and inflammatory markers in Endocrinology, Berlin, Germany; 2Division of Nutrition and Metabolism, healthy volunteers. Department of Paediatrics, Medical University of Vienna, Vienna, Austria; Subjects and methods 3Department of Child and Adolescent Psychiatry, Rheinische Kliniken Sixty-two subjects were voluntary enrolled after they gave their informed Essen, Essen, Germany; 4Leipnitz Insitute for Molecular Pharmacology, consent. They were randomly assigned in either control or omega group. Control Berlin, Germany; 5Institute for Human Genetics University Cologne, group consumed normal eggs while omega group consumed eggs enriched in Cologne, Germany; 6GSF-National Research Center for Environment and omega 3 fatty acids. The content of ALA in omega 3 eggs was 5 times greater than Health, Genome Analysis Center, Neuherberge, Germany. that of control eggs. During the study, all subjects maintained their habitual diets except that egg consumption. Each subject had to consume 6 eggs a week during a 6-week period. Mutations in the hypothalamic expressed MC4R gene are the most frequent cause Blood samples were collected at day 0 (baseline) and at the end of the study. of monogenetic obesity. This Gas-Protein coupled receptor (GPCR) is activated Triglycerides, cholesterol, HDL, LDL cholesterol, ApoA, ApoB, CRP and by endogenous ligands a- and b-MSH and is inhibited by the only known fibrinogen were measured in serum samples. endogenous inverse agonist and antagonist Agouti related peptide (AgRP). Results Naturally occurring mutations help to understand activation mechanisms of the We compared the measured values of the biochemical parameters at baseline and human MC4R. after egg consumption both in control and omega group. Triglycerides were We previously described a constitutively activating MC4R mutation (H158R) significantly reduced in omega group (PZ0.002) after omega-3 enriched eggs found heterozygously in a normal weight proband. This mutation is located in the consumption but not in control group. Fibrinogen level was significantly second intracellular loop and causes a six times higher basal activity, a higher decreased (P!0.001) by omega-3 enriched eggs consumption whereas in control maximal stimulation and a slightly decreased EC50 after stimulation with MSH- group there were no significant changes. No significantly changes were found in ligands when compared to the WT-MC4R. The increased basal activity can be the other parameters of the lipid profile or CRP. dose dependently reduced by stimulation with the inverse agonist AgRP. When Conclusion the WT-MC4R is stimulated with a-MSH in presence of increasing AgRP Omega-3 dietary supplementation decreases trygliceride and fibrinogen level. concentrations, an increase of EC50 is observed, which can not be seen for the Omega-3 enriched eggs can be considered as functional food with beneficial H158R mutant, explaining the normal phenotype of the mutation carrier. The effects on human health. histidine at position 158 is conserved in the MC4Rs of 70 species and also in all 5 human melanocortin receptors but not generally in GPCRs. Exchanging the histidine to further amino acids by site directed mutagenesis decipher the crucial role of histidine 158 for receptor silencing. Additionally, in contrast to activating mutation H158R we describe three inactivating mutations at serine residues located in the third transmembrane domain, which were found in obese patients. P537 S136F causes a loss of function although properly expressed on the cell surface Carbohydrate and lipid oxidation in relation to serum adiponectin and shows a dominant negative effect when co-transfected transiently with concentration in women with anorexia nervosa WT-MC4R. S127L is a partial loss of function mutation with normal cell surface Monika Karczewska-Kupczewska, Irina Kowalska, Marek Straczkowski, expression pattern. Molecular details of modifications on the MC4R structure and Agnieszka Adamska, Agnieszka Nikolajuk, Elzbieta Otziomek & signaling properties caused by these mutants are evaluated using molecular Maria Gorska modelling driven side chain substitutions. Furthermore, S139R resulted in a Medical University of Bialystok, Bialystok, Poland. complete loss of function and impaired membrane trafficking. Exchanging S139 to isoleucine partially rescued these effects. In a computer-generated receptor model, substitution of S139 with the bulky and charged arginine disrupts the Anorexia nervosa (AN) is an eating disorder, with the significant loss of the conserved interaction of serine 85 in TM2 with tryptophan 174 in TM4 and forms adipose tissue. Lack of subcutaneous adipose tissue observed in lipodystrophies is a new constraining interaction to TM4 thus leading to inadequate folding of the
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 receptor. These new findings reveal deeper insight into the intramolecular PZ0.034), and DEXA-lean body mass (RZ0.282, PZ0.016) but not with BMI, mechanism of activity regulation at the human MC4R. DEXA-total or -trunk fat mass, hsCRP, free testosterone, DHEAS, androsten- dione and 17b-estradiol. Adjusted for age, BMI, smoking and IGT the association between RBP4 and HOMA%S remained significant (PZ0.032). However, RBP4 explained only 4.6% of the variation of HOMA%S. RBP4 was higher in metabolic syndrome and in impaired glucose metabolism, but its usability to P539 identify women with metabolic syndrome or impaired glucose metabolism was low (AUCs 0.631, PZ0.041 or 0.660, PZ0.016). Ghrelin gene polymorphisms in Prader Willi Syndrome Conclusions Flavia Prodam1, Simonetta Bellone1, Ginevra Corneli1, Francesca 1 1 1 1 In PCOS RBP4 has a small independent impact on insulin resistance. It is neither Di Rienzo , Sara Giacoma , Anna Rapa , Daniela Vivenza , correlated to hyperandrogenemia, 17b-estradiol or other adrenal steroids nor to Graziano Grugni2, Antonino Crino3, Eliana Di Battista4 & Gianni Bona1 1 markers of adiposity in general. Furthermore, RBP4 does not appear suitable for Division of Paediatrics, Department of Medical Science, University of screening metabolic syndrome or impaired glucose metabolism. Piemonte Orientale, Novara, Italy; 2Division of Auxology, Research Institute, Italian Auxological Institute Foundation, S Giuseppe Hospital, Verbania, Italy; 3Paediatric and Autoimmune Endocrine Disease Unit, Research Institute, Bambino Gesu´ Children’ Hospital, Roma, Italy; 4Department of Paediatric Endocrinology, Research Institute, G Gaslini Hospital, Genova, Italy. P541 Glucagon suppression of total but not of acylated ghrelin is preserved in obesity: the impact on appetite control Introduction Ayman M Arafat1, Aikaterini Adamidou1,Ba¨rbel Otto2, Martin Prader Willi Syndrome (PWS) is a genetic syndrome characterized by O Weickert1, Frank H Perschel3, Joachim Spranger1, Christof Scho¨fl4, hyperphagia, morbid obesity, and many other endocrine alterations. PWS Matthias Mo¨hlig1 & Andreas F H Pfeiffer1 subjects present higher ghrelin levels. The cause of this increase as well as the 1Department of Endocrinology, Diabetes and Nutrition, Charite´-University modulation of ghrelin secretion at fasting and feeding in relation to other Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany; 2Medical metabolic parameters in PWS is largely unknown. It has also been demonstrated Department- Innenstadt, University Hospital Munich, Munich, Germany; that many ghrelin gene (GHRL) polymorphisms are associated with obesity, type 3Department of Clinical Chemistry and Pathobiochemistry, Charite´- 2 diabetes, and hypertension. Despite these data, the physiologic role of University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany; regulation of GHRL expression in normal condition as well as in PWS has not 4Division of Neuroendocrinology, Department of Neurosurgery, Friedrich- been fully clarified so far. Alexander-University Erlangen-Nuremberg, Erlangen, Germany. Subjects and methods To this aim, mutational analysis of the total GHRL in unrelated 90 normal- weighted (CCNW), 81 obese (OB) healthy young subjects, and 34 children or Objective adult PWS were performed. We also evaluated lipid metabolism, fasting glucose The mechanisms underlying the well known glucagon-induced satiety effect are in children and glucose tolerance in adult PWS. Results. The pre-pro GHRL unclear. As we showed recently, the glucagon-induced reduction in total ghrelin, variants and a SNP of the promoter region (rs26802) showed similar allele that might be responsible for this effect, is exerted at hypothalamus–pituitary frequency in CCNW, OB, and PWS. All PWS were carriers for a second common level. The aim of the present study was to further evaluate glucagon’s suppressive polymorphism of SNP in the promoter region (rs27647) (P!0.002 and P!0.003 effect on both total and acylated-ghrelin in obesity with respect to its role in in comparison to CCNP COB, and CCNP or OB, respectively). No significant appetite control. differences in rs27647 were recorded between CCNP and OB. Moreover, the Methods rs26802 genotype (AOC) distribution was different between euglycemic and Prospectively, we studied the endocrine and metabolic responses to intramuscular diabetic adult PWS (P!0.02). No other associations were found between the glucagon administration in 14 lean (6 males; BMI 21.6G0.6 kg/m2) and 12 obese other polymorphisms and the metabolic parameters in PWS. Conclusions. These healthy subjects (6 males; BMI 33.9G1.6 kg/m2). All subjects were proved to data report for the first time that polymorphisms in the 50 flanking region of have an intact pituitary function. GHRL seem differently distributed in PWS compared to normal population Results and that they may be associated to the development of a diabetic phenotype in Age, fasting glucose, glucagon and acylated-ghrelin concentrations were adult PWS. comparable between both groups. Fasting insulin was significantly higher and baseline total-ghrelin was significantly lower in obese than in lean subjects. Total- ghrelin significantly decreased after glucagon administration in both obese (meanGS.E.M.: 706G54 vs 618G47 pg/ml, P!0.01) and lean subjects (1181G 133 vs 1023G102, P!0.01). Acylated-ghrelin did not change significantly in obese, whereas a significant decrease occurred in lean subjects (306G58 vs P540 209G43 pg/ml, P!0.05). However, hunger scores significantly decreased in Retinol-binding protein 4 is independently associated with insulin both groups: lean (3.2G0.3 vs 2.3G0.2, P!0.05) and obese subjects (4.1G0.5 resistance in PCOS women vs 2.9G0.4, P!0.05). Matthias Mo¨hlig1, Martin O Weickert1, Elham Ghadamgahi1, Ayman Conclusions M Arafat1, Joachim Spranger1, Andreas FH Pfeiffer1 & Christof Scho¨fl2 We show that glucagon significantly decreases total- and acylated-ghrelin in lean 1Department of Endocrinology, Diabetes and Nutrition, Charite´-University healthy subjects but fails to affect acylated-ghrelin in obese individuals. The Medicine, Campus Benjamin Franklin and Department of Clinical Nutrition, glucagon-induced satiety effect remained intact indicating the role of changes in German Institute of Human Nutrition Potsdam-Rehbruecke, Berlin, total rather than in acylated-ghrelin in mediating this effect. Germany; 2Division of Neuroendocrinology, Department of Neurosurgery, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
Objective Adiposity, insulin resistance, and hyperandrogenism are features of the polycystic P542 ovary syndrome (PCOS). Retinol-binding protein 4 (RBP4) secreted from adipose The sirtuin activating compound resveratrol decreases GH and liver tissue has been linked to insulin resistance. We here address the impact transcription of RBP4 on insulin resistance in PCOS and its usability to identify women with Jose Luis Monteserin, Johanna Stalla, Gu¨nter Stalla & metabolic syndrome or impaired glucose metabolism (IGT or diabetes). Marily Theodoropoulou Design Max Planck Institute of Psychiatry, Munich, Germany. RBP4 was determined in plasma of 115 PCOS women. Associations with insulin resistance, body composition, and hyperandrogenemia were investigated by correlation and multiple linear regression analyses in 110 non-diabetics. Receiver Caloric restriction is the best known experimental procedure that extends lifespan operating characteristic (ROC) curve analysis was used to evaluate RBP4’s and resistance to aging-related diseases. Part of these actions was found to be usability for identifying impaired glucose metabolism or impaired glucose mediated by the NAD-dependent histone deacetylase Sir2/Sirt1. Resveratrol is a metabolism. polyphenol found in the skin of grapes, which was identified as a Sirt1 activator Results and subsequently proposed as a caloric restriction mimetic. The aim of the present RBP4 increased over tertiles of insulin resistance (PZ0.009). RBP4 correlated study was to determine how resveratrol affects the GH axis, which is central in the with insulin resistance (HOMA%S (RZK0.286, PZ0.002)), WHR (RZ0.233, physiology of aging. Treating rat anterior pituitary cells in primary cell culture
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 and GH3 GH-producing cells with resveratrol decreased GH secretion. Markers of endothelial dysfunction, including soluble E-selectin (sE-selectin) GH promoter is regulated by the cAMP/PKA pathway through CREB-binding are related to insulin resistance and are predictors of type 2 diabetes. Insulin protein (CBP) bound to Pit1. Treatment with resveratrol decreased the binding of resistance is associated with metabolic inflexibility, i.e. an impaired acetyl-histone 3 and Pit1 on the endogenous rat GH promoter. Furthermore stimulation of carbohydrate oxidation and inhibition of lipid oxidation in Pit1 gene expression was found to be reduced in resveratrol treated GH3 cells. In insulin-stimulated conditions. The aim of the present study was to estimate rat cells Pit1 is under the control of itself and CREB. Resveratrol treatment the relationships of serum sE-selectin concentration with carbohydrate and decreased CREB acetylation and the specific Sirt1 activator NAD decreased lipid oxidation in lean and obese women. The study group consisted of CREB transcriptional activity. CREB is mainly acetylated by the histone 80 apparently healthy women: 33 lean and 47 with overweight or obesity. acetyltransferase CBP. Sirt1 immunoprecipitated with CBP and resveratrol Euglycemic hyperinsulinemic clamp and indirect calorimetry in the baseline decreased CBP acetylation, an effect that results in diminishing its acetyltrans- state and during the last 30 minutes of the clamp were performed. Obese ferase activity. Interestingly, resveratrol also decreased CREB phosphorylation at women had lower insulin sensitivity (PZ0.0022) and higher serum sE-selectin Ser133. CREB is usually phosphorylated by the cAMP/PKA pathway. However, concentration (PZ0.034). In the obese group, carbohydrate oxidation was resveratrol treatment did not affect cAMP production. Other kinases, such as, Akt increased in baseline state (PZ0.019) and decreased during hyperinsulin- were also found to phosphorylate CREB. Indeed resveratrol treatment decreased emia (PZ0.048) and lipid oxidation was higher during hyperinsulinemia pAkt-Ser473 levels in a mechanism involving mTOR but not PDK1. Altogether (PZ0.0012). Obese women had also lower increase in carbohydrate oxidation these data demonstrate that resveratrol decreases GH synthesis, similar to the (PZ0.0012) and lower decrease in lipid oxidation (PZ0.034) during the situation observed in caloric restricted rodents, and provide a mechanism linking clamp. Serum sE-selectin was negatively related to insulin sensitivity (rZK the lifespan regulator Sirt1 with the GH axis. 0.27, PZ0.015). Higher serum sE-selectin concentration was associated with a lower increase in carbohydrate oxidation (rZK0.41, P!0.001) and a lower decrease in lipid oxidation (rZ0.29, PZ0.008) during the clamp. Serum sE-selectin was also inversely related to the direct measure of metabolic flexibility, i.e. to an increase in respiratory quotient in response to insulin (rZK0.36, PZ0.001). Our data show that serum sE-selectin concentration P543 is associated with both carbohydrate and lipid oxidation. Higher serum sE-selectin concentration might be linked to metabolic inflexibility of obesity Glucose-dependent insulinotropic polypeptide (GIP) modulates and insulin resistance. inflammatory markers and regulates cell proliferation in subcutaneous adipose tissue O¨ zlem Go¨gebakan, Sandy Mosig, Ines Middelbeck, Martin A Osterhoff, Frank Isken, Natalia Rudovich & Andreas F H Pfeiffer 1German Institute of Human Nutrition, Nuthetal, Germany; 2Endocrinology, Diabetes and Nutrition, Charite´- University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany; 3Friedrich-Schiller-University P545 Medicine, Institute for Vascular Medicine, Jena, Germany. The volume of left hepatic lobe as metabolic marker, correlates with weight and not with height, both in obese or non-obese women and men Dan Peretianu1, Mara Carsote2, Daniela Cristea Staicu1 & Catalina Poiana2 Background 1 2 Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal SCM Povernei, Bucharest, Romania; Department of Endocrinology, hormone that is secreted in response to food intake and modulates b-cell Carol Davila University of Medicine and Pharmacy, Bucharest, Romania. function. Remarkably, GIP looses its insulinomimetic effect in the presence of chronic hyperglycaemia and thus appears to be ineffective in poorly controlled Introduction T2DM at least with regard to insulin release. The mechanism by which this occurs Left hepatic lobe volume (LHLV) has been associated with hyperinsulinemia and is not clear and it is not known. insulin resistance in obese women. Objectives Aim To analyse the effect of GIP-Infusions on changes in adipose tissue gene To study the correlation between LHLV and body weight, regardless the weight expression at different blood-glucose levels in obese men and also detect different and gender of the patient. biomarkers and hormone interactions caused by GIP. Subjects and methods Setting and participants 2 The left hepatic lobe was evaluated with an echographic probe of 3.5 MHz. The Seventeen healthy overweight men (BMI: 28–40 kg/m ; age: 30-65 years) LHLV (cm3) was calculated with the formula: antero-posterior diameter underwent a single-blind intervention with euglycaemic or hyperglycaemic (length)!longitudinal length (right-left)!sagital diameter (length up-down)! clamps in combination with GIP or saline infusions. Each solution was applied at 0.52. The study group consisted of 648 women, aged between 6 and 87 years and physiological concentrations for four hours. Before and after the infusions 219 men, aged between 5 and 83 years. None of them had a known hepatic biopsies from subcutaneous adipose tissue were taken. We isolated total RNA disease. Linear correlation was calculated between body mass index (BMI) and from all fat biopsies and hybridized the RNA to Agilent Whole Human Genome LHLV. Statistical analysis consisted of Student and Pearson test. Microarrays (total 100 arrays). The results were verified by RT-PCR and amended Results by cell culture experiments. LHLV values are presented in the following table. Differences between LHLV in Results non-obese versus obese women and men are highly statistically significant We identified several genes being involved in inflammatory and proliferative cell (P!0.001). Linear correlation between LHLV and BMI in all women was signalling. Under euglycaemic hyperinsulinaemic clamp conditions in com- statistically significant (rZ0.64, P!0.001), as well as in all men (rZ0.62, binations with a GIP-Infusion we find a significant upregulation of chemokine P!0.001). We found no correlation between LHLV and height in both sexes ligand 2 (CCL-2/MCP-1), interleukin Ib (IL-1b), fibroblast growth factor receptor (rZK0.14, resp. rZ0.13). 1 (FGFR-1) and oncostatin M (OSM). We also see an activation of cell proliferation by wnt signalling in adipose tissue after exposure with GIP mediated by cyclin D1, frizzeled homolog 4, frizzeled homolog 10 (FZD 4/10) and several zinc finger proteins like ZNF 397, and ZNF 658. 3 3 Conclusion LHLV (cm ) LHLV (cm ) GIP may play a role in cell proliferation and inflammation in adipose tissue of obese men. Dependent from blood glucose levels GIP also effects lipid and Women Average SD Men Average S.D. glucose metabolism in adipose tissue. All 173.9 67.77 All 203.77 91.36 Non-obese 153.75 49.99 Non-obese 179.00 66.42 Obese 236.93 77.58 Obese 281.32 113.60
P544 Conclusions Serum soluble E-selectin concentration in relation to insulin resistance LHLV is dependent on BMI and not on the patient height: the higher the body fat and metabolic inflexibility in obese women content is, the larger the left hepatic lobe is in both men and women. The Marek Straczkowski, Irina Kowalska, Agnieszka Adamska, quantitative estimation of LHLV may be a useful surrogate marker in the study of Agnieszka Nikolajuk, Monika Karczewska-Kupczewska & Maria Gorska obesity related insulin resistance. Medical University of Bialystok, Bialystok, Poland.
Endocrine Abstracts (2008) Vol 16 jY gpA!d gdQ A gJ d:g2 \dg_gQ8 A _\d8 A b!d8 B
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LL d!_\ gJ YA 2Ad !_ Q_2g2g \2g\: JAA:)!2^ \d p!\Ad \Y g)A\8 :\!)AA8 !d: :Ap A\gd ! \A A\_\dQj8 Y \\!d )g_:j8 !Y\! gd !:8 gY!dd! =Ydj8 j j LLe A d: \2YA 8 Ad: \^ AYdA $ 2Y\b AA A_!\gd gJ Y\QY[Ad\\A [ A!2\A p gA\d !d: bA!)g_\2 \^ J!2g jAp! bAd gJ dA d!_ A:\2\dA 8 d\A \ gJ A)A2^8 A)A2^8 \d gA A\QY !d: g)AA gbAd A b!d d\A Jg !YAb!\28 d\A \ gJ A)A2^8 A)A2^8 ! ^ _ ^j8 !dA ! !^! gQ_8 :\_ A_\ $ J Y!d A b!du j !\gb!dp!! d\A \\8 g^!8 ^A gdQ_:!^ ! !A_b! d\A \8 gdQ_:!^8 ^A !d)_ d\A \8 !d)_8 ^Au )A\8 :\!)AA8 !d: :Ap A\gd ! A !g2\!A: \Y :\\d2 dA gAd:g2 \dA 2Y!dQA \dMAd2\dQ YA AQ_!\gd gJ YA YpgY!_!b p\\! !: Ad!_ r s d g:2\gd Abu p g dg \ ! dg pg\)_A g A!b\dA YA 2Ad !_ Q_2g2g \2g\: _A!A: Y\QY[Ad\\A 2[ A!2\A p gA\d rY[s \d !g2\!\gd \Y JAA:)!2^ \d Yb!d g A \J A_ gJ !d\b!_ ApA \bAd \d A_!\dQ :\A!A YpA \d_\dAb\!8 g)A\8 \d_\d A\!d2A !d: Y\QY )_gg: p A A ! A bg:A_u \Y YA YA_p gJ ! A2Ad_ :AA_gpA: 2gbp!\gd!_ !pp g!2Y A A A \Qd\K2!d \^ J!2g Jg 2! :\g!2_! :\A!Au YA !\b gJ Y\ :\g Ad!)_A: g !:: A Y\ zA\gd g p!\Ad \Y g)A\8 :\!)AA8 g :Ap A\gdu A!_!A: YA 2g A_!\gd )AAAd A b Y[ 2gd2Ad !\gd !d: bA!)g_\2 d g :A g \:Ad\J YA Q_2g2g \2g\: JAA:)!2^ !d: g !d!_A YA ^\dA\2 gJ \^ J!2g \d gA A\QY !d: g)AA gbAdu 2g \2g gp\d !d: 2g \g_ A A!)_\YA: ! Ab gJ :\JJA Ad\!_ Az!\gdu AYg: 2g \2g gp\d A_A!\dQ Yg bgdA A ! !pp_\A: g QAdA !A YA :!! Jg YA A A\QY r L ^Qbs !d: g)AA r ^Qbs LL gbAd A A [ !d!_Au Ad g__A: \dg YA :u YA p!\Ad A A :\\:A: \dg g Q gp !22g :\dQ g A Jgd: Y! )]A2 \Y g)A\8 :Ap A\gd8 pA j :\!)AA8 g \d_\d A b Y[ 2gd2Ad !\gdu YA bA!d A b Y[ 2gd2Ad !\gd ! A!A: pA :\!)AA Y!A pA2\K2 2Y!dQA gJ 2Ad !_ Q_2g2g \2g\: JAA:)!2^ uO bQ:_u gp rdjs 2gd\ gJ A b Y[ BuO bQ:_ !d:8 Q gp p! !bAA u YAA 2Y!dQA gJ JAA:)!2^ p! !bAA \d:\2!A !d !_A A: Apg\d rdBOs 2gd\ gJ A b Y[ uO bQ:_u YA Q gp A A 2gbp! A: Jg AQ_!\gd gJ YA Ab \d Yb!d \Y p2Y\! \2 !d: bA!)g_\2 bA!)g_\2 \^ b! ^A AQ! : gJ 2! :\g!2_! :\A!Au :\A!Au A_ YA bA!d A b Y[ 2gd2Ad !\gd ! uO bQ:_u A\QY8 )g: b! \d:A r s !\ 2\ 2bJA Ad2A8 !Q\!_ !\8 )g: J!8 )_gg: p A A8 \d_\d8 8 !d: \2 !2\: A A \Qd\K2!d_ Y\QY \d gp 2gbp! A: g gp r,uLs YA A ! dg :\JJA Ad2A Jg Q_2gA8 2Yg_AA g_8 \Q_2A \:A8 8 8 ^ A!\d\d8 JA \\d )AAAd YA Q gpu gd2_\gd A A \d Y\ :8 A :AKdA: YA 2g A_!\gd )AAAd \d2 AbAd gJ A b Y[ LLB 2gd2Ad !\gd !d: bA!)g_\2 \^ b! ^A AQ! : gJ 2! :\g!2_! \^u YAA !_!\gd gJ bA!)g_\2 d: gbA \d p!\Ad \Y :\!)AA bA__\ :!! QQA Y! A_A!A: p_!b! Y[ _AA_ b\QY )A !g2\!A: \Y pA \dQ :\JJA Ad 2 \A \!7 !\gd!_ Yg_AA g_ :2!\gd \^ J!2g \d gA A\QY !d: g)AA gbAdu gQ !b :_ A!bAd !dA_ r s !d: dA d!\gd!_ \!)AA A:A !\gd r s !)_A YA 2gbp! \gd gJ :\JJA Ad Y[ Q gpu !d! !]^\d8 :\! g^\28 \]!d! !:g!dg8 !Q!d! gb\2[!Q_\28 !d gb\28 \_Ad! d]\! $ A_]^g dg) d]! ! !bAA gp j rdjs gp rdBOs !_A _\d\2 gJ d:g2 \dg_gQ8 \!)AA !d: A!)g_\2 \g :A 8 _\d\2!_ Ad A g]g:\d!8 g\ !:8 A )\!u QA rA! s OjuLjjuj OujjjjuB A\QY r^Qs BujjOu eBuejBu ,uj r^Qbs OuOLLu euuje ,uj YA !\b gJ YA : ! g 2gbp! A !d: 2 \A \! Jg bA!)g_\2 \2 !2\: rbQ:_s Ouju OujjuB ,uj g_\2 rbb Qs juOuO juLjueO u d: gbA \d :\!)AA bA__\ pA )]A2u \!g_\2 rbb Qs BuOOLue BLueLujj uO g Yd: A: !d: AAd[AAd p! \2\p!d A A \d2_:A:8 j gbAd uO _2gA rbQ:_s eLuBLeuO euOuO Bu A! !d: j bAd !QA: LuLeuLB A! u gp 7 bA!)g_\2 d: gbA d_\d r b_s jujeju jLujjuB uj ) Q gp bA!)g_\2 d: gbA ) u r_gQs ujBOue uOue ,uj g__g\dQ _!)g !g !d: !d gpgbA \2 bA! AbAd A A :gdA7 g!_ 2Yg_AA g_8 \Q_2A \:A8 [ !d: 2Yg_AA g_8 J!\dQ p_!b! Q_2gA8 )g: YA\QY8 )g: A\QY8 !\ 2\ 2bJA Ad2A8 ! A \!_ )_gg: p A Au
d:g2 \dA ) !2 rBs g_ j 10th European Congress of Endocrinology, Berlin, Germany, 2008
P560 P562 Relationship of visceral adiposity with plasma adiponectin Obesity and adipocytokines concentration: effect of weight loss Suheyla Gorar1, Cavit Culha1, Yavuz S Demir1, Ahmet T Turgut2, Esmat Nasseri1, Mostafa Hosseini2, Ahmad Reza Dorosti1 & Pinar Karakaya1, Rustu Serter3, Sema Aral4 & Yalcin Aral1 Maryam Chamari3 1Department of Endocrinology and Metabolism, Ankara Education and 1National Nutrition and Food Technology Research Institute, Faculty of Research Hospital, Ankara, Turkey; 2Department of Radiology, Ankara Nutrition Sciences and Food Technology, Shahid Beheshti University, Education and Research Hospital, Ankara, Turkey; 3Department of Internal M.C., Tehran, Islamic Republic of Iran; 2Department of Epidemiology and Medicine, Ankara Education and Research Hospital, Ankara, Turkey; Biostatistics, School of Public Health, Tehran University of Medical 4Duzen Laboratories Groups, Department of Hormone Research, Ankara, Sciences, Tehran, Islamic Republic of Iran; 3Department of Nutrition and Turkey. Biochemistry, School of Public Health, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran. Aim Comparison of the parameters of obesity with the newly-defined adipocytokines Objective in females applying to our clinic for obesity. To investigate the associations between adiponectin levels and adiposity and body Method fat distribution indices assessed by waist to hip ratio in Iranian women and to Demographical data of 36 obese females were determined. Cases were classified determine if the association differ as a result of ethnicity. as obese and morbid obese according to BMI values. Biochemical parameters Methods were measured for all the cases. Thicknesses of subcutaneous and visceral fatty A cross-sectional study of 76 Iranian women free from metabolic disease was tissues were measured on ultrasonography. Statistical significances were performed. Body mass index (BMI), waist circumferences, waist to hip ratio evaluated by applying Pearson correlation and Student t-test. (WHR), body composition, insulin sensitivity, lipid profiles and plasma Findings concentration of adiponectin were measured. Adiponectin changes after a weight According to the correlation analysis of the entire group, it was seen that plasma loss diet in a subgroup of 42 obese subjects was also assessed. visfatin and apelin measurements had no correlation with parameters other than Results the correlation between them (rZ0.42, P!0.05), and plasma leptin levels WHR (waist to hip ratio) was the only variable independently associated to correlated positively with BMI, subcutaneous and visceral fatty tissue adiponectin (BetaZ0.25, P!0.05). A mean increase of 8.2G24.2% in measurements, and h-CRP. In the correlation analysis of the obese group, it adiponectin concentration was observed in response to the dietary restriction was found that there was correlation between apelin and visfatin; and in the and weight loss (P!0.05). morbid obese group, there was correlation between apelin and systolic blood Conclusions pressure and fasting–postprandial glucose and visceral fatty tissue and h-CRP. Our findings provide evidence for association of serum adiponectin level with When obese and morbid obese groups were compared, it was found that there visceral fat, represented by waist to hip ratio index. Our results also indicate were no statistically significant differences in plasma visfatin and apelin levels, that moderate weight loss result in significant improvements in adiponectin although there were significant differences between BMI, waist circumference, concentration. This provide another biological explanation for the beneficial systolic blood pressure, postprandial glucose, h-CRP, leptin, and thicknesses of effect of body weight loss on reducing cardiovascular and diabetes risks in subcutaneous and visceral fatty tissues. obese patients. Conclusion In our study, increasing of plasma leptin levels with the increasing degree of obesity, and positive correlations with body mass and fatty tissue measurements are consistent with the literature. No correlation was found in our study between the levels of plasma visfatin and apelin levels and BMI, body fat amount, and thicknesses of subcutaneous and visceral fatty tissues, and no significant changes were seen between morbid obese and obese groups regarding the same. P561 We believe that further studies are required to enlighten this issue. The interrelationship between leptin, visfatin and CRP levels and insulin sensitivity assessed by euglycaemic clamp in obese women Dragan Micic1, Mirjana Sumarac-Dumanovic1, Danica Stamenkovic- Pejkovic1, Maja Simic1, Goran Cvijovic1, Svetlana Zoric1, Aleksandra Kendereski1, Darko Stevanovic2, Jagoda Jorga3 & Vladimir Trajkovic4 P563 1Institute of Endocrinology, Diabetes and Diseases of Metabolism, ERK1/2 MAPKs and Wnt signaling pathways are independently Belgrade, Serbia; 2Medical Faculty, Institute of Physiology, Belgrade, involved in adipocyte-mediated aldosterone secretion Serbia; 3Medical Faculty, Institute of Nutrition, Belgrade, Serbia; 4Medical Kim Vleugels, Monika Ehrhart-Bornstein, Stefan R Bornstein & Faculty, Institute of Microbiology and Immunology, Belgrade, Serbia. Alexander W Krug University Hospital Carl Gustav Carus, Dresden, Germany. Visfatin is a newly discovered adipokine found in abundance in visceral fat. Leptin is well known marker of fat mass in the body but also one aspect of leptin One important risk factor for the development of arterial hypertension is is its action as a proinflammatory cytokine. Recent studies, both in vitro and abdominal obesity. Aldosterone, secreted by adrenocortical cells, promotes in vivo, indicated that visfatin is also one of the inflammatory cytokines, sodium and water retention and by that regulates blood pressure homeostasis. although the relationship between visfatin and insulin resistance remains still Increased serum aldosterone levels have been linked to the development of unclear. The aim of our study was to assess the association between visfatin and obesity hypertension. Therefore, identifying the link between obesity and leptin levels in circulation and those of C-reactive protein (CRP), as marker of increased aldosterone secretion is of high importance for the management of systemic inflammation, and also to investigate their relationship with insulin obesity hypertension. sensitivity index in obese women. In that order, thirty obese women (BMIZ Isolated human adipocytes secrete factors that stimulate steroid secretion from 35.59G0.83 kg/m2, ageZ35.53G1.59 years) were included in the study. In human adrenocortical cells with a predominant effect on aldosterone secretion. each of the investigated subjects, following parameters were measured: Visfatin We could show that adipocyte-mediated aldosterone secretion and sensitization of (EIA Phoenix, ng/ml), Leptin (Linco RIA, ng/ml), hs-CRP and M index (mg/kg human adrenocortical cells to angiotensin II (AngII) is mediated via ERK1/2- per min) during euglycemic clamp studies as a marker of insulin sensitivity. MAPKs-dependent upregulation of steroidogenic acute regulatory (StAR) protein Significant positive correlation was found between leptin levels and and CRP activity. Inhibition of MAPKs by UO126 almost completely abolished adipocyte- (rZ0.435, P!0.05) while there were no correlation between leptin and M index induced steroidogenesis. Recent evidence also indicates the involvement of the (rZK0.128, PO0.05). There were no significant correlation between visfatin Wnt-signalling pathway in fat cell-mediated aldosterone secretion. and CRP (rZK0.029, PO0.05), while visfatin significantly correlated with We then evaluated possible interactions of the ERK1/2 MAPKs and the Wnt insulin sensitivity (M index) (rZ0.309, PZ0.055). There was significant signalling pathways in adipocyte-induced adrenocortical aldosterone secretion. negative correlation between CRP and M index (rZK0.439, PZ0.001). Exposure of human adrenocortical NCI H295R cells to Wnt-3a did not affect In conclusion, according our results, visfatin levels are in significant positive ERK 1/2-activation. Accordingly, fat cell-induced ERK1/2 phosphorylation was correlation with insulin sensitivity index calculated during euglucaemic clamp, not inhibited by the Wnt-antagonist sFRP-1. while there was no significant correlation between visfatin and CRP in obese Therefore, ERK1/2 MAPKs pathway and the Wnt signalling pathway seem to be women. Leptin seems to be a better marker of inflammatory state than visfatin in two independent mechanisms in adipocyte-mediated aldosterone secretion. These obese women. mechanisms might be important in the development of obesity hypertension.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P564 differences between these groups. Moreover, the results show positive correlation between plasma leptin and b-carotene intake (rZ0.32, P%0.002) and negative Leptin decreases and glucose deprivation increases the generation of the ZK % soluble leptin receptor (sOb-R) in a cell model correlation between plasma leptin and dietary fiber intake (r 0.28, P 0.01). Michael Schaab1, Daniel Morawe1,Ju¨rgen Klammt2, Wolfgang Wilfert1, Presented results do not confirm unquestionably earlier hypothesis. However, Joachim Thiery1 &Ju¨rgen Kratzsch1 analyzed parameter is only one of many parameters which can be taken into 1Institute for Laboratory Medicine, Clinical Chemistry and Molecular consideration to evaluate the influence of organically produced food on the Diagnostics, University of Leipzig, Leipzig, Germany; 2Hospital for organism. Children and Adolescents, University of Leipzig, Leipzig, Germany.
Objective The soluble leptin receptor (sOb-R) is generated by ectodomain shedding of the P566 membrane-associated Ob-R and may modulate leptin action in metabolic dysregulations. The objective of our study was to investigate whether or not Prospective, Placebo controlled, randomized treatment of 67 obese sOb-R generation may be induced by indicators of energy availability or children/adolescents with metformin Susanna Wiegand1, Dagmar L’Allemand2, Hanna Huebel1, metabolic regulators in a cell model. 1 1 1 3 Material and methods Mareike Burmann , Heiko Krude , Annette Gru¨ters & Reinhard Holl 1Pediatric Endocrinology and Diabetology, Charite´ Childrens’Hospital, The four human Ob-R isoforms were cloned, characterized by binding 2 experiments with 125-iodinated leptin and transfected into HEK 293 cells. Universita¨tsmedizin Berlin, Berlin, Germany; Pediatric Endocrinology and Diabetology, Ostschweizer Kinderspital St. Gallen, St. Gallen, Switzerland; Cells were stimulated with levels of leptin, glucose, phorbol 12-myristate 3 13-acetate (PMA), insulin, human growth hormone, dexamethasone, troglitazone Department of Epidemiology, University of Ulm, Ulm, Germany. and AICAR. Ob-R gene expression was controlled by an isoform specific TaqMan assay. sOb-R levels in cell supernatant were measured by an in-house Background immunofunctional assay. It becomes increasingly evident that features of the metabolic syndrome are Results already present in young obese patients. Especially an impaired glucose ! Leptin incubation of our Ob-R transfected (P 0.01) and non-transfected cells metabolism with insulin resistance is an alarming sign of existing comorbidity ! (P 0.05) lead to a concentration-dependent significant decrease of sOb-R. Total of childhood obesity. Metformin has been argued as one pharmacological option glucose deprivation and PMA stimulation were associated with increased sOb-R to improve impaired glucose metabolism at least in obese adults. So far three results, whereas low levels of glucose restored the normal shedding function of prospective randomized studies were performed in childhood cohorts with !30 the cells. No significant effect on sOb-R was observed after incubation with the patients each (Kay 2001, Freemark 2001, Srinivasan 2006), suggesting a remaining substances. beneficial effect of metformin, however with low significances. To further gain Conclusions evidence for the actual treatment with metformin we conducted a randomized, Presumed that sOb-R levels in supernatant of cells reflect the density of the Ob-R placebo controlled study in larger obesity childhood cohort. membrane receptor, the leptin-dependent decrease of sOb-R suggests receptor Methods down-regulation or leptin resistance. This suggestion is in-line with in vitro data We included obese non-diabetic children and adolescents (age range: 10–17 of obese subjects. In contrast, the increase of sOb-R by glucose deprivation may years.) with insulin resistance (HOMAO97. Perc.) and/or impaired glucose support the hypothesis that Ob-R shedding is associated with reduced energy tolerance (total nZ243). After an initial 6 month weight reduction program only availability of the cell. The consequence of both effects for the net action of leptin those patients with unsuccessful weight reduction and persistent insulin resistance has to be determined in further experiments. Additionally, the increase of sOb-R were recruited for the metformin treatment (nZ67). The 67 patients were concentration after PMA stimulation underlines that the shedding process is PKC randomized and treated either with placebo or 2!500 mg metformin for 6 month. dependent. At baseline and after 6 month anthropometric (BMI-SDS, body composition, waist circumference) and metabolic parameters (oral glucose tolerance, HOMA, ISI, lipids) were measured. Results In 53% vs 36% (metformin vs placebo) the BMI and in 73% vs 54% (metformin versus placebo) HOMA was reduced after 6 month. But statistically comparing P565 the placebo and treatment group did not revealed significant changes of all weight The impact of middle term feeding with organic, low input and or glucose metabolic parameters (BMI-SDS, body composition, HOMA, ISI, conventional diets on body composition and plasma leptin lipids). Drop outs rate was 9% (nZ6; nZ1 metformin, nZ5 placebo). concentration in male rats Conclusion Dominika S´rednicka1, Tomasz Kro´likowski2, Joanna Gromadzka- The lack of significant difference of all tested parameters of glucose metabolism Ostrowska2, Ewa Rembiałkowska1, Lorna Lueck3 & Carlo Leifert3 in the metformin treatment vs placebo group of this so far largest metformin 1Organic Foodstuffs Division, Department of Functional Food and treatment cohort of obese children does not support the use of metformin in Commodities, Faculty of Human Nutrition and Consumer Sciences, childhood obesity to improve insulin resistance, at least in addition to University of Life Sciences – SGGW, Warsaw, Poland; 2Department of multiprofessional obesity programs. Dietetics, Faculty of Human Nutrition and Consumer Sciences, University of Life Sciences – SGGW, Warsaw, Poland; 3Ecological Farming Group (NEFG), University of Newcastle, Nafferton Farm, Newcastle, UK.
The aim of the study was to analyze the influence of feed from different P567 production systems on food intake, body chemical composition and plasma leptin Hyperandrogenism in pre- and post-menopausal obese women concentrations in rats. It is expected, that organically produced feed influences Joana Ferreira1, Selma Souto1, Ana Oliveira1, Paula Freitas1, Flora Correia2, positively rat organism, in that hormone balance. Leptin regulates energy intake Ana Varela1, Davide Carvalho1 & Jose Luis Medina1 and expenditure, as well as basic functions of many tissues. 1Department of Endocrinology, Sa˜o Joa˜o Hospital, Porto, Portugal; 2Faculty The experiment was conducted in 104 Wistar male rats divided into 16 dietary of Food and Nutritional Sciences, Porto, Portugal. groups (organic, conventional and two low input, all in four replications) and one control group (Labofeed H) consuming feed ad libitum for three months. Plasma leptin levels by RIA, body composition by standard chemical methods and total Introduction food intake and body weight gain were determined. Macronutrient and bioactive Obesity has been associated with increased androgenicity in women, however compounds intakes were also calculated. All procedures were approved by the there are conflicting data on this subject. Objectives: To determine whether Local Animal Care and Use Committee in Warsaw. any androgen is independently related to body mass index (BMI), waist-to-hip According to multifactorial statistical analyses, plasma leptin concentrations are ratio (WHR) or age. To access if there is an association between elevated observed to depend significantly on fertilization regime (P!0.02), while crop plasma androgen levels and the presence of either morbid obesity or metabolic protection system does not influence significantly this parameter. At the same syndrome (MS). time, there is strong interaction between crop protection and fertilization regimes Design and Methods (P!0.001). Lowest plasma concentrations of leptin are observed in rats fed one A total of 148 obese women were evaluated in their first obesity medical of low input diets (feed from production system based on conventional fertilizers appointment: 105 premenopausal and 43 postmenopausal. Anthropometric and organic protection) and standard diet (Labofeed H). Plasma leptin levels in variables, plasma androgen (total testosterone; T, free testosterone; FT, other analyzed groups are statistically higher, however there are no significant dehydroepiandrosterone sulfate; DHEA-S, androstenedione) and sex hormone
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 binding globulin (SHBG) concentrations were measured. The correlation Binding events of ligands to receptors are the key for understanding the biological coefficient and Fisher’s exact test were used, respectively, to determine the processes. Gaining insight into protein-protein and protein-ligand interactions strength of the linear relationship and to evaluate the non-random association in solution has recently become possible on an atomic level by new NMR among variables. spectroscopic techniques. Results In this work, the mapping of the interaction of ghrelin with its receptor by NMR The patients had mean age of 41.8G11.7 years and mean BMI of 40.5G techniques in living cells is presented. The evaluation between spectra with stably 7.5 kg/m2; 60.1% of the women had morbid obesity. In premenopausal women, transfected and wild type cells of the same cell line, allowed a mapping of the BMI was negatively correlated with SHBG (rZK0.21; P!0.05) and positively interactions of ghrelin and desacyl-ghrelin with the target GHS-R1a receptor. correlated with FT (rZ0.27; P!0.05) and androstenedione (rZ0.25; P!0.05). Ghrelin was found to have a higher number of residues affected by chemical shift Age was negatively correlated with FT (rZK0.26; P!0.05), T (rZK0.26; perturbation (CSP) or slow conformational exchange (SCE) effects by interaction P!0.05), DHEA-S (rZK0.35; P!0.05), androstenedione (rZK0.33; P!0.05) with the receptor, and the n-octanoic group was seen to be clearly necessary for and T/SHBG ratio (rZK0.34; P!0.05). There was a positive correlation the interaction with the receptor, supporting the conclusion that the NMR data in between WHR and DHEA-S (rZ0.2; P!0.05). On the other hand, in living cells report accurately the functional interaction of these peptides. The postmenopausal women, there was only a negative correlation between BMI large number of SCE effects detected for ghrelin: Ser3, Phe4, Leu5, Val12, and SHBG (rZK0.46; P!0.05). There wasn’t an association between Gln13/Gln14, Lys16/Lys19, Glu17 and Lys24, suggest that the binding to its elevated serum androgen levels and the presence of morbid obesity or metabolic receptor is accompanied of a large conformational change respect to the random syndrome (MS). coil structure described in free solution. Conclusions In this study it was found a correlation between BMI and age with some of the studied androgens, only in premenopausal women.
P570 C-reactive protein and insulin sensitivity in severe obese women with and without metabolic syndrome P568 Maja Simic1, Dragan Micic1, Mirjana Sumarac-Dumanovic1, Relationship between obesity, IL-17 and IL-23 and insulin resistance Danica Stamenkovic-Pejkovic1, Jagoda Jorga2, Goran Cvijovic1, Mirjana Sumarac-Dumanovic1, Dragan Micic1, Maja Simic1, Aleksandra Kendereski1 & Svetlana Zoric1 Danica Stamenkovic-Pejkovic1, Darko Stevanovic2, Jagoda Jorga4, 1Institute for Endocrinology, Diabetes and Diseases of Metabolism, Goran Cvijovic1, Svetlana Zoric1 & Vladimir Trajkovic3 Belgrade, Serbia; 2Institute for Nutrition, Belgrade, Serbia. 1Institute Of Endocrinology, Belgrade, Serbia; 2Institute of Physiology, Belgrade, Serbia; 3Insitute of Microbiology and Immunology, Belgrade, Serbia; 4Insitute of Nutrition, Belgrade, Serbia. It was postulated that different therapeutic approaches could influence the markers of inflammation in obesity but it is unknown whether overweight women with and without metabolic syndrome have the same degrees of inflammatory In most obese patients, obesity is associated with a low-grade inflammation of white state. The aim of our study was to compare level of hs-CRP in obese women adipose tissue resulting from chronic activation of the innate immune system and without other components of metabolic syndrome with hs-CRP in women with which can subsequently lead to insulin resistance, impaired glucose tolerance metabolic syndrome (according IDF criteria). Overweight body mass index- and even diabetes. It is still not clear role of acquired immune response in obesity and matched women without (OW)) (nZ16, (body mass index, 35.56G0.09 kg/m2) related comorbidites such as asthma, cancer or autoimmune diseases. The aim of our and with (May (nZ13) metabolic syndrome (body mass index, 6.76G1.57 study was to compare level s of IL-17 and IL23 in sever obese women with nonobese kg/m2) were included in the study. C-reactive protein (CRP) between groups was healthy women as well as to investigate relationship between these interleukins not significantly different (4.39G0.711 mg/liter for OW vs 6.02G1.55 mg/l for with insulin sensitivity in same persons. In that order, thirty obese women (BMIZ MSy, PO0.05). There was a significant difference in triglyceride levels (1.12G 35.59G0.83 kg/m2,ageZ35.53G1.59 yrs) with normal fasting glucose and 15 0.14 for OW vs 2.86G0.46 mmol/l for MSy, P!0.05, HDL-cholesterol (1.35G healthy control women (BMIZ20.43G0.66 kg/m2, ageZ27.87G0.77 years) were 0.06 for OW vs 1.13G0.05mmol/l for MSy, P!0.05), waist circumference included in the study. In each of the investigated subjects, following parameters were (102.6G2.82 cm for OW vs 112.31G3.03 cm for MSy, P!0.05), but not in measured: IL-17, IL-23, fasting glucose and fasting insulin, HOMA-IR as marker of HOMA-IR index (3.86G0.40 for OW vs 4.46G0.96 for Msy, PO0.05). There insulin sensitivity. There was significant difference in circulating levels of IL-17 was no significant correlation between CRP and BMI neither between CRP and between obese and nonobese women (16.16G1.13 vs 9.42G1.16, P!0.05) as well HOMA-IR. Our results couldn’t confirm higher degree of insulin resistance as in IL-23 (9.35G1.87 vs 2.10G1.33, P!0.05). HOMA-IR was lower in control between severe obese women with and without other component of metabolic women but difference was not statistically significant (4.05G0.44 vs 2.95G0.48, syndrome as well as difference in CRP levels. PO0.05).There was significant correlation between BMI and IL-17 (rZ0.483, P!0.05) as well as BMI and HOMA-IR (rZ0.415, P!0.05). In conclusion, it can be considered that obesity corresponds to a sub-clinical inflammatory condition that promotes the production of pro-inflammatory factors primary involved in acquired immune response but further investigations are necessary to elucidate these interrelationship. P571 Inflammatory parameters in obesity: lack of influence of weight loss Eva Sola´, Ana Jover, Katherinne Garcı´a, Carlos Salvador, Carlos Morillas & Antonio Herna´ndez-Mijares P569 Doctor Peset University Hospital, Valencia, Spain. NMR study of ghrelin and desacyl-ghrelin with the growth hormone releasing receptor type 1a using living cells Introduction Yolanda Pazos1, Manuel Martin-Pastor2, Antonia De Capua2, Carlos J Obesity has been associated with a low-level activation of the acute-phase P Alvarez1 & Felipe F Casanueva1 response. The aim of the present study was to compare inflammatory parameters 1A´ rea de Investigacio´n, Complejo Hospitalario Universitario de Santiago de in patients with obesity and a control group, and to evaluate the effect of weight Compostela, Complejo Hospitalario Universitario de Santiago de Com- loss on these parameters. ´ ´ Methods postela. CIBER Fisiopatologıa de la Obesidad y Nutricion (CB, Santiago de G Compostela, A Corun, Spain; 2Unidad de Resonancia Magne´tica, RIAIDT, Sixty-seven severe or morbid obese patients (51 women, 16 men), aged 34 11 years, were compared with 67 normal-weight controls (45 women, 22 men), Universidad de Santiago de Compostela, Santiago de Compostela, A G Coruna, Spain. aged 32 10 years. After initial evaluation, the patients received treatment for 4 weeks with a very low-calorie diet (VLCD), followed by a low calorie diet (1200–1500 kcal/day) for 2 months. Exclusion criteria were organic, infectious or Ghrelin, the endogenous ligand for the GH secretagogue receptor type 1a inflammatory disease, ischaemic heart disease or stroke, diabetes mellitus, (GHS-R1a), is a peptide with a post-translational octanoyl modification on Ser-3. hyperlipidaemia and hypertension. An anthropometric and analytical evaluation Previous studies of ghrelin derivatives showed that the pendant group at Ser-3 was performed before and after the diet, measuring fibrinogen, CRP, IL-6 and plays an essential role in the bioactivity. The acylated peptide specifically releases TNF-a. Student t-test was used to compare the differences between groups. growth hormone (GH) both in vivo and in vitro, while the desoctanoyl form of Pearson correlation coefficients were calculated to describe the association the hormone is at least 100-fold less potent than the parent peptide. between variables.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Results IRAN. The significant rise of obesity in the last decade resulted in corresponding Obese patients showed higher levels of CRP, IL-6, TNF-a, leukocyte and increase in the prevalence of hypertension. neutrophil count than controls. After adjusting for BMI, differences in CRP Objective remained statistically significant. In obese patients, inflammatory parameters To detect obesity and hypertension, and the relationship between them among (leukocyte count, neutrophil count, and IL-6) were significantly correlated with Semnanian people, Iran, 2007 anthropometric parameters (weight, BMI and waist). None of these correlations Methods was observed in the control group. Sixty-two patients completed 3 months of diet In this cross sectional survey we studied 388 (169 male and 219 female) 40–65 with a mean percentage weight loss of 8.6%. No change was observed in any year-old on the basis of a stratified random sampling. Weight, height and systolic inflammatory parameter after weight loss. and diastolic blood pressure (BP) were measured based on standard methods Conclusions and BMI was calculated. Overweight and obesity were defined as 30OBMI R25 Obesity is associated to a chronic inflammatory state, probably due to and BMI R30 respectively. High blood pressure was defined, as systolic BP O proinflammatory cytokines secretion. Moderate weight loss does not ameliorate 140 mmHg or diastolic BPO90 mmHg. Data analysis was conducted using SPSS this proinflammatory state. soft ware version 11.2. Results Mean of BMI among males and females were 26.8, 30.6 kg/m2 respectively with significant differences (PZ0.0001).The rate of overweight and obesity in total population was 79.3% (CI 95%: 75.2–83.3%) and among males and females were 68.5% (CI 95%:61.3–75.6%) and 87.5% (CI 95%:83.1–91.9%) respectively and the difference was significant (PZ0.0001). The rate of high blood pressure among obese, overweight and others were 26.1%, 20.5% and 8% respectively and the P572 differences were statistically significant (PZ0.007). Significant linear correlation Z Activated protein C levels in obesity and weight loss influence were detected between systolic blood pressure with BMI, and with age(r 0.11, PZ0.02 and rZ0.28, PZ0.0001 respectively) and diastolic blood pressure with Eva Sola´, Francisco Espan˜a, Amparo Vaya´, Amparo Estelle´s, Z Z Z Z Katherinne Garcı´a & Antonio Herna´ndez-Mijares BMI, and with age (r 0.20, P 0.0001 and r 0.16, P 0.001 respectively). 1 2 After adjusting the results for age, this significant correlation was detected again Doctor Peset University Hospital, Valencia, Spain; Research Center, La Fe Z Z University Hospital, Valencia, Spain; 3La Fe University Hospital, Valencia, between BMI with systolic and diastolic blood pressure (P 0.004, P 0.0001 Spain; 4Research Center, La Fe University Hospital, Valencia, Spain; respectively). 5Doctor Peset University Hospital, Valencia, Spain; 6Doctor Peset Conclusion University Hospital, Valencia, Spain. The prevalence of overweight, obesity and high blood pressure are high in this community, especially among women and urgent attention to suitable interventional program is a priority in health sector. Introduction Several haemostatic disturbances have been described in obese patients. Nevertheless, the state of coagulation inhibitors has been scarcely studied in these patients. Activated protein C (APC) is the anticoagulant enzyme formed upon activation of the protein C (PC) by the thrombin-thrombomodulin complex on the surface of endothelial cells. Morbid obesity is associated to endothelial dysfunction, which could cause a reduction in APC generation. Methods Sixty-seven severe or morbid obese patients (51 women, 16 men), aged 34 G 11 P574 years, were compared with 67 normal-weight controls (45 women, 22 men), aged Development of metabolic syndrome is associated with impaired quality 32 G 10 years. After initial evaluation, the patients received treatment for 4 of life: longitudinal data from the North West Adelaide Health Study weeks with a very low-calorie diet (VLCD), followed by a low calorie diet (1200– Patrick Phillips1, Katherine Baldock2, Catherine Chittleborough2 & 1500 kcal/day) for 2 months. Exclusion criteria were organic, infectious or Anne Taylor3 inflammatory disease, ischaemic heart disease or stroke, diabetes mellitus, 1Endocrine and Diabetes Service, The Queen Elizabeth Hospital and Health hyperlipidaemia and hypertension. An anthropometric and analytical evaluation Service, Woodville, South Australia, Australia; 2Diabetes Clearing House, was performed before and after the diet, measuring APC, PC and prothrombin Population Research and Outcome Studies Unit, Department of Health, fragment F1C2 as a marker of hypercoagulability. Student t-test was used to Adelaide, South Australia, Australia; 3Population Research and Outcome compare the differences between groups. Pearson correlation coefficients were Studies Unit, Department of Health, Adelaide, South Australia, Australia. calculated to describe the association between variables. Results Obese patients showed significantly higher levels of APC, PC and F1C2 Background and aims (PZ0.001, PZ0.015 and PZ0.010 respectively). After adjusting for BMI, Longitudinal data from the North West Adelaide Health Study (NWAHS) were differences in APC remained statistically significant (PZ0.047). After three used to examine the effect of development of metabolic syndrome between months of diet, a significant decrease in APC (PZ0.043) and F1C2(PZ0.025) Stage 1 (2000–2003) and Stage 2 (2004–2006) on quality of life. and a non significant decrease in PC (PZ0.067) was observed. Material and methods Conclusions The NWAHS is a random, representative sample of people aged 18 years and over APC levels are increased in obese patients, in part because of greater thrombin living in the north west region of Adelaide. Participants were recruited via generation and higher PC levels. After weight loss, we have found a decrease in telephone interviews to attend the clinic. Of the original cohort (nZ4060), 94.3% APC levels, due in part to a thrombin generation reduction. were contacted at Stage 2, with metabolic syndrome status at follow-up obtained for 79.0% (nZ3206) of original participants. Metabolic syndrome using IDF criteria was defined as waist circumference R94 for men or R80 cm for women plus two of: triglycerides O1.7 mmol/l; HDL cholesterol !0.9mmol/l for men or !1.1 mmol/l for women; blood pressure OZ130/85; FPGOZ5.6 or diagnosed diabetes. Quality of life was measured using the eight subscales of the Short Form 36 (SF-36). Results P573 The prevalence of metabolic syndrome at Stage 1 was 20.1% (18.9–21.4). The Determination of obesity and its relationship with hypertension among three-year cumulative incidence of metabolic syndrome among those without Semnanian adults, Iran metabolic syndrome at Stage 1 was 7.9%. Participants who had metabolic Hamed Pouraram, Ahmad Reza Dorosti, Ibrahim Elmadfa, Mitra Abtahi, syndrome at Stage 1 and Stage 2 were significantly impaired on all SF-36 Saeid Sadeghian & Jafar Jandaghi subscales except Role Emotional and Mental Health, compared to those who did 1National Nutrition and Food Technology Research Institute, Tehran, not have metabolic syndrome. The change in quality of life over time was Islamic Republic of Iran; 2MOH and ME, Tehran, Islamic Republic of Iran; significantly different on the vitality subscale for those who developed metabolic 3Nutrition Department, University of Vienna, Vienna, Austria. syndrome when compared to those who did not. Conclusions Development of metabolic syndrome is associated with impaired quality of life. Introduction Management of factors contributing to metabolic syndrome should consider Obesity and its related diseases like high blood pressure are the main reason of quality of life. coronary heart diseases that are the second main cause of mortality in I.R of
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P575 P577 Novel potent and selective non-peptide ligands of ghrelin receptor: Genetic determination of leptin, insulin and adiponectin levels in the characterization of endocrine and extraendocrine actions Berlin Fat Mouse Inbred 860 line Antonio Torsello1, Elena Bresciani1, Aline Moulin2, Laura Tamiazzo1, Claudia Hantschel, Asja Wagener, Armin O Schmitt, Christina Neuschl & Ilaria Bulgarelli1, Simona Caporali1, Jean-Alain Fehrentz2, Jean Martinez2, Gudrun A Brockmann Daniel Perrissoud3 & Vittorio Locatelli1 Humboldt-University of Berlin, Institute of Animal Sciences, Berlin, 1Department of Experimental Medicine, University of Milano-Bicocca, Germany. Monza, Italy; 2UMR 5247, Institute of Biomolecules Max Mousseron (IBMM), Faculte´ de Pharmacie, Universite´ Montpellier 1, Montpellier, France; 3Aeterna Zentaris, Frankfurt, Germany. Understanding the complexity of polygenic obesity includes the aspect of the hormonal adaptation during the process of selection for high body weight. Therefore we focussed on the analysis of hormones regulating energy Several synthetic peptide and non-peptide ligands of the GHS-R1a have been homeostasis, growth and insulin sensitivity in the Berlin Fat Mouse Inbred 860 described that release GH and stimulate food intake. Starting from a triazole (BFMI860) line which we use as a model for polygenic obesity. The mouse line scaffold, we have designed and prepared novel small molecules with high binding had been selected for low protein and high fat content before it was inbred. Under affinity to the GHS-R1a and we have investigated their effects in vitro on free a standard maintenance diet the endocrine profile of BFMI860 males is typical for intracellular calcium levels and in vivo on food intake and GH secretion in the rat. the obesity status with highly increased leptin and insulin and reduced adiponectin In CHO cells transfected with the GHS-R1a, hexarelin stimulated calcium levels levels compared to C57BL/6 (B6) males. In response to a high fat diet, BFMI860 in a concentration-dependent fashion. Hexarelin is a well characterized males showed marked hyperleptinemia and hyperinsulinemia with high hexapeptide that was used as positive control. The compounds JMV2810, variability in glucose levels. Their adiponectin levels continued to decline JMV3012 and JMV3021 given alone stimulated intracellular calcium levels, under high fat diet. but in combination with hexarelin significantly inhibited its stimulatory effects. To identify the genetic reasons underlying the BFMI860 phenotype a crossbred The GH stimulating activity of the compounds was studied in 10-day old rats, a population of BFMI860!B6 was generated. All F2 animals were fed a high fat model previously validated in our lab. Hexarelin, JMV2951, JMV3012 and diet and analysed regarding the endocrine profile. Mapping quantitative trait loci JMV3021 significantly stimulated GH secretion. Given in association with by linkage analysis has identified a chromosomal region that contributes to high hexarelin, JMV2951 blunted its GH-releasing effects, whereas JMV2810, body weight and fat mass, but not lean mass. Homozygous BFMI860 animals had JMV3012 and JMV3021 did not modify hexarelin activity. In young-adult rats, higher leptin and insulin serum levels corresponding to increased body and fat hexarelin effectively stimulated feeding behaviour. JMV2951 also stimulated mass. Interestingly, males of the BFMI860 phenotype had reduced adiponectin food intake, whereas JMV2810, JMV3012 and JMV3021 had no effects. levels, as expected, while females did not show a reduction in adiponectin levels. Interestingly, JMV2951 given in combination with hexarelin did not modify The BFMI860 males had also higher average levels of insulin and glucose. the stimulation of food intake induced by the latter, whereas JMV2810, JMV3012 In contrast, homozygous BFMI860 females seemed to be more insulin-sensitive and JMV3021 significantly inhibited hexarelin effects on feeding behaviour. In and glucose-tolerant likely due to their higher adiponectin levels. We concluded conclusion our results show that novel triazole agonists of the GHS-R1a might be that homozygous BFMI860 males could have a higher risk to become insulin- endowed with effects on GH secretion divorced from those on feeding behaviour, resistant. Further linkage analysis between the hormone concentrations and further supporting the hypothesis that several receptors or signalling pathways segregation of genotypes is in process to find the genetic factors influencing these might be involved. JMV2951, a potent GHS-R1a agonist stimulating both food hormones. intake and GH secretion, has been selected for further characterization of its effects in a rat cisplatin-induced cachexia model.
Paediatric endocrinology P576 P578 Hypoadiponectinemia but not activation of immune markers is The prevalence of endocrine complications in patients with thalassemia associated with impaired glucose metabolism in morbidly obese patients major Sven Schinner, Kerstin Kempf, Hubert Overmann, Thomas Rotthoff, Mohammad Hassan Moaddab, Mahin Hashemipour & Mahmoud Naderi Matthias Schott, Bettina Rose, Werner A Scherbaum & Christian Herder Isfahan University of Medical Sciences, Isfahan, Islamic Republic of Iran. University Hospital, Dusseldorf, Germany. Background Objectives Frequent blood transfusions and iron overload lead to many complications in Obesity is the major risk factor for the development of impaired glucose tolerance patients with -thalassemia major. Endocrine disorders are detected in these (IGT) and type 2 diabetes mellitus (T2DM). In addition, increased circulating patients with a high frequency. Early diagnosis and treatment of these levels of cytokines and chemokines and decreased adiponectin levels are complications could result in improvement of quality of life. associated with IGT and T2DM. However, a large part of morbidly obese patient Patients and methods remain normoglycemic. Therefore, we investigated if this protection can be A total of 183 patients with thalassemia major aged between 10 and 22 years old attributed to a lower grade of inflammation or higher adiponectin levels. were evaluated for endocrinopathy. Blood samples were taken for determination Methods of serum T4, TSH, FBS, Ca, Ph, cortisol, FSH, LH, estradiol and testosterone Glucose tolerance of morbidly obese patients (nZ2754, body mass index levels.Medical charts were used to assure the regularity of blood transfusion and R40 kg/m2) was assessed by oral glucose tolerance tests. In a case-control design serum ferritin levels. Data were analysed using chi-square, independent t-test, we compared levels of eight immune mediators and adiponectin from patients ANOVA and logestic regression. with IGT/T2DM (nZ52) and normal glucose tolerance (NGT; nZ59). Gene Results expression in peripheral blood was determined by quantitative RT-PCR, and In 62.29% of patients at least one form of endocrinopathy (other than delayed serum concentrations of immune mediators and adiponectin were measured by puberty) was detected. Other endocrinopathies in order of frequency were: growth ELISA and bead-based multiplex technology. failure (36.06%), hypoparathyroidism (16.93%), adrenal insufficiency (12.50%), Results diabetes mellitus (11.47%) and hypothyroidism (8.74%). About 54% of the patients in our morbidly obese cohort were normoglycaemic, There was no significant relation between serum ferritin levels and endocrine while 14% were diagnosed with IGT and 32% with T2DM. There was no disorders; except delayed puberty in males (PZ0.030) and hypoparathyroidism in statistically significant difference in mRNA expression or serum levels of pro- both genders (PZ0.040). Although there was no relation between endocrino- inflammatory markers. Interestingly, we could demonstrate an association of patheies and the age at which Desferal therapy was introduced, there was a NGT with higher adiponectin levels (PZ0.039). Adiponectin levels were significant relation between both growth failure and diabetes mellitus with gender negatively correlated with interleukin (IL)-6 and macrophage chemoattractant (P valueZ0.007 and 0.013, respectively). protein (MCP)-1, but independent the other immune mediators. Conclusion Conclusions This study showed that patients with thalassemia major (are) affected by multiple Lower adiponectin levels were associated with IGT/T2DM, but there was no endocrine disorders. Only some of these endocrinopathies have association with further increase in inflammatory markers with IGT/T2DM in morbid obesity. This increased levels of serum ferritin. Therefore, patients with thalassemia major need suggests that in addition to chronic, low-grade inflammation, adiponectin is an to be evaluated for endocrine disorders periodically, even when serum ferritin important factor in the development of, or protection against, T2DM in obesity. levels are normal.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P579 Five patients from four families (four females, one male) showed severe short The role of thiocyanate in the etiology of residual goiter in Semirom, an stature beginning in the first year of life. All of them had undetectable levels of iodine replete area growth hormone and were subsequently found to be homozygous for a 6.7 kb Mahin Hashemipour, Ammar Hassanzadeh Keshteli, Masoud Amini, deletion in the GH-1 gene. Two families were known to be consanguineous. Ashraf Aminorroaya, Mansour Siavash Dastjerdi, Hassan Rezvanian, Treatment with rhGH normalized growth in all subjects with a current duration of Ali Kachoei, Mohammad Hassan Moaddab & Sassan Haghighi treatment of 1–10 years (mean 5.25 years). One patient has reached final height Isfahan Endocrine and Metabolism Research Center, Isfahan University of (initial height SDS – 7.92 at age 2 10/12 years; final height SDS 0.98). Medical Sciences, Isfahan,, Islamic Republic of Iran. Another patient (initial height SDS – 8.83 at 1 11/12 years; current height SDS 0.9 at 9 5/12 years) has two affected brothers who already had high titers of GH antibodies after having possibly been treated with pituitary derived GH. They Background remained unresponsive to rhGH even in excessive doses of up to 0.35 mg/kg. Despite long standing iodine supplementation in Iran the prevalence of goiter In our experience treatment of IGHD type 1a with rhGH is not associated with a remains high in some areas. This may suggest that factors other than iodine risk of GH antibody production leading to growth arrest. Prior to considering IGF- deficiency may play a role. In the present we investigated the possible role of I as first-line treatment in IGHD type 1a further experimental and epidemiologic thiocyanate (SCN) in the etiology of goiter in Semirom, Iran. studies should evaluate the risk of antibody production on rhGH treatment. Methods One thousand and eight hundred and twenty-eight schoolchildren (7–13 year-old) were selected by multi stage random sampling. Thyroid size was estimated in each child by inspection and palpation. Urinary iodine concentration (UIC) and Urinary thiocyanate (USCN) were measured Urinary SCN and iodine concentration was estimated by the method of Aldridge P582 and digestion method Polyendocrinopathy in children, adolescents and young adults with type Results 1 Diabetes: results from 23837 patients in the German/Austrian DPV- Overall, 36.7% of 1828 students had goiter. The mean UIC was 19.3G9.1 mg/dl. Wiss-database USCN level was estimated in 130 randomly selected schoolchildren (86 goiterous Katharina Warncke1, Wolfgang Rabl1, Sabine Hofer2, Dagobert Wiemann3, and 44 nongoiterous). The meanGS.D. USCN level in goiterous and nongoiterous Angelika Thon4 & Reinhard Holl5 subjects was 0.77G0.80 and 0.64G0.40 respectively (PZ0.67). USCN level in 1Department of Pediatrics, Munich University of Technology, Munich, goiterous and nongoiterous boys was 0.75G092 mg/dl and 0.72G0.45 mg/dl Germany; 2Department of Pediatrics, Medical University of Innsbruck, respectively (PZ0.05). USCN level in goiterous and nongoiterous girls was Innsbruck, Austria; 3Department of Pediatrics, Medical University of 0.75G0.92 mg/dl and 0.72G0.45 mg/dl respectively (PZ0.33). Magdeburg, Magdeburg, Germany; 4Department of Pediatrics, Medical Conclusion University of Hannover, Hannover, Germany; 5Department of In the studied population, thiocyanate overload may play a role in high Epidemiology, University of Ulm, Ulm, Germany. persistence of goiter in boys. In girls it can not explain the still high prevalence of goiter. We suggest the role of other goiterogenic factors should be investigated in this region. Few large-scale multicenter data on additional immune phenomena in patients with type-1 diabetes are available. The DPV initiative aggregates standardized anonymized patient records for quality control and epidemiologic research. This report includes data on 23 837 patients with type-1 diabetes, age !30 years and at least 1 antibody measurement, from 242 specialized centers from Germany and Austria (8012 patients !12 years, 12 866 12–18 years and 2959 patients 18–30 years). At least one B-cell-antibody (ICA, GAD, IA2, IAA at onset) was present P580 in 10 133 patients. B-cell-AB-negative patients were significantly younger at diabetes onset (8.4 versus 9.1 years, P!0.0001). 2459 patients (10.3%) had Structural study on the effect of maternal diabetes on fetal endocrine positive thyroid antibodies (TAK, TPO) with female predominance (62%, pancreas P!0.0001) and association to older age and longer duration of diabetes (both Mohammed Badawoud P!0.0001), but no difference with age at onset. Thyroid-autoimmunity was not King Abdulaziz University, Jeddah, Saudi Arabia. associated with positivity for any B-cell-AB, however the number of B-cell-ABC s detected was slightly higher in patients with thyroid autoimmunity (1.8 versus ! The effect of maternal diabetes on fetal pancreatic islets was investigated before, 1.6, P 0.0001). Antibodies suggestive of celiac disease (tTG, gliadin IgG/IgA or however an extensive and detailed quantitative immunocytochemical investi- endomysium) were present in 3923 patients, with a significantly younger age at onset (7.5 versus 8.2 years, P!0.0001). Parietal cell antibodies were found in 244 gation was not found. Therefore, this investigation was conducted to examine the ! effect of gestational diabetes on the morphology of fetal rat islets. Sections were patients, again associated with older age (15.9 versus 14.1 years, P 0.001). stained with anti-insulin (B cells) antibodies and were used for structural study. Adrenal antibodies were found in 71 patients, this group did not differ clinically The absolute number of stained B cells per islet of the diabetic group was from patients without adrenal antibodies. In 352 patients (61% female, mean age not significantly different from that of the control group. The B cell volume 14.6 years), at least 3 different autoimmune phenomena were present, and 4 organ density was significantly lower in the diabetic group, while islet volume density, systems were involved in 33 patients. In conclusion, Thyroid autoimmunity is islet diameter, islet volume and absolute islet cell number were significantly the most prevalent additional immune phenomenon in type-1 diabetes, especially greater in diabetic group. The nuclear diameter and volume of B cell were not in adolescent and young adult women. Parietal or adrenal antibodies are rare. significantly different in the diabetic group. The results obtained from this study B-cell-autoimmunity is not a predictor for additional autoimmune phenomena in demonstrated that maternal diabetes induces fetal islet hypertrophy and B cell type-1 diabetes. hyperplasia. They further showed that maternal diabetes results in a decrease of fetal islet insulin content.
P583 Comparison of vitamin D status, sun-exposure and personalised UVB- P581 radiation dosimetry of mildly pigmented, breastfed newborns during Successful treatment of isolated growth hormone deficiency type 1a with their first 6-8 weeks of life in Perth, Western Australia and Berlin, recombinant human growth hormone Germany Aris Siafarikas1, Volker Hesse4, Max K Bulsara3 & Timothy W Jones2 Theda Wessel, Dirk Schnabel, Heiko Krude & Annette Gru¨ters 1 Charite´ University Children’s Hospital, Berlin, Germany. Princess Margaret Hospital, Department of Endocrinology and Diabetes, University of Western Australia, Hospital for Child and Adolescent Medicine Lindenhofand German Centre for Growth and Development, Isolated growth hormone deficiency (IGHD) type 1a is caused by defects of the Subiaco, Perth, Australia; 2Princess Margaret Hospital, Department of GH-I gene resulting in severe short stature. Treatment with growth hormone may Endocrinology and Diabetes, Telethon Institute for Child Health Research, become ineffective due to significant production of growth hormone antibodies. University of Western Australia, Subiaco, Perth, Australia; 3School of However, this has only been reported in patients treated with pituitary derived Population Health, University of Western Australia, Perth, Australia; growth hormone. We present five cases with IGHD type 1a successfully treated 4Hospital for Child and Adolescent Medicine Lindenhof and German Centre with recombinant human growth hormone (rhGH). for Growth and Development, Berlin, Germany.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
The prevalence of vitamin D deficiency in at-risk groups is rising even in sunny countries. Aim of this study was to compare vitamin D status and effect of vitamin Two dominant inherited disorders of phosphate homeostasis, X-linked hypo- D supplementation of moderate risk (mildly pigmented, WHO skin type 2) phosphatemia (XLH), and ADHR are known to be caused by inactivating breastfed newborns from sunny and temperate climate zones. Newborns in Perth mutations in the PHEX gene or activating mutations in the FGF23 gene (fibroblast (308S, group 1:5 male, 6 female) did not receive any vitamin D supplementation, growth factor 23), respectively. Both diseases show a similar phenotype with newborns in Berlin (52.58N, 17 male, 23 female) were randomised into nZ20 on renal phosphate wasting and inappropriately normal or low 1,25-(OH) -Vitamin 250 units (group 2) and nZ20 on 500 units (group 3) of vitamin D3 per day. 2 D serum levels, leading to hypophosphatemic rickets and osteomalacia. We compared serum 25 OH vitamin D (25OHD), alkaline phosphatase, albumin; 3 The differential diagnosis can be achieved by molecular genetic analysis of the serum and urine calcium, phosphate and creatinine; sun exposure in hours/day involved genes. and UVB exposure (minimal erythema dose, MED). Measures were obtained on The index patient presented at the age of 2 years with growth retardation (K3.1 day 5 and 6-8 weeks after delivery. UVB exposure was continuously quantified by SDS; 4 cm !3. Percentile), genua vara, severe rickets, and osteomalacia, leading spectral analysis using bio-weighted dosimeters. Surrounding factors and to bone pain and restricted mobility. Serum phosphate levels were low nutrition were assessed by questionnaires and analysis of meteorological data. (0.8 mmol/l; normal range 1.1–2.0 mmol/l), tubular phosphate reabsorption 25OHD levels did not vary significantly between groups on day 5 (nmol/LG (58%) and tubular phosphate transport maximum (0.8 mmol/l; normal range S.E.M., groups1/2/3): 49.2G7.7/68.9G8.1/64.1G5.8; 6–8 weeks later only 1.2–2.6 mmol/l) were decreased. Calcium, 1,25-(OH) -Vitamin D and PTH newborns in Perth presented with subclinical vitamin D deficiency: 45.9G14; 2 3 levels were normal. Based on these findings, hypophosphatemic rickets was group2:128.8G10.6, group3:151.1G18.3, P!0.05. Sun exposure time (h/dayG diagnosed and the boy was treated with phosphate (550 mg/d) and 1,25-(OH)2- S.E.M.) was significantly lower in Perth: 0.5G0.08/2.14G0.13/1.7G0.3, P!0.05. Vitamin D3 (0.4 mg/d). During treatment, radiological signs of rickets and Dosimetry revealed similar UVB exposure (MED/dayGS.E.M.) for all groups: osteomalacia decreased. The growth rate improved, although body height at the 0.03G0.02/0.04G0.02/0.03G0.02. The remaining parameters were normal in all age of 7 years remains low (3. Percentile). participants. Mutations in the PHEX gene were excluded, but analysis of the FGF23 gene Newborns in Perth did not achieve sufficient 25OHD levels despite living in a revealed a novel heterozygous missense mutation in exon 3, resulting in sunny climate. To improve vitamin D photobiosynthesis their sun exposure can be the substitution of the amino acid arginine at position 176 by tryptophane optimised without increasing the risk of skin cancer; otherwise vitamin D (CGGOTGG, R176W). The mutation R176W affects the cleavage site of FGF23 supplementation is needed. In Berlin, Germany, 250 units of vitamin D3 per day that is formed by the 176RXXR179 motif, and is predicted to prevent proteolytic resulted in sufficient vitamin D supply. cleavage and inactivation of FGF23. In conclusion, in this patient genetic testing allowed for the reliable differentiation of ADHR and XLH.
P584 P586 Growth hormone deficient children born small-for-gestational-age need The role of desmopressin test in the diagnosis of young patients with higher than replacement dose of hGH for successful treatment Cushing’s disease Ferenc Pe´ter1, Andrea Luczay2, Eniko So´lyom3, Bala´zs Gelle´n4, Paola Sartorato, Elisa Zulian, Miranda Testa, Nora Albiger, Marie Tama´s Niederland5, Eniko Felszeghy6,La´szlo´ Sa´godi3,Ja´nos So´lyom2 & Eve Brunner, Cecilia De Marchi, Sergio Ferasin, Franco Mantero & A´ gota Muzsnai1 Carla Scaroni 1Buda Children’s Hospital, Budapest, Hungary; 2Semmelweis University, Endocrinology Unit, University of Padua, Padua, Italy. 2nd Pediat Department, Budapest, Hungary; 3Child-health Centre, Miskolc, Hungary; 4Szentgyo¨rgyi University, Pediat Department, Szeged, Hungary; 5Petz Alada´r Hospital, Pediat Department, Gyor, Hungary; 6University In the diagnosis of Cushing’s disease (CD) desmopressin (dDAVP) stimulation Pediat Department, Debrecen, Hungary. test may be a convenient and more readily available alternative to CRH test; however the sensibility and specificity of ACTH response to dDAVP test has been reported in adult patients inferior to CRH test. In childhood patients with CD there Growth hormone deficient (GHD) children born small-for-gestational-age (SGA) are no data for the use of dDAVP test in this clinical setting. We studied 9 patients receive the same hGH dose as the children born with appropriate weight/length for ranging in age from 11 to 19 years (7 females and 2 males) with a suspected gestational age (AGA). There are very few data on their lower growth response to the diagnosis of CD. Preoperative endocrine assessment included CRH, dDAVP, usual GH replacement dose. The aim of this multi-centre retrospective study is to overnight 8 mg dexamethasone tests. CRH and dDAVP tests (positive if ACTH analyse the hGH dose dependency of GHD children with SGA. and cortisol levels were respectively more than 50% and 20% of the baseline) SGA was defined as a birth weight/length below – 2 SD for gestational age compared resulted both positive in 8/9 cases but a more relevant mean increase has been to the national standard. The data of hGH treated GHD (GH peak !7 ng/ml in two found for ACTH levels after dDAVP stimulation. In all patients we observed a provocative tests) children and Turner syndrome (TS) with SGA. Some positive response (drop in cortisol levels more than 50% of baseline values) to the characteristics of the 41 prepubertal children (treated with hGH over 2 years) are dexamethasone test. At MRI scans 6 patients presented a normal pituitary gland 3 the following: age: 8.37G3.72 (2.71–15.87) years; sex: boy/girl 18/23; HSDS: a microadenoma. All the patients underwent transphenoidal neurosurgery that K3.49 G1.0 (between – 1.7 and – 5.56); hGH dose: 0.69G 0.18 (0.4-1.05) IU/kg/w; was successful in 7/9 (at hystology 6 adenomas and 1 normal pituitary tissue), the DHSDS/2 years: 0.76G0.74 (between K0.42 and C2.48). other 2 patients underwent pituitary radiotherapy. Conclusions: In children and The DHSDS was found 0.92G0.77 in 13 children treated with a mean dose adolescents with CD a same percentage (88%) of positive response to dDAVP and R0.8 IU/kg per w and 0.68G0.73 in the other 28 children received !0.8 IU/kg CRH stimulation tests was observed. Moreover an high percentage of negative per w. The same parameters proved to be 1.2G0.6 and 0.73G0.5 resp. in the MRI scans was found and in these cases the combined positive response to the younger (!6 years) age (P!0.01). This dose dependency was more significant CRH and dDAVP stimulation tests, and particularly the marked response to the in the children to be SGA for birth weight: growth response of 15 among 21 was latter, were useful tools in the diagnosis of CD !1.0 DHSDS/2 yrs treated with !0.8 IU/kg per w (P!0.01). These results confirm the previous data of de Zegher et al. (1998), that the great majority of GHD children with SGA need higher than replacement dose of hGH for optimum growth response, probably because of some IGF-I resistance of these children. P587 Evaluation of Intergrated [18F]FDOPA–PET/CT for identification of focal forms of Congenital Hyperinsulinism (CHI) Oliver Blankenstein1, Klaus Mohnike2, Khalid Hussain3, Peter Kuehnen1, Winfried Barthlen4, Frank Fuechtner6 & Wolfgang Mohnike5 P585 1Paediatric Endocrinology, Charite´-Universita¨tsmedizin Berlin, Berlin, Autosomal dominant hypophosphatemic rickets (ADHR) due to a novel Germany; 2Paediatric Department, Otto von Guericke Universita¨t, Magde- mutation in the FGF23 gene burg, Germany; 3National Institute for Child Health, Great Ormond Street Susanne Clausmeyer1, Christoph Jacobi2, Karsten Ha¨ffner2, Martin Pohl2, Hospital, London, UK; 4Peadiatric Surgery, Charite´, Berlin, Germany; Egbert Schulze1 & Friedhelm Raue1 5DiagnostischTherapeutisches Zentrum am Frankfurter Tor, Berlin, 1Endocrine Practice, Heidelberg, Germany; 2Department of Pediatrics and Germany; 6Inst. for Radiopharmacy, Forschungszentrum Dresden Adolescent Medicine, University Hospital, Freiburg, Germany. Rossendorf, Dresden, Germany.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Deficiency of 3 beta-Hydroxysteroid-Dehydrogenase Type II is caused by mutations in the HSD3B2 gene and accounts for about 1–10 percent of Objective cases of CAH. CHI is the most frequent cause of severe hypoglycaemia in infants. Two distinct Patient anatomical forms have been described which require different therapeutic 18 This report is about a 2-year-old patient of Turkish origin referred to our center strategies. We evaluated the predictive value and accuracy of integrated [ F] with clinical finding of penoscrotal hypospadias and micropenis (stretched penile FDOPA-PET/CT as a new tool in identification of focal lesions in an length 1.5 cm). Testicles were palpable bilaterally in the scrotum. Due to initial observational study. biochemical and hormonal findings moleculargentic analysis of CYP21A2 gene Patients and methods was already done, showing heterozygous germline mutations p.Val281Leu, From 2005 to 2007, 73 infants and children from the UK (30) and Germany (42) 18 p.Leu307fs, p.Gln318Stop and p.Arg356Trp. His parents are cousin-german to with CHI were examined with [ F]FDOPA-PET/CT for localization diagnostic. each other. Since 2007 a high-resolution 64line CT-scan were used. A special angiographic Methods enhancement protocol was developed and anatomical landmarks were identified Genomic DNA was extracted from peripheral blood leukocytes. Coding regions to improve the localization within the organ and to guide the surgeon. and corresponding exon-intron boundaries of the CYP21A2 gene and the HSD3B2 Results gene were amplified by PCR and subjected to direct sequencing. In 69 of 72 patients a differentiation between focal and diffuse form was possible. Results Focal cases were treated surgically. The diagnosis was histological confirmed in 18 A compound heterozygous state of these mutations was excluded by sequencing 22 of 23 focal cases. In 9 cases the precise localization by the [ F]FDOPA- analysis of CYP21A2 genes of both parents (father has no mutation). PET/CT enabled minimal invasive laparoscopic surgery. Further hormonal studies suggested a 3 b-Hydroxysteroid dehydrogenase type Subtotal pancreas resection was necessary in 3 diffuse cases while the others are II deficiency and justified sequence analysis of the HSD3B2 gene. A novel manageable with medical therapy so far. We present the metabolic and neurologic homozygous germline mutation (p.Trp355Arg) was found, for which both parents outcome of the cases. are heterozygous carriers. Conclusion 18 Conclusion Integrated [ F]FDOPA-PET/CT was able to discriminate between focal and To judge a case of CAH in the right way it is important to look at all clinical diffuse forms in 95% of the cases and accurately localize the lesion in focal aspects in a differentiated way. Comprehensive (clinical, biochemical, hormonal) CHI. It is a valuable tool to support the determination of further therapy analysis should be conducted and approved by moleculargenetic analysis in line (medical or surgical) and finally to guide the surgeon in limited pancreatic with a genetic counseling. resection.
P588 P590 Epigenetic defects at GNAS DMRs in PHP-Ia patients lacking coding GNAS mutations Increased hyperinsulinism and insulin resistance, and decreased Sara Bondioni1, Giovanna Mantovani1, Pamela Labarile1, Luisa de Sanctis2, antioxidant defense, in children and adolescents with pre-metabolic Erika Peverelli1, Andrea Lania1, Paolo Beck-Peccoz1 & Anna Spada1 versus metabolic syndromes 1 2 3 1Endocrine Unit, Department of Medical Sciences, University of Milan, Vesna Dimitrijevic-Sreckovic , Branko Sreckovic , Emina Colak , 1 1 3 Fondazione Policlinico IRCCS, Milan, Italy; 2Department of Pediatrics, Predrag Djordjevic , Fadil Canovic , Dragana Vukosavljevic & 3 Regina Margherita Children’s Hospital, University of Turin, Turin, Italy. Jecka Stojanovic 1Institute of Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Serbia, Belgrade, Serbia; 2Institute of Cardiovascular Diseases, Pseudohypoparathyroidism (PHP) is a disorder characterized by hypocalcemia Clinical Center of Serbia, Belgrade, Serbia; 3Institute of Medical and hyperphosphatemia due to end-organ resistance to the action of PTH. The Biochemistry, Clinical Center of Serbia, Belgrade, Serbia. two main subtypes of PHP, PHP type Ia and Ib are caused by heterozygous loss-of-function mutations in GNAS exons 1–13, which encode Gsa, and by methylation defects in the imprinted GNAS cluster, respectively. Individuals Background and aims affected with PHP-Ia typically show clinical abnormalities referred to as The aim was to analyze insulin resistance (IR), glycoregulation disorders, lipid Albright hereditary osteodystrophy (AHO) together with resistance toward status, C-reactive protein (CRP), plasminogen activator inhibitor (PAI-1) and several additional hormones, such as TSH, gonadotropins and GHRH. PHP-Ib antioxidant defense in children and adolescents with pre-metabolic (Pre-MS) and differs from PHP-Ia in that affected patients do not have the AHO phenotype metabolic (MS) syndromes. and hormone resistance appears to be limited to the actions of PTH and, Material and methods occasionally, TSH. About 30% of patients with PHP-Ia features lack GNAS The study included 30 obese individuals (age 10–20 years, body mass index coding mutations. We investigated the presence of typical PHP-Ib epigenetic (BMI) or waist circumference (WC) R90 percentile). Three of the following five defects at GNAS differentially-methylated regions (DMRs) in 10 PHP-Ia criteria were used for MS diagnosis in children and adolescents: WCR90 Pct. for cases lacking GNAS mutations. We found loss of methylation at A/B DMR age and sex; triglycerides (TG) O1.7 mmol/l; high density lipoprotein cholesterol in 6 cases and defects at other GNAS DMRs in 3 of them. In one patient we (HDL-C) !1.0; hypertension R90 Pct. for height, age and sex; glycaemia O6.0. found the presence of STX16 gene 3.3 kb deletion, that characterizes familial Patients with less than three afore mentioned criteria were indicated as patients PHP-Ib cases. with Pre-MS. In conclusion, we confirm that GNAS methylation defects can explain about Insulin sensitivity was determined by HOMA IR. Serum CRP was measured by 50% of PHP-Ia cases lacking GNAS coding mutations and suggest that PHP- immunometric assay. Activities of markers of antioxidant defense, superoxide Ia patients should be screened not only for GNAS coding mutations but for dismutase (SOD) and glutathion peroxidase (GSH-Px) were determined in epigenetic defects at the same locus as well. erythrocytes. Results Metabolic syndrome was found in one third of patients (BMI 33.84G5.5 kg/m2; WC 103.9G15.6 cm; blood pressure 123.8G11.1/80.0G9.6 mmHg; increased HOMA IR (5.42G2.6); increased triglycerides (1.9G0.6 mmol/l); decreased P589 HDL (0.88G0.23 mmol/l); increased LDL/HDL ratio (3.5G1.37); increased Hypospadias and micropenis in congenital adrenal hyperplasia: a case CRP (11.64G15.9 mg/l); increased PAI-1 (5.62G1.28 U/ml); low SOD and study GSH-Px (1001.2C117.4 U/grHg and 35.3C17.9 U/grHg respectively). The other Sandra Fleischer, Ute S Groß, Hjo¨rdis HS Drexler, Achim Wu¨sthof & two thirds showed 1-2 metabolic syndrome criteria (mostly WC 91.6G16.0 cm; Heinrich M Schulte decreased HDL 1.07G0.16 mmol/l), increased HOMA IR (6.1G4.4, l), normal Endokrinologikum Hamburg, Hamburg, Germany. CRP (1.4G2.1 mg/l), increased PAI-1 (3.41G2.38 U/ml) and decreased antioxidative defense (SOD 932C0.81 U/grHg; GSH-Px 31.0C6.7 U/grHg). Conclusion Introduction PAI-1 and proinflammatory cytokines with CRP directly accelerate atherosclerosis Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive and thrombosis. Positive correlations between PAI-1 and WC and BMI, and diseases with increased adrenal androgens secretion from the adrenal cortex, negative correlations between BMI and antioxidative defense in the pre-metabolic characterized by simple virilizing and salt wasting forms. Deficiency of syndrome patients show that this early stage preceding MS is also characterized 21-hydroxylase, caused by mutations in the 21-hydroxylase gene (CYP21A2)is by evident hyperinsulinism and IR and atherosclerotic complication risks. the most frequent CAH, accounting for more than 90 percent of CAH cases.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P591 P593 Prevalence of obesity and metabolic syndrome among Spanish Final height and timing of menarche after treatment for idiopathic adolescents central precocious puberty (CPP) Emilio Garcı´a-Garcı´a, Rafael Galera, Sara Go´mez-Bueno, Marı´a- Elpis Vlachopapadopoulou1, Dimitrios Thomas2, Feneli Karachaliou1, Dolores Ga´mez, Encarnacio´nLo´pez-Ruzafa, Ana Ruiz-Sa´nchez, Marina Vakaki1, Philipos Kaldrymidis2 & Stefanos Michalacos1 Patricia Oliva, Manuel Martı´n, A´ ngeles Va´zquez & Antonio Bonillo 1Department of Growth and Development and Department of Radiology, Torreca´rdenas Hospital, Almerı´a, Spain. Children’s Hospital ‘P and A Kyriakou’, Athens, Greece; 2Metaxa Department of Endocrinology, Memorial Cancer Hospital, Athens, Greece. Purposes To report the prevalence of obesity, metabolic syndrome (MS) and its related In true precocious puberty, the increased gonadal steroid secretion increases components among adolescents living in the city of Almerı´a (south of Spain). height velocity, somatic and psychosocial development, and the rate of skeletal To examine the distribution of HOMA-IR (homeostasis model assessment of maturation and can lead to short adult height. The aim is to assess the impact of insulin resistance). suppression therapy of CPP with triptorelin on final adult height and the timing of Methods menarche and pattern of menstrual cycle post-treatment. A total of 373 subjects attending secundary school (aged 12–17 years) Materials and methods participated in a community-based cross-sectional survey. IOTF (International Nineteen girls, with CPP, which had completed at least two years of triptorelin Obesity Task Force) criteria were used to identify obesity and overweight. therapy and have attained final height at the time of last evaluation, were Criteria for the MS were the presence of three or more of the following incorporated in the study. The diagnosis of PP was based on combined data components (criteria for adolescents to Adult Treatment Panel III): 1) central concerning early occurrence of secondary pubertal signs, advanced bone age obesity (waist circumference R90th percentile, age and gender specific; (BA) and accelerated growth rate based on multiple height measurements and 2) elevated triglyceride concentrations (R110 mg/dl); 3) low HDL cholesterol LHRH response consistent with CPP. Seven girls with central precocious puberty, concentrations (%45 mg/dl); elevated blood pressure (systolic and/or diastolic which did not initiate triptorelin therapy mainly due to their parents’ refusal and R90th percentile, age and gender specific); or 5) elevated fasting glucose levels had attained the final height, were used for comparisons. The mean (S.E.M.) (R100 mg/dl). HOMA-IR was calculated and linear regression identified factors chronological age at diagnosis was: 8.42 (0.15) years and 8.44 (0.57) years and associated. (BA) 10.76 (0.32) and 11.2 (0.43) yrs for patients and controls respectively. Results Girls were treated with triptorelin (Arvecap, IPSEN, Greece) every 4 weeks at a About 8.0% of this sample was obese and 20.4% was overweight. The prevalence dose of 3.75 mg. of MS was 6.2% (95% confidence interval 4.8–7.6). It was 26.7%, 14.5% and Results 1.5% among adolescents who were obese, overweight and normal weight. 8.3% Mean final height was not statistically different from mean target height (157.28 of the adolescents had two components and 26.0% had one component, with low vs 159.55 cm, PZ0.055). Mean age of menarche was statistically different HDL cholesterol the most common component (19.8%). Mean HOMA-IR was between treated girls and controls (12.45 vs 11.02 years PZ0.004). Menarche 2.07. Triglyceride concentrations and waist circumference were the most was observed 1.37 yearsG0.73 (range: 0.4–3.57) following triptorelin discon- important determinant of HOMA-IR (bZC0.30; P!0,001; bZC023; tinuation. Menstrual cycle was regular ranging from 28 to 40 days in 17 (89.5%) PZ0.013). out of 19 girls. Conclusions Conclusions Obesity and MS are major problems for Spanish adolescents. The prevalence of Suppression therapy seems to be effective on attainment of final height in the the MS is higher in obese as opposed to non-obese subjects. range of target height. Spontaneous menarche occurs in all patients followed by regular menstruation in the vast majority of treated subjects.
P592 Kinetic study of ldl oxidation in female progeny with positive family history of cardiovascular diseases and/or hyperlipidemia P594 Kali Makedou, Anargyros Kourtis, Areti Hitoglou, Christos Iliadis, The coincidence of Poland syndrome and Turner syndrome Norma Vavatsi-Christaki & Georgios Papageorgiou Beata Wikiera1, Elzbieta Wojcik2 & Anna Noczynska1 Aristotle University, Thessaloniki, Greece. 1Department of Endocrinology and Diabetology for Children and Adolescents, Medical University, Wroclaw, Poland; 2Department of Paediatry, Allergology and Kardiology, Medical University, Wroclaw, Aim Poland. The present study was designed in order to investigate the lipid profile, as well as LDL oxidizability in vitro, of female progeny (girls and young women) with positive family history of cardiovascular diseases (CVD) and/or hyperlipidemia. Poland syndrome (PS) is a defect consisting in unilateral deficiency of the Patients and methods pectoralis major muscle and anomaly of the ipsilateral upper limb, usually in the In the present study, 30 healthy female subjects were recruited, aged 3 to 30 years form of syndactyly or synbrachydactyly. The absence of a nipple and the aplasia old (meanGS.D. 14.4G8.02 years old). These subjects were progeny of families of a mammary gland are frequently found. The incidence of PS ranges from with history of CVD and/or hyperlipidemia. Kinetic study of LDL oxidation with 1:7000 to 1:100 000. Cu2C took place in vitro. Lag time (tlag) and malonyldialdehyde (MDA) were The authors present a 5-year-old girl with a very rare coincidence of PS and used as indexes of LDL oxidizability. Moreover, lipid profile parameters were Turner syndrome. The child was born after 38 weeks of gestation (weight 2400 g, determined, such as total cholesterol (CH), triglycerides (TG), HDL, LDL, length 49 cm, head circumference 30 cm, 10 points on Apgar scale) with the feet apolipoprotein A1 (apoA1) and B100 (apoB100) and lipoprotein (a)(Lp(a)), after lymphoedema and the right hand anomaly. overnight fast. At the age of two a marked difference in height between the girl and her peers was Results observed. The endocrinological consultation was performed after surgical Mean valuesGS.D. of the parameters under study were: tlag 82.16G16.5 min, correction of her hand at the age of 3. On physical examination the following MDA 18.19G4.79 nmol/mg LDL, apoA1 1.39G0.35 g/l, apoB100 1.16G were confirmed: height 83 cm (!3c,K2.4 SDS), weight 10 kg (!3 c), 0.56 g/l, Lp(a) 24.4G21.55 g/l. Mean valuesGS.D. of the lipid parameters for underdeveloped right pectoralis maior muscle and right upper limb, angular all subjects !16 years old (nZ18) and R16 years old (nZ12), were: CH 222.85G nails placement, cranial disproportion with prominent forehead, small jaw, gothic 99.2 and 214.58G45.01 mg/dl, TG 64.2G23.55 and 93.1G93.41 mg/dl, HDL palate, lower ear settle, systolic hear murmur, clitoris enlargement, condition after 44.1G9.47 and 47.3G10.47 mg/dl and LDL 165.9G95.1 and 149.1G syndactyly operation, deformed elbows and knees. 40.54 mg/dl, respectively. Two thirds of the subjects were of medium or high The bone age was delayed half a year. GH max. during nocturnal profile was risk for a future cardiovascular disease or hyperlipidemia. Moreover, tlag 5.91 ng/ml, FSH 38.2 mIU/ml, TSH 1.64 uIU/ml, FT4 1.64 ng/dl, IGF 1 presented significant positive correlation with HDL serum levels (rZ0.536, 27.7 ng/ml. PZ0.002). On the ground of clinical picture PS was diagnosed and the suspicion of Turner Conclusions syndrome was suggested. The results of genetic examination confirmed the In female progeny with family history of CVD and/or hyperlipidemia, lipid monosomy of X chromosome. The girl started GH treatment at the age of 4.5. profile should be determined for early detection of progeny of high risk for CVD. Poland’s anomaly in our patient demands lasting rehabilitation. However, her HDL serum levels should be high above recommended, as long as they seem to be therapeutic program is more complex because of the coincidence with Turner correlated with increased resistance of LDL to oxidation. syndrome.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P595 The level of LPO in all DS groups was lower than in CG groups (DS-0Z 1.57 nmol/ml vs CG-0Z1.83; DS-1Z1.46 vs CG-1Z1.58; DS-2Z1.41 vs Day profiles of salivary 17-hydroxyprogesterone for the control of Z glucocorticoid therapy in adolescents with congenital adrenal hyper- CG-2 1.44). plasia due to 21-hydroxylase deficiency Conclusions Timo Deutschbein1, Nicole Unger1, Berthold Hauffa2, Klaus Mann1 & The high activity of SOD-1 in children with CHD with arterio-venous shunt (as Stephan Petersenn1 well DS as CG) indicates a disturbances in the antioxidative system in this 1Division of Endocrinology, Medical Center, University of Duisburg-Essen, children. Essen, Germany; 2Division of Pediatric Endocrinology and Diabetology, The higher activity of SOD-1 may play an important role in lipid peroxidation University Children’s Hospital, University of Duisburg-Essen, Essen, process, which express lower LPO concentrations. Germany.
Introduction Optimizing glucocorticoid (GC) therapy in patients with congenital adrenal hyperplasia (CAH) remains a challenge. While overdosing may result in Cushing’s syndrome, underdosing is associated with female virilization and P597 adrenal insufficiency. This study evaluated day-profiling of salivary 17-hydroxy- New clinical features and detailed genetic analysis of heterozygous progesterone (17OHP) for the biochemical control of adolescents with CAH due 17q12 deletion syndrome, leading to loss of TCF2 and MODY5 to 21-hydroxylase deficiency. Klemens Raile1, Theda Wessel1, Dorothee Deiss1, Dominik Mueller2, Methods Denise Horn3, Wolfgang Riebel4, Reinhard Ullmann5, Eva Klopocki3 & Twelve patients (4 males; age 19.3G0.6; BMI 28.0G1.9) were enrolled after Annette Grueters1 transfer from pediatric to adult care. Sampling was performed at 0700, 0930, 1Institute for Experimental Pediatric Endocrinology and Diabetes, Charite´ 1200, 1500, 1800, 2200, and 2400 h. 43 healthy volunteers (22 males; age 37.8G Campus Virchow, Berlin, Germany; 2Department of Paediatric Nephrology, 1.8; BMI 25.7G0.7) served as a control group, and upper normal 17OHP cutoffs Charite´, Campus Virchow, Berlin, Germany; 3Institute of Medical Genetics, (meanC2S.D.) were calculated for each time point. Results are expressed as Charite´ Campus Virchow, Berlin, Germany; 4Department of Paediatric meanGS.E.M. 17OHP was measured by RIA (DPC Diagnostic Products Corp). Radiology, Berlin, Germany; 5Max-Plack-Institute for Molecular Genetics, Results Berlin, Germany. Initial evaluation revealed elevated 17OHP baseline values in 64% of patients. Five patients were tested only once (1.8G0.6 sampling times elevated, mean HC-equivalent dose 33.3G10.3 mg), while 7 patients were repeatedly tested. For Objective the latter, 6.0G0.4 sampling times were elevated in the initial day profiles (mean MODY5 is caused by abnormalities in the TCF2 gene encoding the transcription HC-equivalent dose 25.0G1.1 mg). In contrast, 2.9G1.0 elevated sampling times factor HNF1b. We investigated cases of MODY5 for the underlying type of TCF2 were found after adaption of medication, such as addition of longer-acting anomaly. glucocorticoids (mean HC-equivalent dose 24.1G2.0 mg). With respect to all Case presentations profiles, results of single morning evaluation and day-sampling were similar in From 623 children and adolescents with diabetes mellitus followed at our diabetes 38%. Seventy eight percent of profiles with normal 17OHP levels at 0700 h clinic in 2006, 64 were negative for islet cell autoantibodies (GAD, IA-2, ICA) demonstrated increased 17OHP throughout the day. within the first year of diagnosis and out of these, four patients presented clinical Conclusion features of MODY5. These features were in all patients: renal disease (single A relevant proportion of patients with CAH demonstrated insufficient cysts, cystic dysplasia or uretero-pelvic obstructions), elevated liver enzymes, biochemical control during adolescence. Salivary 17OHP day profiles led to reduced birth weight and reduced postnatal growth as well as diabetes with changes in GC application with improved 17OHP suppression, while daily GC adolescent onset. Additional features in some patients were pancreas dysplasia dose remained stable. Determination of single morning 17OHP levels did not and exocrine insufficiency (2/4), genital malformation (3/4), and mental allow for reliable control of androgen excess. retardation (2/4). Single cases presented also extreme pre- and postnatal growth deficit, congenital cholestasis with bile duct dysplasia, immune defect (CVID) or cataract at diabetes onset. Results DNA of the patients was analysed for TCF2 point mutations and if normal by QMPSF for gene deletions. All MODY5 patients found in our cohort had no TCF2 mutation but had monoallelic loss of the entire TCF2 gene. Array CGH and FISH analysis confirmed a large genomic deletion of w1.5–1.7 Mb in size that P596 was not detected in any of the patients’ parents. Conclusion The superoxide dismutase and lipid peroxide in children with Down The phenotype of patients with 17q12 deletion syndrome is highly variable. Up to syndrome and congenital heart disease now, 17q12 deletion syndrome was claimed to be one of the few contiguous gene Elzbieta Wojcik, Ewa Barg, Malgorzata Gromkowska, Ewa Maslowska, deletion syndromes without mental retardation but our two cases with mental Beata Wikiera, Danuta Kalita, Elzbieta Gamian, Barbara Turczyn & retardation question this hypothesis. The molecular defect identified in all cases Anna Skoczynska was a 1.5–1.7 Mb deletion and paired, segmental duplications along with Wroclaw Medical University, Wroclaw, Poland. breakpoints were most likely involved in this recurrent chromosomal microdeletion. Metabolic disturbances occur more often in patients with Down Syndrome (DS, trisomy 21) than in the health population. Superoxide dismutase (SOD-1), the main enzyme in the antioxidative system, is coded on chromosome 21. Disturbances in the antioxidative system may play a major role in the development of complications of CHD with arterio-venous shunt. P598 The aim was to evaluate the activity of SOD-1 and concentration of LPO in Aspects and features of type 2 diabetes and the metabolic syndrome in children with DS and CHD. obese children and adolescents Sixty-two children with DS (mean 6.7 years) were divided for 3 groups:without Z Z Susanna Wiegand, Almut Dannemann, Angela Galler, Theda Wessel, CHD (DS-0, n 18/CG-0, n 13); CHD with insignificant arterio-venous shunt Annika Bickenbach & Annette Gru¨ters Z Z G (DS-1, n 26/CG-1, n 26) and CHD with significant arterio-venous shunt ´ Z Z Pediatric Endocrinology and Diabetology, Charite Childrens’ Hospital, pulmonary hypertension (HP) (DS-2, n 18 / CG-2, n 14).) As a control group Universita¨tsmedizin Berlin, Berlin, Germany. were 53 healthy children (mean 10.4 years) as a control group (CG). The activity of SOD-1 and concentration of LPO were evaluated. The activity of SOD-1 was statistically higher in DS than in CG group, which is Background genetically determined, but only in children without CHD (DS-0 vs CG-0: Obesity is a rising problem in developed and developing countries. Currently little 0.0441 U/mg protein vs 0.0319 U/mg protein, P! 0.05). is known about prevalence and prognosis of type 2 diabetes and the metabolic SOD-1 was higher in CG2 -children than in CG0- children, as well DS as CG. syndrome in obese children and adolescents in Europe. (CG-2 vs CG-0: 0.0608 vs 0.0319 and DS-2 vs DS-0: 0.0568 vs 0.0441; P!0.05). Patients and methods In CG2 children the activity of SOD-1 was higher even in CG than in DS (CG-2 vs About 491 obese children (mean-age 11.2 years; mean-BMI 30.3 kg/m2) were DS-2: 0.0608 vs 0.0568). examined (lipid-profile; blood pressure, insulin-resistance1) and in 102 of them
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 with risk factors for type 2 diabetes (type 2 DM) according to the ADA-criteria P600 (positive family history, acanthosis, ethnic risk group) two oral glucose tolerance High incidence of obesity and insulin resistance in prepubertal children, tests (OGTT) were performed with 9–12 months interval. The influence of born too small for their gestational age puberty, BMI and therapy was verified by a multivariate analysis. Renata Stawerska, Malgorzata Szalapska, Joanna Smyczynska, Results Mciej Hilczer & Andrzej Lewinski Hypertension (2nd Task Force) was present in 18.3%, hyperlipidemia (total- O O Chair Endocrinology and Metabolism Diseases Medical University of Lodz, cholesterol 200 mg/dl, triglycerides 150 mg/dl) in 27.7% and insulin- Research Institute, Polish Mother Memorial Hospital, Lodz, Poland. resistance (R-HOMAO3) in 46.3%. Overall in 64% of the patients at least one sign of a metabolic syndrome was present. In the diabetes-risk group the OGTT revealed impaired glucose tolerance (IGT) in 36% and type 2 DM in 8% of the Fetal undernutrition is at the base of disorders in the differentiation process of patients (all white Caucasian). Longitudinally insulin-resistance was strongly pancreatic beta cells. Abnormal insulin activity leads to restriction of fetal growth influenced by progression of puberty (Odds-ratio 7.80; PZ0.009) and increase of and to obesity, insulin resistance and diabetes mellitus type 2 (DM2), either in BMI (Odds-ratio 3.25; PZ0.031). Participation on an obesity-training- childhood or adulthood. The aim of the study was to assess the incidence of programme improved insulin-resistance independent from BMI-change (Odds- obesity and insulin resistance in prepubertal children, born with body mass too ratio 4.4; PZ0.008). small for their gestational age (SGA). Conclusions Material and methods The metabolic syndrome is not only a feature of obesity in adults but also very Sixty-eight (68) prepubertal children (aged form 6 to 10 years, born as SGA (the frequent in children and adolescents mirroring the dimension of childhood obesity birth weight below K2.0 standard deviation for gestational age and sex), were and related complications. Type 2 diabetes mellitus in obese children and enrolled into the study. The comparison group comprised twelve (12) healthy adolescents is no longer restricted to minority groups. Dyslipidemia, reduced children, matched for age and sex, born with body weight appropriate for insulin sensitivity and impaired glucose tolerance are closely correlated. gestational age (AGA). In each child, its actual height and weight were measured Longitudinal studies are needed to establish reliable screening criteria and non- and BMI was calculated, fasting cholesterol and triglycerides concentrations were pharmacological and pharmacological prevention strategies for obese children assessed and glucose and insulin concentrations during oral glucose tolerance test and adolescents. (OGTT) were performed. Based on the results of OGTT, IR index, according to Matthews DR et al. Diabetologia 1985 28 412–9. HOMA, and IR index, according to Belfiore, were calculated, too. Results Neither glucose intolerance nor DM2 was observed in any of the examined children. No lipid concentration disorders were found in any of the children. Obesity was recognized in 32.3% children with SGA. In about 50% of the children with SGA and obesity, insulin resistance was identified. No statistical P599 correlation was observed between birth body mass and: glucose, insulin, Autoimmune polyendocrine syndrome type 1 in West Northern France: cholesterol and triglycerides concentrations, however, a negative correlation phenotypic and genotypic description, and use of immunosuppressive was noted between birth body mass and IR indices. therapies Conclusion Proust-Lemoine Emmanuelle1, Saugier-Ve´ber Pascale2, Lefebvre Herve´3, Low birth body mass is a risk factor of obesity and insulin resistance in Lalau Jean-Daniel4, Reznik Yves5, Prin Lionel6, Cardot-Bauters Catherine1 prepubertal children. & Wemeau Jean-Louis1 1Endocrinology, Clinique Linquette, Lille, France; 2Molecular Genetics, INSERM U614, Rouen, France; 3Endocrinology, Rouen, France; 4Endo- crinology, Amiens, France; 5Endocrinology, Caen, France; 6Immunology, EA2686, Lille, France.
Autoimmune polyendocrine syndrome type 1 (APS1) is an autosomic recessive P601 disease due to AIRE gene mutations, inducing central immune tolerance Prolactinomas in pediatric age breakdown. It was poorly known in France. Ana Catarina Matos, Filipe Mota, Olinda Marques, Ana Antunes & Objectives Rui Almeida To describe clinical and immunological phenotypes, to determine main genotypes Hospital de S Marcos, Braga, Portugal. in West Northern France (9 millions inhabitants), to identify factors that could influence phenotypes, and to analyse immunosuppressive therapies indications in APS1. Introduction Methods Prolactinomas are the most common pituitary adenomas in paediatric patients, Clinical and immunological datas have been collected thanks to West Northern except in the first decade of life, when ACTH secreting adenomas are more France endocrinologists and paediatricians collaboration. Pathological mutations frequent. were identified by DNA sequencing. Objective Results Analysis of clinical, diagnostic and therapeutic data of prolactinomas in About 19 patients (7 females, 12 males, age 31G13 yr) from 13 families have paediatric age. been identified. Clinical manifestations varied greatly among patients, from 1 to Methods 10 components. Candidiasis and adrenal insufficiency frequently occurred in Retrospective study of 15 patients whose symptoms began before 18 years of age. respectively 17 patients (89%) and 15 patients (79%). Surprisingly, hypopar- Results athyroidism was diagnosed in only 12 cases (63%), whereas alopecia was particularly frequent, in 10 patients (53%). In 3 patients presenting with atypical forms, molecular diagnosis confirmation was essential. Four different AIRE gene mutations were identified, and 13bp-deletion in exon 8 (c.967-979del13) was the G most prevalent. A correlation between this mutation on at least one allele and *Mean S.D. Macro Micro Z alopecia occurrence was identified (P 0.003). There was an elevation of mean No of boys/girls 3/4 0/8 C G 3 C CD4 lymphocytes concentrations (1103 256/mm ) while mean CD8 Age at beginning of symptoms* (year) 15.4G1.9 15G2.4 G 3 C G 3 (412 156/mm ) and CD20 (174 131/mm ) lymphocytes concentrations Age at diagnosis* (year) 18G2.9 18.8G6.4 G were diminished, with a mean elevated CD4/CD8 ratio (2.51 1.24). Four Basal prolactin levels 35.7G40.2 4.2G1.6 patients were treated by immunosuppressive therapies: 2 for hepatitis, one for *(elevation above reference) severe malabsorption and one for a T-cell large granular lymphocytes leukaemia. Those therapies were very efficient but a patient deceased of septicaemia (C. Albicans). Conclusion APS1 frequency in West Northern France was about 1/500 000. Phenotypes In girls, secondary amenorrhea (58.3%) and galactorrhea (41.7%) raised varied greatly, and molecular diagnosis was determinant in atypical cases. diagnostic investigation whereas in boys (all macroadenomas) this was made Immunosuppressive therapies remain essential in severe manifestations, but their by mass effect symptoms. All patients were treated with dopamine agonists and initiation should be preceded by candidiasis and other infections careful research one was submitted to transsphenoidal surgery. Nowadays, 8 have normal and treatment. prolactin levels, 2 without therapy; the remaining have high levels but are asymptomatic.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Discussion 3-MR imaging demonstrated a mass developing in the clivial region invades the Most cases were diagnosed after 18 years of age, with a mean of 3 years between cavernous sinus, the para sellar and the temporal regions. A trans temporal the beginning of symptoms and diagnosis. In females, menstrual irregularities and surgery removed apart of the tumour. galactorrhea may have led to a precocious investigation and higher prevalence of 4-Pathological findings: physalliphorus cells arranged in lobules and embedded in microadenomas. In males, mass effects symptoms caused by larger lesions a mucoid stroma prevailed since endocrine symptoms are insidious and more difficult to notice. 5-Post operative course was uneventful, two months later the tumour had growth Treatment with dopamine agonists was effective and without major side effects. explosively, became exophytic behind the temporal region, and the patient died. Conclusion Conclusion Prolactinomas should always be considered in the evaluation of menstrual Chordomas is uncommon tumours in child in the case report the insipidus irregularities in girls or pubertal delay in both sexes. They assume special diabetes have revealed them. The para sellar localisation explains the importance because of good outcomes with medical treatment in normalizing hypopituitarism. The explosively evolution may be explained by a sarcomatous prolactin levels and reducing tumour size. transformation or the expression of growth factors: TGF alpha, BFGF and the strong fibronectine.
P602 Molecular genetic analysis of a patient with hyperinsulinism and Reproduction deafness P604 Klaus Brusgaard1, Mohammed Albalwi2, Lone Svargo1 & 1 Age-adjusted variations in dynamics of the follicular growth in relation Henrik Christesen to ovarian steroid hormones in the domestic hen 1Odense University Hospital, Odense, Denmark; 2Department of Molecular Irina Lebedeva1, Vladimir Lebedev2, Roland Grossmann1 & Nahid Parvizi1 Pathology and Laboratory Medicine, King Abdulaziz Medical City, Riyadh, 1Institute for Farm Animal Genetics, Mariensee, FLI, Neustadt a.Rbg, Saudi Arabia. Germany; 2Research Institute for Farm Animal Genetics and Breeding, St Petersburg-Pushkin, Russian Federation. Congenital hypoglycemic hyperinsulinemia (CHI) is a clinical and genetic heterogeneous entity. Clinical manifestations can vary from serious life In birds similar to mammalian species, the reproductive performance in females threatening to milder difficultly identifiable cases. Children who do not react deteriorates with age. In the present study, relationships between the growth of adequate to medical treatment are subject to pancreatic recession. The molecular preovulatory follicles (PF), reproductive aging and sex steroids were investigated ethiology are from recessive mutations of the ABCC8 (SUR1) and KCNJ11 using young hens with long clutch (YLC), old hens with long clutch (OLC) and (Kir6.2) to dominant mutations of the GCK or GDH genes. Focal dysplasia old hens with short clutch (OSC). 1) hens were killed 1.5 and 14.5 h after assumed characterised by loos of maternal Chromosome 11 and hereby ABCC8 and ovulation. 2) YLC hens were killed 3.5 h after treatments with LH and/or KCNJ11 is a common cause of CHI. In some studies mutations in the ABCC8 aminoglutethimide (AG), an inhibitor of steroid synthesis. Volumes of PF (F1-F5) promotor have been shown to cause CHI. In approximately 50% of the incidences and plasma concentrations of ovarian steroids were determined. 3) Granulosa the disease is still genetically unexplained necessitating the search for other (GC) and theca cells (TC) from F3 follicles of YLC and OSC hens were exposed genetic factors. in vitro to estradiol-17beta (E , 1 ng/ml) and the proliferative activity (PA) of the ABCC8 and KCNJ11 is localised to chromosome 11p15. Interestingly the USH1C 2 cells was examined using CellTiter 96 Aqueous One Solution Assay. In YLC and gene is localised upstream of ABCC8. Usher syndrome type I caused by mutations OLC groups, the total follicular volume (TV) rose between 1.5 and 14.5 h after in USH1C is an autosomal recessive sensory defect involving congenital profound ovulation (YLC: from 31.8G1.3 to 43.2G2.6 ml; OLC: from 35.7G2.0 to sensorineural deafness, vestibular dysfunction, and blindness due to progressive 46.4G2.5 ml, P!0.01), negatively correlating with the plasma level of E retinitis pigmentosa. 2 (P!0.01). By contrast, there was no growth of PF in the middle of the ovulatory The adjacent USH1c gene and ABCC8 gene of chromosome 11p15 were analysed cycle in the OSC group, with a positive correlation being present between E and using quantitative realtime PCR and microsatellite markers to analyse for Loss of 2 TV (P!0.05). In young hens, AG caused a decline in levels of steroids and a rise heterozygosity (LOH), and sequencing. in TV, which was associated with a fall in E (rZK0.54, P!0.05). E increased The microsatellite D11S902 was absent. By PCR of ABCC8 it was shown that 2 2 in vitro the rate of viable GC (YLC: from 201 to 250%; OSC: from 175 to 210%, only exon 23* to 39 are present. All of KCNJ11 is present. In the same way only P!0.01) and did not affect PA of TC from both groups. E seems to play a dual exon 1 and 2 of the USH1c gene was shown to be present. By sequencing, a 2 role; it stimulates the follicular growth in old hens, whereas it may inhibit the homozygous contiguous partial gene deletion was identified, starting in USH1c growth of PF in young animals. intron 2, c.90C592, and ending in ABCC8 intron 21. We here report the analysis of a patient with a complex phenotype that can be explained by a large deletion involving two genes.
P605 The relationship between semen parameters and blood hormone in men with congenital absence of vas deferens P603 Wen Ren-Qian, Tang Li-Xin, Deng Shun-Mei, Jiang Yang-Jia, Insipidus diabetes revealing a chordomas of a skull base in a child Wang Qi-Ling, Cheng Ai-Ping, Ma Chun-Jie, Jiang Fang & Miao Zhu-Lin M Bensalah, S Ait Abderahmanc & Z Kemali Family Planning Research Institute of Guangdong, Guangzhou, China. Department of Endocrinology, Central Hospital of Army, Algiers, Algeria. Aim Introduction To investigate the ralationship between semen parameters and serum follicale- Chordomas are rare tumours that usually occur in adults, in children since 1923, stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T), prolactin !100 cases has been reported. It represent few than 5% of these tumours and (PRL) in a group of Chinese men with congenital absence of vas deferens most frequently develop in the skull base. (CAVD). Para cellar localisation is uncommon, cause hypopituitarism and oculomotor Methods nerves palsy. Ninety patients with CAVD were investigated. During the physical examination Chordomas are believed to behave more aggressively than chordomas in adults. the body hair distribution, testicular size, epididymides and vas deferens were Case report carefully inspected and palpated. Semen analysis including liquefy, volume, pH A 14-year-old boy presented in December 2006 with polyuropolydipsia syndrome were done. Blood hormone of FSH, LH, T and PRL from 47 cases was detected. and headache. The relationship between semen parameters and blood hormone was analyzed by 1-On examination: he had SPSS programe. † Short stature (!K2S.D). Results † Hypothyroidism signs. In all of 90 patients there were a normal body hair distribution. The testicular size † Pubertal stage G1P1 of Tanner. was 16.17G4.07 ml. Seventy-six (76/90, 84.44%) cases with bilateral absence of † Left oculomotor nerves palsy. vas deferens and 14 (14/90, 15.56%) cases with unilateral absence (3 for the left † Ophthalmologic evaluation: normal visual field. and 11 for the right) were found. There was a normal liquefy time (17.72G 2-Serum hormonal investigation: found hypopiytuitarism and insipidus diabetes. 5.34 min), lower semen volume (0.71G0.38 ml) and lower pH (6.47G0.32).
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
There was a normal FSH, LH, T and PRL level in most of patients except elevated the control group. HDL-C and its subfractions were lower in postmenopausal FSH, LH, T, PRL in 2 (4.26%), 9 (19.15%), 2 (4.26%), 7 (14.89%) and lower T, women than in controls and they improved after hormonal therapy. The same PRL in 4 (8.51%), 5 (10.64%), respectively. There was a positive correlation tendency was observed concerning apo-A1. There were no correlations between between FSH and testicular volume (rZ0.367), liquefying time (rZ0.307), NOx and lipids or apolipoproteins. We conclude that low E2 levels in semen pH (rZ0.291), LH and semen pH (rZ0.312). A negative correlation postmenopausal women were associated with lower NOx levels. Estrogen therapy between PRL and semen volume (rZK0.313) was found. improves NO synthesis and relaxation of the vessels. Conclusion In the azoospermia men with lower semen volume, low semen pH and normal liquefying time the clinical diagnosis of CAVD should be suggested. It is importance for the FSH detected in the patients with CADV. To constitute the distinction between CADV and other obstructive azoospermia, for example, P608 vasectomy, the results of semen volume and semen pH may be useful parameters. Expression of ghrelin receptor, GHSR-1a in the pig ovary and its role in ovarian function Agnieszka Rak1, Dawid Szczepankiewicz2 & Ewa Gregoraszczuk1 1Jagiellonian University, Krako´w, Poland; 2Agricultural University, P606 Poznan, Poland. Pituitary primary cell culture and effect of its secretion on endocrine activity of incubated ovarian follicles (Study of pituitary–ovary axis): in Ghrelin, a 28 amino acid peptide, was recently isolated from the stomach of rat, and the model of fish (common carp) was identified as the endogenous ligand for the growth hormone secretagogue Negin Salamat1, Naeem Alboghobeish1, Mahmoud Hashemi Tabar2, Akram receptor, GHSR. Two GHSR subtypes, generated by an alternative splicing of a Ahangar Poor2 & Mehrzad Mesbah1 single gene, have been identified: the full-length type 1a receptor and truncated type 1Shahid Chamran University of Ahvaz, Ahvaz, Islamic Republic of Iran; 1b. The GHS-R1a is the functionally active, signal transduction form of the receptor. 2Jondishapoor University of medical Science, Ahvaz, Islamic Republic of Ghrelin is recognized as an important regulator of growth hormone secretion (GH), Iran. food intake and a factor which controls reproduction. In addition, ghrelin and GHSR- 1a expression were detected in reproductive tissue: placenta, ovary and testis. Recent date has suggested that ghrelin may also have an effect on sex hormone secretion and In this study, pituitary of five carp fish were collected. The pituitary cells were cell apoptosis. The aim of the study was analyze 1). Expression of GHSR-1a in dispersed enzymatically and cultivated as monolayers in MEM for 72 h. Then the ovarian follicles and the effect of GH on GHSR-1a expression; 2). Involvement of culture media were collected and frozen in K20 8C. GHSR-1a in estradiol secretion, aromatase activity and caspase -3 activity. Pig The carp ovaries were also collected and their follicles were separated ovarian follicles (3–4 mm) were collected from prepubertal animals. To examined mechanically and incubated in BSS Cortland medium in 24 well microplates the expression of GHSR-1a and influence of GH on GHSR-1a expression we used for 48 h in room temperature. Then the incubated ovarian follicles were divided in Western Blott and RT-PCR methods. Using antagonist of ghrelin receptor (D-Lys-3)- two groups: GHRP-6 (50 ng/ml), involvement of GHSR-1a in estradiol secretion, aromatase A. Control group which were incubated in BSS medium. activity and caspase-3 activity were examined. Estradiol concentration was B. Experimental group which divided to three subgroups according to treated with measured using direct enzyme immunoassay. Aromatase activity was measured different concentration of collected pituitary medium (50, 100, 200 ml/ml). using fluorometric substrate and caspase-3 activity colorimetric substrate. We Follicles culture media were collected after 72 h and were analyzed for 17-b- demonstrated presence of GHSR-1a in prepubertal pig ovary and no influence of GH Oestradiol (E2) and 17-a-Hydroxy progestron (P4) content by radioimmunoassay on both GHSR-1a protein and mRNA expression. Moreover, our study confirmed the (RIA). involvement of GHSR-1a receptor in estradiol secretion and aromatase activity but The results showed that the steroid hormones (E2 and P4) secretion in incubated not in cells apoptosis. In conclusion, our study provides the novel evidence for the ovarian follicles were increased significantly by low concentration (50 ml/ml)of expression of the GHSR-1a in the pig ovary and suggest involvement of this receptor pituitary media (respectively P!0.001 and P!0.05) but the high concentration in the control of key ovary function. (200 ml/ml) decreased the secretion of E2 and P4 significantly (respectively P!0.01 and P!0.05). The concentration of 100 ml/ml of pituitary culture media had not affected on steroid hormones secretion significantly. The interesting finding is that pituitary culture media (which content P609 gonadotropin hormones) were stimulated ovarian follicles for steroid secretion in vitro, whereas the high concentration of pituitary secretion decreased the A comparison between flutamide and finasteride plus flutamide responsiveness of the ovarian follicles which it may occurred due to down – combination in the treatment of hirsutism regulation of the pituitary hormone receptors on the ovarian follicles. Kursad Unluhizarci, Demet Ozel, Fatih Tanriverdi, Zuleyha Karaca & Fahrettin Kelestimur Department of Endocrinology Erciyes University Medical School, Kayseri, Turkey.
P607 Objective To investigate the clinical efficacy and safety of the finasteride (5 mg/day) plus Serum stable metabolites of nitric oxide (NOx) concentrations in pre- and post-menopausal women on transdermal estradiol therapy flutamide (125 mg/day) combination therapy in unselected women with moderate Grazyna Bednarek-Tupikowska & Urszula Tworowska-Bardzinska to severe hirsutism. Medical University of Wroclaw, Wroclaw, Poland. Patients and methods Thirty hirsute women were randomly assigned to two treatment groups. Sixteen patients (group 1) were treated with flutamide (125 mg per day) and 14 patients Since estrogens are known to have some antiatherosclerotic properties and (group 2) were treated with finasteride (5 mg per day) plus flutamide (125 mg per influence on endothelial function, including nitric oxide (NO) synthesis, the day) for 12 months. Hirsutism score was measured according to the modified purpose of this study was to determine NOx levels after menopause and to find Ferriman–Gallwey scoring system. Pre and post-treatment evaluation of hirsutism whether the administration of estrogen therapy restores plasma NOx levels back score, and serum FSH, LH, estradiol, total testosterone, free testosterone, to normal. The study group consisted of 26 women with surgically induced androstenedione, DHEAS and SHBG were obtained. Blood chemistry and side menopause, mean age 50.9G2.9 years, and the controls were 40 healthy pre- effects were evaluated during the study. menopausal women, mean age 48.3G2.3 years. Post-menopausal women Results were treated for four months with transdermal estradiol. Blood samples were At the sixth month of the treatment, flutamide alone and combination therapy collected for estimation of E2, FSH, NOx and lipid profile before and after resulted in similar improvements. The reductions in hirsutism score (% of the therapy. Serum NOx concentration in the study group was significantly lower than baseline) at 6 months were 35% for group 1 and 33% for group 2. Combination in controls (P!0.01) and it increased after treatment (P!0.01) reaching the therapy also resulted in (49%) similar improvement to flutamide alone (45%) at values observed in the controls. The statistical analysis showed significant 12th months of the treatment. correlation between NOx concentration and E2 concentration in menopausal Conclusion group before (rZ0.25, P!0.05) and after (rZ0.46, P!0.001) treatment. TC, Although both drugs have different action mechanisms, combination of flutamide LDL-C, TG, and azpo-B levels were higher in postmenopausal group comparing and finasteride is not better than flutamide alone in women with hirsutism. to controls, and after estrogen therapy they decreased to the values observed in
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P610 P612 Quantitative determination of aromatase and 5-a reductase mRNA and Developmental and genetic changes in chemosensory activation of polymorphisms in the aromatase and 5-a reductase genes in idiopathic testicular testosterone response to a receptive female and sexual hirsutism behaviour in laboratory male mice Munis Dundar1, A Okay Caglayan1, Nuran Ahu Baysal2, Fatih Tanriverdi2, Ludmila Osadchuk, Irina Salomacheva, Arkady Bragin & Yusuf Ozkul1, Kursad Unluhizarci2 & Fahrettin Kelestimur2 Alexander Osadchuk 1Department of Genetics, Erciyes University Medical School, Kayseri, Institute of Cytology and Genetics, Novosibirsk, Russian Federation. Turkey; 2Department of Endocrinology, Erciyes University Medical School, Kayseri, Turkey. Chemosensory cues from receptive females produce the activation of the pituitary–testicular axis and facilitate a complex display of sexual behavior in Objective male mice. Testosterone output in response to a receptive female and the pattern Hirsutism, affects between 5% and 10% of women during reproductive age. of sexual behaviour were investigated in male mice (nZ190) of three inbred Hirsutism associated with normal ovulatory function and normal circulating strains BALB/cLac, CBA/Lac and PT at puberty (45 days of age) and in androgen concentrations is defined as idiopathic hirsutism and little information is adulthood (90 days). Sexually naive pubertal or adult male was exposed for available regarding the molecular pathogenesis. 10 min to a receptive female separated by a plastic grill, which would not allow Aim contact between them. Male behaviour was recorded by measuring the time the Significance of polymorphisms of the genes involved in androgen/oestrogen male spent at the grill and the number of approaches to it (sexual motivation). The biosynthesis (SRD5A2,CYP19) and their expressions inmodulating the suscep- grill was then removed and sexual behavior (the number of mounts, nasal and tibility to idiopathic hirsutism were studied. anogenital sniffing) was recorded for next 20 min. An increase in serum Methods concentration and testicular content of testosterone was used as a reflexive Hirsutism was scored using a modified Ferriman–Gallwey scoring system. The endocrine index of the sensitivity to female pheromones. Testosterone was score O8 was considered as hirsutism. All the patients had idiopathic hirsutism. determined by the competition enzyme immunoassay. It has been shown We assessed the expression of the genes for type 2 (SDR5A2) 5-alpha reductase significant effects of developmental and genetic factors on the testosterone isoenzyme and aromase (CYP19) in hair follicle removed from midline response to sexual stimuli and sexual behaviour. The pubertal BALB/cLac males subumblical region in 8 untreated idiopathic hirsute patients and 8 normal were characterised by the adult pattern of precopulatory behaviour and the women. SDR5A2 and CYP19 expression were estimated by Real-Time-PCR evident testosterone respond to a female. The PT males showed the lowest level of using the gene of the ubiquitously expressed protein b-actin as an internal control. behaviour towards a female and no testosterone response at both ages. The Results CBA/Lac’s demonstrated the developmental increase in endocrine responses and No differences were found in SDR5A2 expression levels between patients and sexual behaviour, the highest number of mounts and the moderate testosterone normal women. CYP19 gene expression levels were lower in the patients when respond to a female at adulthood. The patterns of sexual behavior and testosterone compared with the controls (P!0.05). response to a receptive female in three inbred mouse strains demonstrate the Conclusion genotype-related maturation of the pituitary–gonadal axis and neural circuits of Decreased aromatase activity may contribute to the pathogenesis of idiopathic sexual behavior, and provide confirmation that genetic differences are a major hirsutism. source of variation in reproductive maturation. Supported by TUBITAK (SBAG-106S170).
P611 P613 Endometriotic cell proliferation and survival are inhibited by Growth hormone improves semen volume, sperm count and motility in somatostatin analogues and GHRH antagonists men with idiopathic normogonadotropic infertility Marta Annunziata1, Letizia Trovato1, Fabio Settanni1, Cristina Grande1, Sanjay Kalra, Bharti Kalra & Amit Sharma Davide Gallo1, Marco Camanni2, Francesco Deltetto2, Ezio Ghigo1 & Bharti Hospital, Karnal, India. Riccarda Granata1 1University of Turin, Torino, Italy; 2Valdese Hospital, Torino, Italy. Objective The aim of this exploratory study was to assess the effect of growth hormone on Somatostatin (SST) and growth hormone-releasing hormone (GHRH) are semen parameters in men with primary infertility and normogonadotropic hypothalamic hormones that, respectively, inhibit and stimulate pituitary GH idiopathic oligoasthenospermia. secretion. In addition, in peripheral tissues somatostatin and its analogues inhibit, Method whereas GHRH stimulates, both normal and cancer cell growth and survival. This study was performed as a prospective, open- label, non-randomized Furthermore, both somatostatin receptor 2 (SSTR-2) and GHRH expression have observational study in a private practice in fourteen men, aged 26 to 35, with been shown in normal human endometrium. Endometriosis is a common normogonadotropic idiopathic oligoasthenospermia. Growth hormone 1.5 IU/day estrogen-dependent disorder defined by the presence of endometrial cells outside was administered for 6 months and semen parameters assessed on a monthly the uterus, resulting in pelvic pain and infertility. With respect to eutopic basis. All were normogonadotropic, with normal sexual function, normal body endometrium, the ectopic shows higher local oestradiol bioavailability, hair pattern and masculinization, normal testicular volume and penile size. All abnormalities in gene expression, impaired sensitivity to apoptosis and increased had received various treatments for infertility in the past, including successful cell proliferation. treatment for pyospermia in seven of the cases. Fine needle aspiration cytology Aim of this study was to investigate the expression of GHRH and SST receptors in revealed normal to – depressed spermatogenesis, with cells of all stages visible, in ectopic endometrium of patients with endometriosis and to test whether SST all patients. analogues and GHRH antagonists would inhibit in vitro proliferation and survival Results of primary endometrial cells obtained from endometriotic implants. In ectopic The initial sperm count varied from 0.1 to 10 million/ml, with motility ranging endometria (nZ18) RT-PCR experiments showed the expression of all five from 1 to 50%. Semen volume, count and motility improved in all patients. somatostatin receptor subtypes (SSTR1 to 5), and of the splice variant-1 (SV1) of Volume increased from 0.63G0.40 ml to 1.24G0.42 ml (ZZ3.68; P!0.01), the GHRH-receptor (GHRH-R). By Real-time PCR we found that in 64% of count from 3.76G3.42 to 5.87G6.76 million/ml (ZZ1.04; PZ0.05), and patients SSTR2 and SSTR5 were significantly more expressed in ectopic than in motility index from 19G11.67% to 24G12.1% (ZZ1.11; PO0.05). The increase eutopic tissues. Importantly, the SST analogues Lanreotide and Octreotide dose- was most marked during the first three months of therapy. Not much improvement dependently reduced ectopic more than eutopic endometrial cell growth and was noticed during the later half of treatment. None of the patients experienced survival. Noteworthy, GHRH antagonist JV-1-36 showed significant inhibitory any side effects. Three subjects fathered children over the next 1 year, two with effect on stromal endometrial cell proliferation and viability. the help of intrauterine insemination. In conclusion, these findings suggest that SST analogues, as well as GHRH Conclusion antagonists, may be useful molecules for inhibiting proliferation and survival of Growth hormone can be explored as an effective treatment for men with primary ectopic endometrial cells in patients with endometriosis. infertility and normogonadotropic idiopathic oligoasthenospermia.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P614 and complained of an unsatisfactory work and a conflictual relationships within Expression and direct effects of adiponectin in rat testis family. Conversely, subjects with higher phobic anxious symptoms displayed a JE Caminos Pinzo´n1,5,6, R Nogueiras1, F Gaytan3, R Pineda3, ML Barreiro3, more robust relational functioning. Similar results were observed in subjects with CR Gonzalez1, JP Castan˜o3,4, MM Malagon3, L Pinilla3, J Toppari2, obsessive-compulsive symptoms, who also reported a lower prevalence of HSD. C Dieguez1,4 & M Tena-Sempere3,4 Finally, subjects with somatization symptoms showed the worst erectile function. 1Department of Physiology, University of Santiago de Compostela, Santiago Conclusions de Compostela/A Corun˜a, Spain; 2Departments of Physiology and The main value of this study is that it alters various clinicians that many Pediatrics, University of Turku, Turku, Finland; 3Department of Cell psychiatric symptoms can be found among ED patients. Systematic testing of Biology, Physiology and Immunology, University of Co´rdoba, Cordoba, patients with ED, through psychiatric questionnaires, is recommended to detect Spain; 4CIBER (CB06/03) Fisiopatologı´a de la Obesidad y Nutricio´n, even slight or moderate psychopathological distresses, which specifically Instituto Salud Carlos III, Madrid, Spain; 5Department of Physiology and associate and exacerbate sexual disturbances. Genetic Institute, Faculty of Medicine, National University of Colombia, Bogota, Colombia; 6Endocrine Department, Hospital Juan Canalejo, A Corun˜a, Spain.
The adipose tissue is an active endocrine organ involved in the control not only of P616 metabolism and energy balance, but also of other relevant body functions, Estimated cardiovascular risk and arteriogenic erectile dysfunction including reproduction. Adiponectin is an adipocyte hormone, with relevant roles Giovanni Corona1, Edoardo Mannucci3, Alessandra Fisher1, in lipid metabolism and glucose homeostasis, recently involved in the control of Francesco Lotti1, Giancarlo Balercia4, Luisa Petrone1, Gianni Forti2 & different endocrine organs, such as the placenta, pituitary and, likely, the ovary. Mario Maggi1 However, whether as described previously for other adipokines, such as leptin and 1Andrology Unit, University of Florence, Florence, Italy; 2Endocrinology resistin, adiponectin is expressed and/or conducts biological actions in the male Unit, University of Florence, Florence, Italy; 3Diabetes Section Geriatric gonad remains unexplored. In this study, we provide compelling evidence for Unit, University of Florence, Florence, Italy; 4Endocrinology Unit, the expression, putative hormonal regulation and direct effects of adiponectin in Polytechnic University of Marche, Ancona, Italy. the rat testis. Testicular expression of adiponectin was demonstrated along postnatal development, with a distinctive pattern of RNA transcripts and discernible protein levels that appeared mostly located at interstitial Leydig cells. Objectives Testicular levels of adiponectin mRNA were marginally regulated by pituitary Recommending general dynamic penile color doppler ultrasound (D-PCDU) gonadotropins, but overtly modulated by metabolic signals, such as glucocorti- screening in patients with erectile dysfunction (ED) has been questioned due to an coids, thyroxine and the PPAR-g ligands. In addition, expression of the genes inadequate cost-benefit ratio. The aim of the present study is to asses the validity encoding adiponectin receptor 1 (AdipoR1) and AdipoR2 was detected in rat of different risk scores in the identification of patients being screened for testis, with developmental changes and gonadotropin regulation for AdipoR2 arteriogenic ED at D-PCDU. mRNA, and prominent levels of AdipoR1 in seminiferous tubules. Moreover, Design and methods recombinant adiponectin significantly inhibited basal and human CG-stimulated A consecutive series of 738 (mean age 53.6G9.2 years) patients with ED was testosterone secretion ex vivo, while it failed to change relative levels of several studied. All patients underwent D-PCDU. Arteriogenic ED was defined when Sertoli cell-expressed mRNAs, such as stem cell factor and anti-mu¨llerian peak systolic velocity (PSV) was lower than 25 cm/s. The assessment of hormone. In sum, our data are the first to document the expression, regulation and cardiovascular risk was evaluated using different risk engines, derived from the functional role of adiponectin in rat testis. Taken together with its recently Framingham, the PROCAM and the Progetto Cuore studies. An iterative ROC reported expression in the ovary and its effects on luteinizing hormone secretion curve analysis was used to determine the most proper threshold for different and ovarian steroidogenesis, these results further substantiate a multi-faceted role scales for the screening of arteriogenic ED. Sensitivity and specificity at those of adiponectin in the control of the reproductive axis, which might operate as thresholds were calculated. endocrine integrator linking metabolism and gonadal function. Results Among the patients studied, 52 (7%) had PSV!25 cm/s. The area under the ROC curves for pathological PSV in relation to cardiovascular risk estimated with different engines was 0.762G0.03, 0.716G0.03 and 0.667G0.03 for Progetto Cuore, Framingham and PROCAM engines, respectively. Sensitivity and specificity of Progetto Cuore estimated risk were 67, 71% when a threshold of P615 15% was chosen. Corresponding figures for Framingham and PROCAM engine were 74, 57% and 69, 55%, respectively. Association between psychiatric symptoms and erectile dysfunction 1 2 2 3 Conclusions Giovanni Corona , Valdo Ricca , Elisa Bandini , Edoardo Mannucci , O 1 1 1 4 If D-PCDU is performed only on patients with cardiovascular risk 15%, who Luisa Petrone , Alessandra Fisher , Francesco Lotti , Giancarlo Balercia , represent about 1/4 of all patients (26.8%), as estimated by Progetto Cuore, about Carlo Faravelli2, Gianni Forti1 & Mario Maggi1 1 2 70% of cases of arteriogenic ED can be identified. This means that well over two Andrology Unit, University of Florence, Florence, Italy; Psychiatric Unit, thirds of cases can be diagnosed by performing D-PCDU on one patient out of University of Florence, Florence, Italy; 3Diabetes Section Geriatric Unit, 4 four. Estimated cardiovascular risk, assessed through risk engines, could be used University of Florence, Florence, Italy; Endocrinology Unit, Polytechnic to identify patients who should undergo D-PCDU evaluation for the diagnosis of University of Marche, Ancona, Italy. arteriogenic ED.
Objectives Erectile dysfunction (ED) is often associated with a wide array of psychiatric symptoms, although few studies systematically address their specific association with ED determinants. Aim of this study is to explore the relationship between ED P617 and different psychopathological symptoms. Anti-Mu¨llerian hormone levels in women with polycystic ovary Design and methods syndrome before and after metformin therapy G A consecutive series of 1388 (mean age 51 13 years) male patients with ED was Analia Tomova1, Ralitza Robeva1, Philip Kumanov1, Georgi Kirilov1 & studied. Several hormonal and biochemical parameters were investigated, along Zvetozar Mechandjiev2 with SIEDY (13 item Structured Interview, which identifies and quantifies the 1Clinical Centre of Endocrinology, Sofia, Bulgaria; 2SHATAG ‘Maychin contribution of organic, relational and intrapsychic domains of ED) and the dom’, Sofia, Bulgaria. Middlesex Hospital Questionnaire (a self-reported test for the screening of mental disorders in a non-psychiatric setting). Results Recently was established, that in the ovary Anti-Mu¨llerian hormone (AMH) is Psychiatric symptoms resulted differentially associated with SIEDY domains. produced by the granulose cells and correlated with the count of small antral Depressive and phobic-anxiety symptoms were associated with the relational follicles. As AMH is largely expressed throughout folliculogenesis, it is domain, somatization with the organic one, while free-floating anxiety, obsessive- considered that the serum levels of AMH may represent both the quantity and compulsive and phobic symptoms were significantly related with higher intra- quality of the ovarian follicle pool. To determine the changes of AMH in women psychic SIEDY scores. In addition, relevant depressive symptomatology (D) was with polycystic ovary syndrome (PCOS) we have studied 22 patients with this associated with hypogonadism, the presence of low frequency of intercourse, disorder and compared their results to those of 20 healthy women at the same age hypoactive sexual desire (HSD), and conflictual relationships within the couple without hyperandrogenism. The AMH levels in women with PCOS (42.34G and the family. Patients with high free-floating anxiety symptoms were younger, 6.42 pmol/l) were significantly elevated in comparison with those of the controls
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
(21.58G3.41 pmol/l), P!0.01. AMH concentrations in the overweight patients expirienced ultrasonographer who was blinded to clinical data. IMT was were with 32.16% higher than in the normal weight women, but the difference measured from the B-mode screen by 7.5 MHz linear probe of both common was not statistically significant. After six months metformin therapy carotid arteries. Statistical analyse was done by ANCOVA using cholesterol, 2550 mg/daily the levels of AMH decreased from 44.84G10.07 to 35.97G HDL, LDL, triglyceride and baseline insulin level as covariable (separatly). 7.06 pmol/l, but not significantly, whereas the total testosterone levels reduced Results significantly from 3.51G0.33 to 2.58G0.26 nmol/l, P!0.05. We found statisticaly significant difference between IMT in PCOS women Significant inverse correlations of serum levels of AMH with insulin (0.51G0.06 mm) versus healthy controls (0.42G0.03 mm). Only PCOS effect concentrations (rZK0.452, P!0.05) as well as with homeostasis model was significant. assessment (HOMA) index (rZK0.613, P!0.05) were found in the controls. Conclusions In conclusion, the serum levels of AMH are increased in women with PCOS and In this group of patients, differences in IMT seems to be atributable to PCOS AMH measurement can be used as a marker with high specificity and sensitivity facors other than insulin, cholesterol and trigyceride levels. for PCOS.
P620 P618 Basal INSL3 levels predict LH and androgen response to GnRH analogue in PCOS women. Catecholestogens inhibit endothelial cell growth in an angiogenesis Laura Patton, Alessandra Gambineri, Rosaria De Iasio, Flaminia Fanelli & bioassay Renato Pasquali Giuseppina Basini, Simona Bussolati, Sujen Eleonora Santini & Alma Mater Studiorum University of Bologna, Bologna, Italy. Francesca Grasselli Dipartimento di produzioni Animali, Biotecnologie Veterinarie, Qualita` e Sicurezza degli Alimenti, Sezione di Fisiologia, Via del Taglio 8, 43100 In a previous study, we demonstrated that the concept of functional ovarian Parma, Italy. hyperandrogenism (FOH), as documented by the exaggerated 17OHP response to buserelin (GnRH-analogue) does not represent a specific feature of all women with PCOS, being present in less than half of PCOS and is a condition Little is known about the negative regulation of angiogenesis in the ovary. Recent characterized by more severe hyperandrogenemia, glucose-stimulated B-cell evidence has revealed that estradiol 17b and its metabolites may play an 1 2 insulin secretion and worse insulin resistance. INSL3 is produced in the Leydig important role in this fine tuning . In a previous work , we set up an assay to cells and at reduced levels in ovarian thecal cells. We previously found that in quantify 2-hydroxyestradiol (2-OHE) and 4-hydroxyestradiol (4-OHE) in PCOS serum INSL3 levels were significantly higher than controls and that in follicular fuids. In order to get an insight on the angiogenic effect of 4-OHE PCOS they were positively correlated with basal LH and 17OHP response to and 2-OHE, the objective of this research was to study their possible modulatory buserelin. We therefore carried out this study in two groups of PCOS role on VEGF-induced endothelial cell growth. To this purpose, we set up a characterized by normal (NR, nZ6) or high (HR, nZ6) 17OHP response to reliable bioassay which allows the study of porcine aortic endothelial cells (AOC) Z 3 buserelin, and matched controls (n 44) to investigate whether INSL3 circulating growth on a three dimensional fibrin gel matrix . AOC were cultured on levels may differ in PCOS subgroups, GnRH stimulation affects basal INSL3 microcarries beads and then pipetted into a solution of fibrinogen and thrombine; concentration and whether a relationship exists between basal INSL3 levels and cells were then treated with VEGF (100 ng/ml) in the presence or absence of 8 hormone response to buserelin. INSL3 concentratiosn were significantly higher in 4-OHE or 2-OHE (1, 10 and 100 ng/ml) and incubated at 37 C under humidified PCOS respect to controls (PZ0.001). Moreover, in HR INSL3 levels were higher atmosphere (5% CO2) for 48 h. Endothelial cell proliferation was measured by than in NR (PZ0.006). Within PCOS the levels of INSL3 positively correlated means of the public domain NIH program Scion Image Beta (Scion Corporation, with FAI (PZ0.013) and negatively with SHBG (PZ0.018). Moreover, a ! MA, USA). A significant (P 0.001) inhibition of AOC growth was induced by positive correlation with the % increase of LH after 60 min (PZ0.037) and with both catecholestrogens. No differences have been observed among the different the LH PZ PZ ! AUC after 60 min ( 0.014) and after 24 h ( 0.014) was found. Finally, concentration tested (P 0.001). These data suggest that 4-OHE and 2-OHE, the INSL3 levels did not change after buserelin stimulation. These data confirm that endogenous estradiol metabolites present in the ovarian follicle, can potentially PCOS women with FOH are more hyperandrogenic that those without it. act as physiological antiangiogenesis regulators. Moreover, we have found that INSL3 levels may predict ovarian LH and This research was supported by a FIL grant. androgen response to buserelin, which further suggests a potential role of INSL3 1. Basini et al. Steroids 2007 72 660–665. in the pathophysiology of hyperandrogenism in PCOS. 2. Basini et al. Reprod Domest Anim 2007 42 211. 3. Basini et al. Biofactors 2007 29 11–18.
P621 P619 Semen quality in men with obesity and metabolic syndrome Ralitza Robeva, Nina Sestrimska, Iliana Atanasova, Analia Tomova, Intima-media tickness of carotid artery in young women with polycystic Georgi Kirilov & Philip Kumanov ovary syndrome Clinical Center of Endocrinology, Sofia, Bulgaria. Mirjana Stojkovic1, Milorad Civcic2, Biljana Beleslin1, Jasmina Ciric1, Slavica Savic1, Djordje Marina1, Bozo Trbojevic1 & Milos Zarkovic1 1Clinical Center of Serbia, Institute of Endocrinology, Belgrade, Serbia; Aim 2Clinical Center of Serbia, Institute of Radiology, Belgrade, Serbia. The aim of the study was to compare the semen quality in men with metabolic syndrome/MS/ and healthy controls. Materials and methods Background Semen samples were collected from 35 males (mean age – 27.45G8.00 years). Polycystic ovary syndrome (PCOS) is a common endocrine-metabolic disease Nineteen of them had the features of the metabolic syndrome according to the IDF that occurs in about 10% of women in reproductive age. Today, PCOS is definition and 16 were healthy volunteers. The semen samples were analyzed by considered not only reproductive edocrinopathy but also a metabolic disorder only one experienced researcher according to the World Health Organization associated with long-term health risks, including diabetes mellitus and guidelines. cardiovascular disease. Results Objectives The patients with MS had similar age, ejaculate volume, percentage of The aim of this study was to evaluate the presense of early vascular demage in spermatozoa with normal morphology, sperm concentration (in million per normal-weight women with polycystic ovary syndrome. milliliter), and total sperm count compared to the controls. However, they had Methods higher percentage of non-motile spermatozoa (PZ0.032). Men with obesity The study group consisted of 15 normal weight young women with PCOS (BMI (BMIR30) had significantly lower sperm concentration (PZ0.03) and total 23.4G4.8 kg/m2, age 25.1G5.4) and 10 healthy controls (BMI 20.7G1.5 kg/m2, sperm count (0.021) in comparison to normal – or overweight males. age 26.8G6.5). A complet hormonal assay was performed in each subject. Serum Conclusion glucose, basal insuline levels, holesterol, HDL, LDL, and triglyceride were Reduced semen quality could be established in patients with obesity and MS. measured. Arterial structure was evaluated by intima-media tickness (IMT) of Further investigations are necessary to clarify the changes in the exocrine carotid artery which is a morphological marker of precocious atherosclerosis. testicular function in males with MS and their consequences for the reproduction. Longitudinal ultrasonografic scan of the carotid arteries were performed by
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P622 P624 Low-grade chronic inflammation in first-degree relatives of women with Role of lysosomal acid lipase on the hydrolysis of LDL-transported polycystic ovary syndrome DHEA-fatty acid esters in HeLa cells Agnieszka Lenarcik, Bozena Bidzinska-Speichert & Urszula Tworowska- Feng Wang, Wei Wang, Kristiina Wa¨ha¨la¨, Herman Adlecreutz, Bardzinska Matti J Tikkanen & Elina Ikonen Department of Endocrinology, Diabetology and Isotope Treatment, Helsinki University, Helsinki, Finland. Wroclaw, Poland. Background and aims Polycystic ovary syndrome (PCOS) is a common endocrine disorder in Dehydroepiandrosterone fatty acid esters (DHEA-FAEs) belong to a unique women of reproductive age characterized by chronic anovulation and family of naturally occurring hydrophobic steroid hormone derivatives with long- hyperandrogenism, and also associated with insulin resistance. Subclinical lasting hormonal activity. DHEA-FAEs function through hydrolysis of DHEA- chronic inflammation might be an important pathogenetic factor in the FAEs into free DHEA and further metabolized to biologically active steroids. The development of insulin resistance, type 2 diabetes and recently has been also lysosomal acid lipase (LAL) mediates the intracellular hydrolysis of cholesterol observed in PCOS. There is evidence for a familial predisposition not only esters. This study aims to study the possible role of LAL on the hydrolysis of to hormonal abnormalities but also to metabolic disorders in first-degree DHEA-FAE in cultured HeLa cells. relatives of women affected by PCOS. Methods This study was performed to determine whether sisters and brothers of We used LAL short-interfering RNA (siRNA) oligonucleotides to knock down women with PCOS had evidence for a low-grade chronic inflammation and the expression of LAL in HeLa cells. To control for unspecific RNAi effects, to evaluate the associations between the markers of chronic inflammation control cells were transfected with nonsilencing siRNA oligos without known and various components of insulin resistance, hormones, and metabolic similarities to human sequences. We incorporated labelled DHEA-FAEs into parameters. LDL by incubating 3H-DHEA with VLDL-free plasma. These siRNA-treated One Hundred women with PCOS, 40 sisters and 40 brothers of these cells were labelled with 3H-DHEA -FAE-LDL for 6 h and chased for 14 and 20 h probands were studied. Levels of hormones (T, DHEA-S, androstendione, in the presence of Acyl-CoA:cholesterol acyltransferase inhibitor, PKF 58-035. 17-OHP, LH, FSH, PRL, TSH) SHBG, hsCRP, fibrinogen, WBC count, Cellular and medium fractions were collected and immediately extracted. We serum lipid profile, glucose and insulin (at baseline and during OGTT – 00, used a variety of chromatographic techniques to identify metabolites in the 300,600, 1200) were measured. Insulin resistance was assessed by fasting cellular and medium fractions. 3H-cholesterol-oleate-LDL was used as control in insulin, HOMA-IR, FIRI and area under the curve for insulin during the parallel experiments to test the validity of the assay. OGTT. Results Insulin resistance, hyperinsulinaemia and decreased SHBG level was Anti-LAL western blot showed that most of the LAL protein was depleted by common in family members of PCOS women independently of BMI. We LAL siRNA. After 14 hours chase, more 3H-DHEA-FAE remained unhydrolyzed observed higher levels of hsCRP, fibrinogen and WBC count in women with in the LAL siRNA experiment (71.4%) than that in control experiment (51.8%). PCOS but not in sisters and brothers. Markers of chronic inflammation When the chase time was extended to 20 h, the difference between two groups positively correlated with BMI and insulin resistance. disappeared (14.9% and 11.9%, respectively). The probability of finding the metabolic disorders, particularly insulin Conclusion resistance, in the first-degree relatives of women with PCOS is higher than Our preliminary studies suggest that LAL is involved in the hydrolysis of in the control groups. It appears that a low-grade chronic inflammation is 3H-DHEA-FAEs in cultured HeLa cells. stronger related with central obesity than with PCOS status per se.
P625 Hydrolysis and metabolism of LDL-transported DHEA-fatty acid esters in HeLa cells Feng Wang, Wei Wang, Kristiina Wa¨ha¨la¨, Herman Adlercreutz, P623 Elina Ikonen & Matti J Tikkanen Pathogenesis of the congenital forms of hypogonadotropic Helsinki Univeristy, Helsinki, Finland. hypogonadism Vita Zektser, Irena Ilovayskaya, Ekaterina Zakcharova, Julia Keda & Galina Melnichenko Background and aims National Research Center for Endocrinology, Mscow, Russian Federation. Dehydroepiandrosterone (DHEA) is an important prohormone and precursor of all sex steroids. DHEA fatty acid esters (DHEA-FAEs) belong to a unique family of naturally occurring hydrophobic steroid hormone derivatives with long-lasting In purpose to elucidate pathogenetic mechanisms of congenital forms of hormonal activity, which are exclusively transported in lipoproteins. In the hypogonadotropic hypogonadism we have examined 25 women with idiopathic circulation, DHEA is esterified in a reaction catalyzed by lecithin-cholesterol hypogonadotropic hypogonadism (IHH), mean age 26 years and 7 months acyltransferase associated with HDL particles. The physiological role of DHEA- (group 1). All patients had amenorrhea, little breast development (Tanner 2–3), FAEs remains to be clarified. This study aims to study the metabolic fate of absence or little axillery and pubic hair, infantile uterus and decreased ovary lipoprotein-transported DHEA-FAEs in cultured HeLa cells, derived from volume. There were no pathological changes during MRI-investigation. Twenty epithelium of reproductive tract. healthy women were included in control group (group 2). Methods Six patients had no significant difference in serum gonadotropins compared with We incubated 3H-DHEA with VLDL-free plasma which resulted in formation of control group (LH 4.7G2.4 U/l; FSH 5.2G1.2 U/l versus LH 5.43G0.57 U/l; 3H -DHEA -FAEs contained in LDL. We then incubated the labelled LDL FSH 5.63G0.31 U/l respectively). Peaks of LH and FSH every 10 min during 4 h particles with cultured HeLa cells in the presence of the ACAT inhibitor, PKF were measured. There was a significant difference of basal LH and FSH 58-035. After different time points, cells and medium were harvested and concentration in patients with IHH and in the control group (LH 3.7G3.1 vs 6.9G immediately extracted with organic solvents. Unesterified 3H-DHEA was 3.1 P!0.05; FSH 5.2G1.8 vs 7.5G1.7 P!0.05). The significant decrease in the separated from 3H-DHEA-FAE by hydrophobic chromatography on Sephadex gonadotropin oscillations was found on the scattering diagrams comparing to the LH-20, and two-dimensional TLC was used to identify labelled steroid control group. metabolites. The genetic study showed polymorphism in gene of receptor to GnRH (Ser151Ser Results (AGC-AGT) and in b-subunit of FSH gene another polymorphism was found Increased accumulation of 3H-DHEA -FAEs in the cellular fractions were (Y76Y). These changes were previously described in literature and did not lead to discovered with incubation time up to 24 hours. In the medium fractions, minimal the amino acid replacement. amounts of 3H-DHEA-FAE were observed but increasing amounts of free The presence of antipituitary autoantibodies was detected in 8 (33.3%) patients 3H-DHEA and two metabolites, androstanedione and androstenedione, appeared with IHH and in 1 (5%) healthy woman (P!0.001). after 48 hours. Conversely, the cellular fractions only had 3H-DHEA-FAE. Conclusions Conclusions Patients with normal basal serum LH and FSH have it significantly lower Our preliminary studies suggest that 1.3H-DHEA-FAEs transported by LDL oscillations, 2) polymorphisms found in these patients with IHH are not entered HeLa cells via LDL-receptor-mediated intake, 2.3H-DHAE-FAEs were clinically important and 3) disorders of the humoral autoimmunity can be a hydrolyzed inside the HeLa cells, 3. The free 3H-DHEA was metabolised into reason of IHH. androstanedione and androstenedione, which were secreted into the medium.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P626 P628 Influence of the 5 a-reductase inhibitor type 2 on circulating Bilateral cavernous neurotomy induces hypogonadotropic hypo- neuroactive steroids gonadism in rat: effect of testosterone and tadalafil supplementation Michaela Duskova1, Martin Hill1, Miroslav Hanus2, Michaela Matouskova2 Sandra Filippi1, Annamaria Morelli2, Linda Vignozzi2, Rosa Mancina2, & Luboslav Starka1 Enrico Silvestrini2, Aravinda Chavalmane2, Mirca Marini3, 1Institute of Endocrinology, Prague, Czech Republic; 2Urocentrum, Prague, Gabriella Barbara Vannelli3 & Mario Maggi2 Czech Republic. 1Interdep. Lab of Functional and Cellular Pharmacology of Reproduction, Department of Pharmacology and Clinical Physiopathology, University of Florence, Florence, Italy; 2Andrology Unit, Department of Clinical The 5a-reductase is one of the enzyme of steroid synthesis and founded in two Physiopathology, University of Florence, Florence, Italy; 3Andrology Unit, isoformes. Two distinct 5a-reductase isoenzymes, type I and type II, are found Department of Anatomy, Histology and Forensic Medicine, University of across mammalian species. Each of these isoenzymes is differentially expressed Florence, Florence, Italy. in tissues and during distinct developmental stages and also in different species. The 5a-reductase is enzyme responsible for the reduction of testosterone to dihydrostestosterone, progesterone to dihydroprogesterone and deoxycorticoster- A previous study demonstrate that chronic tadalafil administration (2 mg/kg per one to dihydrodeoxycorticosterone. These steroids and their metabolites (termed day) was able to prevent some, but not all, penile alterations induced by long-term neuroactvive steroids) have rapid non-genomic effects on brain function and (3 months) bilateral cavernous neurotomy (BCN) in the rat. In particular, in vitro behavior, primarily via an enhancement of g-aminobutyric acid (GABA)ergic acetylcholine responsiveness and reduced eNOS and nNOS expression were not inhibitory neurotransmission. Neuroactive steroids have through GABA receptor preserved, while PDE5 down-regulation, along with muscle/fiber ratio and anticonvulsant, antidepressant and anxiolytic effects. Finasteride is the first 5a- hypoxygenation (hypoxyprobe) were significantly restored by chronic tadalafil (J reductase type II inhibitor that was introduced to clinical practice in 1992 for the Sex Med 2006 3 419–431). During the course of the previous study a reduction of treatment of benign prostatic hyperplasia in the dose of 5 mg/day and few years testis weight from BCN rats was noticed. Aim of this study is to clarify the role of later for androgentic alopecia in dose of 1 mg/day. There are some reports androgens in BCN. suggesting finasteride induction of depressive symptoms and anxiety in human. Sprague–Dawley rats were divided in 5 groups: a) control, b) BCN, c) BCNC The steroid profile of patients treated by finasteride was detected only in analyse tadalafil (2 mg/kg per day), d) BCNCtestosterone (T, 30 mg/kg per week), e) of urine (it was strikingly similar to that of male pseudohermaphrodites with BCNCtadalafil CT and parameters were recorded as before (J Sex Med 2006 3 inherited 5 alpha-reductase deficiency). In our study a group of 32 men (12 men 419–431), including hormonal values. Castrated SD rats was used as control. with androgenetic alopecia and 20 men wih bening prostatic hyperplasia) was BCN reduced testis weight, number of Leyding cells, gene expression of the examined. In all individual, their hormonal profile of steroids hormones in blood sterodogenetic enzyme 3b-HSD, prostate weight and circulating T, while LH was determined. Finasteride in the daily dose of 1 mg (men with androgenetic concentration resulted unchanged, suggesting BCN-induced hypogonadotropic alopecia) or 5 mg (men with benign prostatic hyperplasia) was administrated hypogonadism. Hypoxygenation, still present in some cavernous endothelial cell for 4 months. After the treatment the same hormonal profile was determined. in BCNCtadalafil, was completely absent in T-substituted rats. T alone or in In addition to the decrese of dihydrotestosterone level after treatement, the combination with tadalafil rescued PDE5 gene level up to control and normalized alteration in other 5 alfa steroids metabolites was found, which could explain the hyper-sensitivity to the nitric oxide donor SNP. More importantly, T treatment depresive symptomatology. restored eNOS expression and acetylcholine responsiveness. Conversely, nNOS The study was supported by grant No.NR/8525 – 5 of the IGA MZCR. gene expression resulted still down-regulated in T-treated (w or w/o tadalafil) BCN rats. We described for the first time the presence of hypogonadotropic hypogonadism in long-term BCN, and demonstrated that T substitution can ameliorate the positive effect of chronic tadalafil administration fully restoring penile oxygenation and responsiveness to acetylcholine. The P627 possibility that hypogonadism complicate the radical prostatectomy-associ- Effects of testosterone undecanoate (TU) administered alone or in ated deleterious effect on penile activity in humans should be tested in combination with letrozole or dutasteride in female to male transexuals forthcoming studies. (FtM) Maria Cristina Meriggiola1, Francesca Armillotta1, Paola Altieri1, Antonietta Costantino1, Silvia Cerpolini1, Marta Berra1, Anna Myriam Perrone1, Farid Saad2 & Giuseppe Pelusi1 1Center for Sexual Health, Ob Gyn Department, University of Bologna, Bologna, Italy; 2Bayer-Schering Pharma, Men’s Healthcare, Berlin, Germany. P629 TU is an effective option for androgen replacement in FtM subjects, but long-term Effect of phosphatidylinositol 3-kinase inhibition on estradiol-induced physiological effects and the significance of T and its metabolites dihydrotes- proliferation and hyperplasia formation in the mouse uterus tosterone (DHT) and estradiol (E) on physiological functions are unclear. The aim Andrei Gunin, Alla Samoilova & Irina Kapitova of our study was to investigate the effects of long-term TU treatment on bone Chuvash State University, Cheboksary, Russian Federation. metabolism, body composition and lipid profile in FtM subjects and to evaluate the relationship between the observed effects and circulating levels of T, E and DHT. This was a 1-year, randomised treatment, open label, uncontrolled safety It is suggested that phosphatidylinositol 3-kinase pathway is involved in study. Ovariectomized FtM were randomly assigned to receive 1000 mg TU regulation of estrogen effects in the uterus. Therefore, effects of posphatidyl- injection at week 0, 6, 18, 30, 42 and 54 alone (TU-alone, nZ5) or in combination inositol 3-kinase blocker, wortmannin, on proliferative and morphogenetic with letrozole 2.5 mg, orally (TUCL, nZ5) or dutasteride 5 mg, orally (TUCD, reactions in the uterus under long-term estrogen treatment were examined. nZ5). The Ethics Committee of the S Orsola Hospital approved the study. Ovariectomized mice were treated with estradiol dipropionate (4 mg per 100 g; Outcome parameters included measurement of reproductive hormones, bone s.c., once a week) or vehicle and wortmannin (0.1 mg per 100 g; s.c.; once a metabolism, body composition and lipid profile. Hormones at baseline and at day) or vehicle for a month. In animals treated with estradiol and wortmannin, week 54, in group TU-alone, TUCD and TUCL respectively were: uterine mass was decreased, abnormal uterine glands and atypical endometrial Total T (nmol/l) 7.9C6.0 and 13.6C2.6; 7.1C6.3 and 18.4C4.6§; 4.8C4.8 and hyperplasia were found rarely. Wortmannin produced a decrease in the 18.2C4.2§; E (pmol/l) 64.4C43.4 and 89.6C36.3; 41.4C19.4 and 76.0C47.4; numbers of mitotic and bromodeoxyuridine-labelled cells in luminal and 37.8C23.1 and 18.0C0.0*; DHT (nmol/l) 1.3C1.2 and 2.2C0.9; 1.0C0.7 and glandular epithelia, in stromal and myometrial cells. Levels of estrogen 0.4C0.1*; 0.9C0.7 and 2.7C1.3; *ZP!0.05% change versus TU-alone; §Z receptors-alpha and progesterone receptors in uterine epithelia, stromal and P!0.05 versus baseline. TU-alone and TU CD treatments were successful in myometrial cells were increased in mice treated with estradiol and terms of hormone adjustment, did not result in any adverse effects and were well wortmannin. Expression of beta-catenin in luminal and glandular epithelia tolerated. BMD decreased by an average of 0.9 g/cm in the TU CL group and the was also elevated in mice treated with estradiol and wortmannin. Thus, addition of dutasteride resulted in a failure to gain lean mass. phosphatidylinositol 3-kinase inhibitor wortmannin diminishes proliferative Conclusions and morphogenetic effects of estradiol. Action of wortmannin is associated This study confirms that TU is a successful and safe treatment for FtM subjects. with changes in expression of estrogen receptors-alpha, progesterone receptors Results indicate that E has an important role in bone metabolism and that DHT and beta-catenin in the uterus. This work was supported by grant from RFBR might play a role in muscle development. (07-04-00023).
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P630 P632 Systemic and seminal antioxidant systems in infertile men with chronic Dynamic changes in the serum inhibin A and B levels correlated to alcohol abuse reproductive hormones in women Antonio Mancini1, Roberto Festa1, Giuseppe Grande1, Vincenzo Di Donna1, Olga Ianas, Roxana Rosca, Suzana Vladoiu, Sabina Oros, Carmina Busu, Marco Di Nicola2, Luigi Janiri2, Luca Tiano4, Gian Paolo Littarru4, Dana Manda, Dana Dinu & Pavel Jalba Alfredo Pontecorvi1 & Elisabetta Meucci3 C I Parhon Institute of Endocrinology, Bucharest, Romania. 1Chair of Endocrinology, Catholic University School of Medicine, Rome, Italy; 2Institute of Psychiatry and Psychology, Catholic University School of Medicine, Rome, Italy; 3Institute of Biochemistry and Clinical Biochem- To examine the hormonal characteristics related to age of reproductive axis, istry, Catholic University School of Medicine, Rome, Italy; 4Institute of serum hormone profiles and inhibins A and B were investigated in fertile and Biochemistry, University ‘Politecnica delle Marche’, Ancona, Italy. menopausal women. Subjects Forty-three cycling women (23–40-year-old) and 75 menopausal women (55–70- Oxidative stress is associated with chronic alcoholic abuse; it is also a mechanism year-old) were studied. Serum 17-OHP, DHEA, DHEAS, androstendion, involved in male infertility. To further investigate the relationships between these estradiol, estrone, progesterone, testosterone, free testosterone, DHT, SHBG, two conditions, we studied 6 patients with diagnosis of Alcohol Dependence inhibin A and inhibin B, LH, FSH, Prl, TSH, GH, IGF1, insulin, cortisol and (DSM-IV) during post-detoxification phase, who consulted our centre for thyroid hormones were measured. infertility. We evaluated seminal parameters, hormone pattern, Total Antioxidant Results Capacity (TAC) and the lipophilic antioxidant Coenzyme Q10 (CoQ10), both in Fertile women: The pattern of change in the plasma concentration of inhibin A blood and seminal plasma. Patients mean age was 40.3G11.8, with history of was: % low in follicular phase negatively correlated to 17-OHP (PZ0.003), alcohol consumption of 7G3 years; at the time of the study they were taking low DHEAS (PZ0.008), progesterone, (PZ0.001), estrone (P!0.001), free dosages of mood-stabilizers or benzodiazepines. Six age-matched fertile controls (PZ0.04) and total testosterone (P!0.001), dihidrotestosterone (P!0.001), were also studied. In a fasting blood sample, testosterone, estradiol, LH, FSH, total (P!0.001) and free triodothyronine (P!0.001), and positively with inhibin FT3, FT4, TSH were determined. Standard semen analysis was performed B(PZ0.023), TSH (PZ0.003) and T4 (P!0.001); % significantly increased in according to WHO guidelines. CoQ10 was assayed by HPLC (in blood plasma it mid-cycle, negatively correlated with testosterone (PZ0.032) and inhibin B was also normalized for cholesterol levels); TAC was evaluated using the system (PZ0.021) and positively with estradiol (PZ0.001) and hGH (PZ0.025). metmyoglobin-H2O2, which interacting with the chromogen ABTS generates a Inhibin B showed a decreasing trend throughout menstrual cycle. In folicular radical spectroscopically revealed; latency time (Lag) in its appearance is phase, the higher levels of inhibin B were negatively correlated with DHEA proportional to antioxidant content. All patients exhibited as thenozoospemia (PZ0.002), androstendion (PZ0.01), progesterone (P!0.001), testosterone (20.5G2.1% forward progressive motility) and normal hormone values. Blood (P!0.001), free T3 (PZ0.013) and hGH (P!0.001). In mid-cycle inhibin B plasma CoQ10 levels were significantly lower than controls (0.69G0.09 vs negatively correlated with 17OHP (PZ0.04), estradiol (PZ0.04), progesterone 0.81G0.12 mg/ml; CoQ10/cholesterol ratio 164.44G29.10 vs 214.63G (PZ0.009) and positively with testosterone (PZ0.004). 17.23 mmol/nmol);similarly Lag was significantly lower (52.5G3.5 vs 76G Menopausal women: Both inhibins significantly decreased. There were no 10 s). On the contrary, a discordance was present in seminal plasma, with CoQ10 significant correlations between secretion of inhibins and both gonadal and lower than controls (0.05G0.01 vs 0.10G0.02 mg/ml), as expected considering gonadotropin hormones. asthenozoospermia, but Lag not different from controls (105G27.8 vs 101G Conclusion 5.6 s). These preliminary data confirm a lower antioxidant defence at systemic The current study suggests that inhibins A and B contribute to follicular levels in such patients, but the mechanism of infertility seems to be more maturation by primary mechanism that mediates gonadal steroids action in the complex, not simply related to a local oxidative unbalance. reproductive tract.
P633 P631 Polymorphisms of the sex hormone-binding globulin gene contribute Development of an Elecsysw Testosterone II Immunoassay with an to the interindividual variation of gonadal steroid hormone blood levels improved performance for measurement of testosterone in women in men Judit Oldekamp, Klaus Hirzel, Erich Schneider & Dieter Gassner Griet Vanbillemont, Veerle Bogaert, Dirk De Bacquer, Bruno Lapauw, Roche Diagnostics GmbH, Penzberg, Germany. Stefan Goemaere, Youri Taes & Jean-Marc Kaufman Ugent, Ghent, Belgium. Immunoassays for testosterone produce sometimes incorrectly high results in female samples. The reasons of this phenomenon are not fully understood, but Sex hormone binding globulin (SHBG) is a plasma glycoprotein responsible for interference by cross-reacting substances and inaccurate calibration can be high-affinity binding and transport of sex steroids. In men there is a large critical. One known endogenous interfering substance is dehydroepiandrosterone interindividual variation of SHBG levels, and consequently of serum total sulphate (DHEA-S). Other substances still have to be identified. testosterone (T) and serum total estradiol (E2) levels. Family and twin studies An Elecsysw Testosterone II assay using a new high affinity sheep monoclonal suggested a strong genetic contribution to this variation, besides a hormonal and antibody (Bioventix SMA testo3.6A3) is currently in the development pipeline metabolic influence. The aim of this study was to examine the influence of a for the Elecsys and cobas e immunoassay platforms. The new assay shows missense mutation (Asp327Asn), resulting in an additional N-glycosylation site, improved recovery if compared with sensitive liquid chromatography tandem and a (TAAAA)n-repeat in the promotor region, resulting in altered transcription, mass spectroscopy (LC-MS/MS). In method comparison studies with routine on SHBG and sex steroid serum levels in a population of healthy men covering samples versus current Elecsysw Testosterone assay the number of some falsely several decades of adult life. SHBG and hormone levels were measured in 1485 elevated results is decreased. In addition, the cross-reactivity with DHEA-S and healthy men (aged 24 to 86 years). Carriers of the Asn327 allele were identified some other potentially interfering substances is reduced. The high affinity of the using restriction analysis; the number of TAAAA-repeats was determined by sheep monoclonal antibody for testosterone enables a low sample volume (20 ml) fragment analysis. Prevalence of the variant Asn-allele was 21.5%. The Asn- as well as an inclusion of a high protein content in the assay buffer. As a allele was associated with higher SHBG (Asp/Asn and Asn/Asn 27.1 nmol/l; consequence an enhanced robustness against interferences caused by a variability Asn/Asn 24.8 nmol/l; P!0.001) and T levels (Asp/Asn and Asn/Asn 497 ng/dl; in the sample matrix is obtained. Asn/Asn 471 ng/dl; PZ0.01), whereas for E2 no differences were found. For the The new assay uses a delayed competitive test principle. Firstly, sample is (TAAAA)n-repeat, 7 different alleles were observed ranging from 5 to 11 incubated with the biotinylated antibody. Binding sites of the labelled antibody TAAAA repeats with six, eight or nine repeats occurring the most frequently. become occupied partly by the sample analyte. Secondly, streptavidin-coated Carriers of six TAAAA-repeats presented with significant higher SHBG (13.6%; microparticles and ruthenium-labelled hapten are added. Still free binding sites P!0.001), T (9.9%;P!0.001) and E2 levels (6.1%; PZ0.002) compared with are occupied by the hapten conjugate. Total assay time is 2!9 min. The non-carriers. For free T a marginal increase was found for carriers, whereas free measuring range of the assay extends from w0.02 to 15 ng/ml. E2 did not differ between carriers and non-carriers. Our findings show that the w The Elecsys Testosterone II shows improved correlation with LC-MS/MS and Asp327Asn polymorphism and the (TAAAA)n-repeat contribute to the provides total imprecision and functional sensitivity that will meet customers interindividual variation in total serum T levels in healthy men through variation needs. in SHBG concentrations.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P634 Conclusion Leydig cells activity is impaired in patients with Sertoli cell-only Our data suggest that Tadalafil is efficacious in improving sleep-related syndrome erections. Furthermore in normal men Tadalafil improved NPTRM also in the Matteo Baldi, Marc Craig Luetjens, Frank Tuettelmann, Eberhard Nieschlag second night after 24 h from the drug assumption. & Manuela Simoni Institute of Reproductive Medicine of the University, Muenster, Germany.
Sertoli cell-only syndrome (SCOS) is characterized by a lack of germ cells and thickened seminiferous tubule walls and is a frequent finding among men with non-obstructive azoospermia. Spermatogenesis is dependent upon the function and number of Sertoli cells (SC) to support the developing germ cells. Klinefelter syndrome is the most frequent genetic cause of SCOS and presents histological features in common with idiopathic SCOS. P636 Aim of this study was to analyze the relationships between histological Gonadotropin releasing hormone analogue in cyclophosphamide- features and hormonal picture in SCOS patients (n: 37; AZ), Klinefelter induced premature gonadal failure prevention patients (n: 14; KL) and vasectomized patients as a control group (n:14; Paula Revert1,O´ scar Moreno1, Juan Miguel Lo´pez-Go´mez2, VA). Testicular tubule wall thickness was different in the three groups Francisca Sivera2, Sandra Martı´nez1, Miguel Perdiguero3, Eliseo Pascual2 & (P!0.05), with the highest values (12.2G0.9 mm) in KL and the lowest in Antonio Pico´1 VA (6.7G1.3 mm). Leydig cells number per grid was different between the 1Department of Endocrinology and Nutrition, Alicante University General three groups, with the highest number in KL (255.7G22.5) and the lowest Hospital, Alicante, Spain; 2Department of Rheumatology, Alicante in VA (48.1G16.4, P!0.001). The SC number per tubule was higher in AZ University General Hospital, Alicante, Spain; 3Department of Nephrology, (44.5G2.8) compared with VA (21.8G6.6, P!0.001), whereas the Alicante University General Hospital, Alicante, Spain. difference did not reach significancy between KL (132.0G44.2) and either AZ or VA. Total testosterone levels were higher in VA (15.0G3.7 nmol/l) compared with KL (9.4G1.6 nmol/l, P!0.02) and AZ (12.8G0.7 nmol/l, Background P!0.05). A significant negative correlation between the Leydig cell number Premature ovarian failure (POF) due to cyclophosphamide (Cyc) therapy is well per grid and total testosterone levels (P!0.001) was found analyzing all documented in systemic lupus erythematosus (SLE) patients. Studies show that patients together, but not single groups. SC number per tubule was the use of gonadotropin releasing hormone (GnRH) analogues appears to protect positively related to total testosterone levels (P!0.001) and was negatively women from POF. We present our experience in SLE patients treated with correlated with tubule walls thickness in AZ only (P!0.001). In conclusion, triptorelin. our data show that lower total testosterone levels are related to a higher Methods number of Leydig cells, thicker tubule walls and a smaller tubule width in Observational study of 15 women diagnosed of SLE who have received concomitant treatment with Cyc and GnRH analogues (triptorelin). Cyc was all the study groups, thus supporting the hypothesis of a major role of 2 androgens on tubular structure maintenance regardless of genetic or administered as 6–12 intravenous pulses at a dose of 0.5–1 g/m (adjusted for environmental subject characteristics. SCOS patients seem to have lower leucopenia and renal function) every 3–4 weeks, and triptorelin by intramuscular total testosterone levels as a consequence of an impaired Leydig cells injection at a dose of 0.06 mg/kg every four weeks from the first through the last secretive activity. pulse. All patients were asked about menstrual status (formula, disturbances), gestational formule, reproductive desire. Gonadotropin and estradiol serum levels were determined. We also evaluated the SLICC scale for cumulative SLE damage. The median age at menarchia was 13 years (p25 12, p75 14), SLE duration 7 years (range 2–19). All patients received Cyc due to renal disease and had received corticosteroids (median accumulated dose of 15.4 g). Median SLICC was 1 (range 0–4). They received GnRH analogues (median dose 0.063 mg/kg per m) concomitantly with Cyc (median total dose 16 g; range 7.5–27.7). Median age 24 years (range: 15–35) when beginning Cyc treatment. Median time of follow-up after therapy: 22 months. Results P635 All patients had adequate gonadal suppression and 14/15 also had hot flushes as a symptom of hypoestrogenism. Fourteen recuperated menstruation a median of Effects of Tadalafil on nocturnal penile tumescence and rigidity in 3 months (range 1–10) after withdrawing GnRH analogues. Although menstrual normal men: randomized, placebo-controlled, crossover study disturbances increased after therapy, mainly dysmenorrhea, only one patient Antonio Raffaele Michele Granata, Bruno Madeo, Giovanni De Mola, presents POF, with amenorrhea after 11 months of follow-up, and three patients Alessandro Guidi, Valeria Pugni, Vincenzo Rochira & Cesare Carani altered ovarian reserve. There have been no pregnancies after Cyc therapy. Chair of Endocrinology, Integrated Department of Medicine, Endo- Conclusion crinology, Metabolism and Geriatrics, University of Modena and Reggio Our data show a low prevalence of amenorrhea and POF, supporting the treatment Emilia, Modena, Italy. with triptorelina in these patients.
Subjects and methods We performed nocturnal penile tumescence and rigidity monitoring (NPTRM) in order to study the effects of Tadalafil on sleep-related erections in 23 adult healthy men (age: 34.27G8.48 years). The subjects were randomly administered Tadalafil, 10 mg tablet, the 1st (N1) or the 2nd (N2) night (Group A and B respectively) of 3 consecutive nights of erections’ monitoring. In Group A the 3rd night monitoring was regarded as control (N-ctr); in Group B the 1st night. Tadalafil was administered 2 h P637 after last food assumption before bedtime. The NPTRM parameters analyzed R R Topographical effects of functional prostanoid and oxytocin receptors were: number of valid erections, total duration of rigidity 60% and 70% on mid-cycle contractions in isolated human myometrium maximum rigidity, maximum increase of tumescence and total duration of 1 2 2 3 R Deborah Fischer , Peter O’Donovan , Diane Farrar , David Woodward & increase of tumescence 30 mm. Kay Marshall1 Results 1University of Bradford, Bradford, West Yorkshire, UK; 2Bradford Royal Number of valid erections (p N-ctr vs N1: !0.01; p N-ctr vs N2: 0.01), total 3 R Infirmary, Bradford, West Yorkshire, UK; Allergan Inc., Irvine, duration of rigidity 70% (p N-ctr vs N1: 0.03; p N-ctr vs N2: 0.05) and California, USA. maximum increase of tumescence (p N-ctr vs N1: 0.03; p N-ctr vs N2: 0.03) were significantly higher in nights 1 and 2 after Tadalafil than in control night; no differences occurred between the 2 nights after Tadalafil. Total duration of Dysfunctional prostanoid and oxytocin receptors have been implicated in the rigidity R60% (p N-ctr vs N1: 0.03; p N-ctr vs N2: ns) and total duration of development of myometrial hyperactivity, causing dysmenorrhoea and infertility. increase of tumescence R30 mm (p N-ctr vs N1: !0.01; p N-ctr vs N2: 0.06) The aim of the present study was to investigate the topographical differences in showed higher values only in night 1 after Tadalafil than in control night. In functional contractile PG and oxytocin receptors in mid-cycle isolated parenthesis values are meanGS.E.M. myometrium.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Longitudinal, full-thickness sections of the anterior uterus were obtained from P639 consenting pre-menopausal donors (aged 39–48 years) undergoing hyster- Weight loss determines a complete remission of the polycystic ovary ectomy for benign disorders. Approval for this study was obtained from the syndrome in most of obese women Local Regional Ethics Committees. Specimens were harvested at the follicular Z Ilaria Grassi, Lara Giovannini, Giulia Forlani, Laura Patton, stage of the menstrual cycle (n 14) and myometrial strips were dissected from Alessandra Gambineri & Renato Pasquali lower and fundus ends. For contraction recordings, individual strips were Endocrinology Unit, Bologna, Italy. mounted in organ baths under physiological conditions and attached to isometric force transducers. Following tissue equilibration, myogenic responses K9 to vehicle (saline), sulprostone (an EP3/1 agonist), PGF2a, U46619 (10 M– Obesity is strictly connected with Polycystic Ovary Syndrome (PCOS). However, K K K 10 5 M) (a stable thromboxane mimetic) and oxytocin (10 12 M–10 6 M) we still do not know whether a form of PCOS secondary to obesity exists or were measured. Estimates of maximal effect (Em) and curve mid-point (pEC50) whether obesity exacerbates manifestations of the syndrome. To answer this were expressed as meansGS.E.M. and analysed using two-way ANOVA with question we contacted seventy obese patients with PCOS that attended our Bonferroni’s post hoc test. Endocrinology Unit in the last 3 years and that lose weight after at least 6 months The amplitude of phasic spontaneous activity was 19.6 percent greater in of dietary treatment. Sixty-five out of 70 patients agreed to take part to the study lower segment tissue compared to the fundus (P!0.001). Similarly, and gave their informed consent. The diagnosis of PCOS was performed at responsiveness to uterotonins was more pronounced towards the cervix baseline according to the NIH criteria (oligo/amenorrhea and hyperandrogenism with PG-induced myogenic activity enhanced in a concentration-dependent or hyperandrogenemia) and was re-evaluated after weight loss using the same manner compared to time-matched controls (P!0.01–P!0.001). In contrast, criteria. At baseline 59/65 women executed also a pelvic ultrasonography that oxytocin significantly augmented myometrial activity in lower (pEC50 confirmed the diagnosis of PCO, whereas only 23/65 repeated it after weight loss. 6.99G0.75; P!0.001) but not fundus tissues (pEC50 8.59G0.80). After weight loss PCOS disappeared in 45/65 women (Responders – R), whereas The results indicate that functional regionalisation of the human uterus PCOS did not disappeared in 20/65 patients (Non-Responders – NR). This result drives the propagation of intrinsic contractile waves from the lower segment was not related to the reduction of body weight that did not differ between the two towards the fundus. This may direct retrograde sperm transport and facilitate groups (mean reduction of body weight: R K14.3G7.3 kg; NR K14.7G8.8 kg, embryo implantation during the periovulatory stage of the menstrual cycle. P NS). At baseline NR had higher waist, waist-to-hip ratio (WHR) and Contractile receptor dynamics and mechanotransduction pathways are androstenedione levels respect to R (waist: R 97.3G10.4 cm; NR 106.5G currently being investigated further to improve the development of 15.9 cm, P!0.01; WHR: R 0.851G0.077; NR 0.915G0.097, P!0.01; treatments for aberrant myometrial function. androstenedione: R 354G147 ng/dl; NR 482G151 ng/dl, P!0.01). All the other anthropometric, hormonal, and metabolic parameters did not differ between the two groups. Only R group significantly reduced DHEAS (K0.31G 0.89 mU/ml, P!0.01), LH (K4.51G8.45 mIU/ml, P!0.05), and FSH (K0.99G2.28 mIU/ml, P!0.05) levels after weight loss. Insulin resistance and hyperinsulinemia similarly improved in both groups. These data show that a secondary form of PCOS related to obesity does exist and that insulin-resistance and hyperinsulinemia are not the main pathogenetic mechanisms of this variant.
P638 P640 The importance of the (TTTA)n polymorphism of aromatase (CYP19) The role of sex hormone-binding globulin (SHBG) and aromatase gene in menarche (CYP19) gene variants in the development of polycystic ovary syndrome Nectaria Xita, Anthoula Chatzikyriakidou, Ioanna Stavrou, Chris Zois, (PCOS) Ioannis Georgiou & Agathocles Tsatsoulis Nectaria Xita, Leandros Lazaros, Ioannis Georgiou, Vasiliki Psofaki, University of Ioannina, Ioannina, Greece. George Kolios & Agathocles Tsatsoulis University of Ioannina, Ioannina, Greece. Background of study Twin studies have shown that age at menarche may be subject to hereditary Background of study influences but the specific determinants are unknown. Estrogens are known to Experimental research supports the hypothesis that fetal exposure to androgen excess have an important role in menarche. Since aromatase is responsible enzyme for may programme in utero the development of PCOS in adult life. Potential the conversion of androgens to estrogens, the aromatase (CYP19) gene could be a mechanisms for prenatal androgenization could be a reduced binding capacity of candidate gene for the regulation of menarche. The aim of this study was to androgens by SHBG or reduced aromatization of androgens by aromatase. The aim investigate the possible association of the CYP19(TTTA)n polymorphism with age of this study was to examine whether the SHBG(TAAAA)n polymorphism, known to at menarche. be associated with SHBG levels and the CYP19(TTTA)n polymorphism, known to Methods affect aromatase activity, may play a synergistic role in the development of PCOS. We studied 130 healthy adolescent females from a closed community in Methods northwestern Greece. Information on menarche was obtained through interviews. We studied 180 women with PCOS and 160 healthy women of reproductive age. The body mass index (BMI) was recorded. The CYP19(TTTA)n polymorphism The body mass index (BMI) was recorded and the hormonal profile was determined was genotyped. on 3–5th day of menstrual cycle. DNA was extracted from blood leucocytes and the Results SHBG(TAAAA)n and CYP19(TTTA)n polymorphisms were genotyped. The mean age at menarche was 12.9G1.2 years and the BMIZ19.8G Results 2.3 kg/m2. Genotype analysis revealed 5 CYP19(TTTA)n alleles containing Genotype analysis revealed 6 SHBG(TAAAA)n alleles with 6–11 repeats and 6 7–11 TTTA repeats. As short allele (S) was characterized the allele with ! CYP19(TTTA)n alleles with 7–12 repeats. Women were subdivided in 4 groups: 9 TTTA and as long allele (L) the allele with R9 TTTA repeats. The women with short SHBG (%8TAAAA repeats) and CYP19 alleles (%9TTTA subjects were subdivided into two groups based on median age of menarche. repeats), women with short SHBG–long CYP19 alleles, women with long SHBG– Group 1 included girls with menarche !13 years and group 2 girls with short CYP19 alleles and women with long SHBG and CYP19 alleles. Women with menarche R13 years. Among girls with SS genotypes, 52.9% were in group PCOS had at greater frequency long SHBG–short CYP19 alleles compared to 1 compared with 47.1% in group 2 and among girl with SL and LL controls (57.3% vs 42.4%, PZ0.07). Among patients, those with long SHBG–short genotypes 45% were in group 1 compared with 55% in group 2. This CYP19 alleles had the lowest SHBG levels (PZ0.02), and the highest total difference was due to the allele with 7 TTTA repeats, since 65.5% of the testosterone (PZ0.008), free androgen index (PZ0.002), DHEAS (PZ0.02) and girls being homozygous for this allele were in group 1 compared with testosterone/estradiol ratio (PZ0,03) compared to other genotypes. This 43.1% of the girls with other genotypes (PZ0.03). Furthermore, association was independent of age, BMI and insulin resistance indexes. homozygous girls for the allele with 7 TTTA repeats had earlier menarche Conclusion (12.45G0.9 years) than girls carrying other genotypes (13.04G1.2 years; The SHBG and CYP19 genes may have a synergistic role in the developmental PZ0.02). This difference was independent of BMI. programming of PCOS by affecting androgen bioavailability and aromatization, Conclusion respectively. Women with long SHBG(TAAAA)n and short CYP19(TTTA)n alleles There is evidence for a genetic contribution of the CYP19 gene to the age at may be exposed to excess androgens even during intrauterine life and this may menarche. ‘programme’ the development of PCOS in adult life.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P641 P643 Serum concentrations of atherogenic proteins Neutrophil gelatinase- Simultaneous profile of prostanoids in pregnant preterm non labouring, associated lipocalin and its complex with Matrix Metaloproteinase-9 are term non labouring and term labouring myometrium using ESI-LC-MS significantly lower in women with Polycystic Ovary Syndrome: hint of a Joanne Durn1, Kay Marshall1, Anna Nicolaou1, Diane Farrar2, protective mechanism? Peter O’Donovan2 & David Woodward3 Evanthia Diamanti-Kandarakis1, Sarantis Livadas1, Stylianos Kandarakis1, 1University of Bradford, Bradford, UK; 2Bradford Royal Infirmary, Alexandra Margeli2 & Ioannis Papassotiriou2 Bradford, UK; 3Allergan Inc., Irvine, California, USA. 1Endocrine Section, First Department of Medicine, Laiko General Hospital, University of Athens Medical School, Athens, Greece; 2Department of Clinical Biochemistry, Aghia Sophia Children’s Hospital, Athens, Greece. The aim of this study was to simultaneously profile, using electrospray ionization liquid chromatography mass spectrometry (ESI-LC-MS), prostanoids (PG) produced in samples of: pregnant preterm non labouring (PTNL); term non Background labouring (TNL): and term labouring (TL) myometrium. Neutrophil gelatinase-associated lipocalin (NGAL) and the Matrix Metalopro- Lower segment samples were obtained at Caesarean section from consenting teinase-9 (MMP-9) have been considered as important mediators of vascular pregnant women (18–36 years of age) at term (38–41 weeks) and preterm (33 remodeling and plaque instability. The formation of a complex with NGAL and weeks) gestation. Samples were transported to the laboratory and immediately MMP-9 is crucial for atherotic plaque erosion and thrombus formation. In women bathed in physiological Kreb’s solutionGindometacin (1 mM) for 1 h at 4 8C with Polycystic Ovary Syndrome (PCOS) the incidence of cardiovascular clinical (samples without indometacin are referred to as untreated (U) or treated (T) if events is not increased, despite the fact that they display a wide spectrum of risk indometacin was present), prior to freezing and subsequent solid phase extraction. factors. Since the instability of atherosclerotic plaque is a key factor in the clinical Extracts analysed using ESI-LC-MS were quantified using calibration lines made manifestations of cardiovascular disease, molecules challenging the plaque up of commercially available standards. Results are expressed as mean pg/mg stability should be investigated. protein (as estimated by Lowry method). Aim To determine serum levels of NGAL and MMP-9/NGAL complex in women with PCOS. PTNL (nZ1) TNL (nZ6) TL (nZ3) Subjects and methods C C Forty PCOS subjects were compared with 40 matched for age and BMI controls. In U-PTNL myometrium, In TNL(U T) myometrium, In TL (U T) myometrium, In each subject, fasting levels of glucose, insulin, gonadotropins, estradiol, the three most abundant the three most abundant the three most abundant androgens, C-reactive protein (CRP), NGAL and MMP-9/NGAL were PGs (ranked from highest PGs (ranked from highest PGs (ranked from highest determined. to lowest) were: TXB2, to lowest) were: 6-keto- to lowest) were: 6-keto- Results 6-keto-PGF1a and PGD2 PGF1a, PGD2 and PGF2a PGF1a, PGF2a and PGD2 NGAL and MMP-9/NGAL complex levels were significantly lower in PCOS group compared to control one (30.4G24.3 vs 70.7G37.9 mg/l, P!0.0001) and (31.5G26.6 vs 115.1G66.9 mg/l, P!0.0001) respectively. When patients and Disruption of the thromboxane/prostacyclin balance may be implicated in the controls were stratified according to BMI, it was shown that NGAL and MMP- onset of preterm labour. Our data are consistent with the role of prostacyclin as a 9/NGAL levels were significantly lower in lean (P!0.0002 and P!0.0001 mediator of uterine quiescence at term and the role of PGF2a as an elicitor of respectively) and overweight (P!0.0004 and P!0.002 respectively) PCOS myometrial contractions at term labour. subjects compared to controls. Conclusions These findings indicate that NGAL and MMP-9/NGAL complex, two molecules which activate atherotic plaque erosion, are in lower concentrations in PCOS subjects. The role of NGAL and MMP-9/NGAL complex needs to be further investigated, since suppression of these atheromatous molecules might have a protective role in women with PCOS. P644 The incidence of adiponectin gene polymorphism and its relation to serum adiponectin and androgen levels, insulin resistance and clinical parameters in polycystic ovary syndrome Hu¨seyin Demirci1, Erkan Yurtcu2, Murat Yilmaz3,Go¨ksun Ayvaz1, 2 1 P642 M Ali Ergu¨n & Metin Arslan 1Department of Endocrinology and Metabolism, Gazi University Faculty of PACAP and PACAP receptors in the testis of cartilaginous fish Torpedo Medicine, Ankara, Turkey; 2Department of Medical Genetic, Gazi marmorata University Faculty of Medicine, Ankara, Turkey; 3Department of Marina Prisco, Salvatore Valiante, Elisa Apicella, Marisa Agnese, Endocrinology and Metabolism, Bilim University Faculty of Medicine, Giuseppina Del Giudice, Francesco Angelini, Vincenza Laforgia & Istanbul, Turkey. Piero Andreuccetti University of Naples Federico II, Naples, Italy. Aim The present study was designed to examine the relationship between adiponectin The pituitary adenylate cyclase-activating polypeptide (PACAP), isolated for gene (T45G in exon 2) polymorphism and clinical and hormonal characteristics in the first time from hypothalamic extracts (Miyata et al. 1989), was localized women with polycystic ovary syndrome (PCOS). in some peripheral tissues such as adrenal, gastrointestinal tract, ovary and Materials and methods testis (Arimura et al. 1991, Watanabe et al. 1992, Gathei et al. 1993, Shioda Ninety-six patients with PCOS and 93 healthy subjects were included in the study. et al. 1994, Kononen et al. 1994). It was previously demonstrated that in the Serum levels of sex steroids, insulin and adiponectin levels were measured. testis PACAP was involved in the steroidogenesis regulation (Lacombe Insulin resistance was evaluated by homeostasis model assessment (HOMA). We et al. 2006). In our investigation we studied the distribution and the used the PCR to examine adiponectin gene T45G polymorphism. expression of PACAP and its receptors, PAC1, VPAC1 and VPAC2, in the Results testis of a cartilaginous fish, Torpedo marmorata, by using immunohis- Serum adiponectin levels lower in PCOS patients than control group. There tochemistry, in situ hybridization, western blot and RT-PCR. We showed was no statistically significant difference in the incidence of gene that PACAP was highly expressed in Torpedo testis as well as PAC1 and polymorphism and genotype distribution between PCOS and control groups. VPAC1, while VPAC2 was found to a lesser extent. Particularly, PACAP We have shown that polymorphism of T45G adiponectin gene in exon 2 is not and its receptors were found in those cells actively involved in the testis related to clinical findings, antropometric parameters, increased serum steroidogenesis such as Leydig cells (differently from other vertebrates androgen levels and decreased adiponectin levels in PCOS. Nevertheless, studied so far), pre-spermatogonia and Sertoli cells within cysts containing fasting insulin level and insulin resistance were significantly higher in poly- pre-spermatogonia and spermiated cysts. Further, we showed that in germ morphic group. cells PACAP and its receptors were expressed during spermioistogenesis. Conclusion Our data strongly suggest that PACAP has a role in the male reproductive Our study suggests that adiponectin gene T45G polymorphism is not related the processes of cartilaginous fish Torpedo marmorata, intervening in phenotypic features of PCOS but it plays an important role in the development of steroidogenesis and in the spermioistogenesis. insulin resistance in the PCOS.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P645 Background Serum osteoprotegerin in polycystic ovary syndrome Nonalcoholic fatty liver disease (NAFLD) has been associated with insulin Katerina Zajickova, Martin Hill, Katerina Dvorakova, Sona Stanicka, resistance. As polycystic ovary syndrome (PCOS) is also associated with insulin Karel Vondra & Jana Vrbikova resistance, the presence of NAFLD has been investigated in patients with the Institute of Endocrinology, Prague, Czech Republic. syndrome and there are data showing an increased prevalence of abnormal aminotransferance activity and/or ultrasonographic evidence of hepatic steatosis. Objective Osteoprotegerin (OPG) is a potent inhibitor of osteoclastic bone resorption. Besides In the present prospective study women with PCOS were evaluated with osteoblasts, OPG is expressed by both endothelial and vascular smooth muscle cells. abdominal ultrasonography and biochemical testing in order to assess the Moreover, elevated serum OPG has been found in conditions associated with insulin presence of NAFLD and to identify factors associated with NAFLD in PCOS. resistance such as obesity, diabetes and/or Cushing syndrome. Patients-methods The aim of the present study was to investigate the relationship between serum OPG Thirty-seven patients (Androgen Excess Society criteria), aged 16–48 years and insulin resistance in women with polycystic ovary syndrome (PCOS). In a cohort (25.8G7.0), with a BMI 16.8–45.3 kg/m2 (29.4G7.6) (17 obese, 8 overweight, of 39 women (age 25.3G4.6 years, BMI 25.96G5.34 kg/m2) PCOS was diagnosed 12 lean) were studied in the early follicular phase. None of the women had a according to Rotterdam criteria. After signing informed consent approved by the history of liver disease or reported significant alcohol consumption. None was local Ethical Committee, blood pressure, steroid hormones, gonadotropins, SHBG, receiving any medication at the time of the study. They had a clinical blood glucose, insulin and lipid spectrum were determined in fasting state and examination, a biochemical evaluation (fasting glucose and insulin, lipid profile, homeostasis model assessment for insulin resistance (HOMA-IR) was calculated. In liver function tests, FSH, LH, Prl, E2, testosterone, D4, DHEA-S, SHBG) and addition, insulin sensitivity was determined as glucose disposal in euglycemic underwent a liver and a pelvic ultrasound. Ultrasonography was performed by the hyperinsulinaemic clamp. same radiologist. Insulin resistance was assessed by homeostasis model Mean serum levels of OPG were 6.33G1.32 pmol/l. In Spearman analysis, assessment (HOMA-IR). circulating OPG significantly correlated with total cholesterol (rZ0.35, P%0.03). Results In partial correlations, OPG was positively related to age (rZ0.46, P%0.01), total Ultrasonography detected fatty infiltration of the liver in 15/37 patients (41.7%). cholesterol (rZ0.49, P%0.01) and FSH (rZ0.48, P%0.007), whereas negative Patients with abnormal liver ultrasonography were older (P!0.05), had a higher correlations were found between serum OPG and diastolic blood pressure, BMI (P!0.01), waist circumference (P!0.001), fasting insulin (P!0.005), HOMA-IR and/or HDL cholesterol (rZK0.5, P%0.005, rZK0.46, P%0.01 and HOMA-IR (P!0.005), serum triglycerides (P!0.05), free androgen index rZK0.45, P%0.012 respectively). There was no significant relationship between (P!0.05) and a lower SHBG (P!0.001) and HDL-cholesterol (P!0.005) versus glucose disposal and serum OPG levels. patients with normal liver ultrasonography. No differences were found concerning In the present cohort of women with PCOS, serum OPG levels were significantly levels of aminotransferance activity and the presence of polycystic ovarian associated with diastolic blood pressure, insulin resistance assessed by HOMA-IR morphology on ultrasound. Abnormal aminotransferance activity (SGPTO and an adverse lipid profile. A possible contribution of OPG to insulin resistance and 40 IU/l) was detected in 8/37 patients (21.6%), 5 of them having abnormal vascular endothelial dysfunction in PCOS needs to be further investigated. liver ultrasonography. No differences were found between patients with abnormal and those with normal aminotransferance activity. Conclusion PCOS patients are at increased risk for developing NAFLD. Despite hepatic steatosis on ultrasound, liver biochemical tests may be normal, so liver P646 ultrasonography is the best option for the detection of NAFLD. Metabolic abnormalities of the syndrome seem to be related with the presence of NAFLD. Relation of proatherogenic lipid profile and insulin resistance in PCOS Djuro Macut1, Dimitrios Panidis2, Biljana Glisic3, Nikolaos Spanos2, Milan Petakov1, Jelica Bjekic4, Ivana Bozic1 & Svetozar Damjanovic1 1Institute of Endocrinology, Diabetes and Metabolic Diseases, Clinical 2 Center of Serbia, Belgrade, Serbia; Division of Endocrinology and Human P648 Reproduction, 2nd Department of Obstetrics and Gynecology, Aristotle University of Thessaloniki, Thessaloniki, Greece; 3Institute of Medical Insulin resistance in patients with polycystic ovary syndrome and Biochemistry, Clinical Center of Serbia, Belgrade, Serbia; 4Department of idiopathic hirsutism Endocrinology, CHC Bezˇanijska kosa, Belgrade, Serbia. Homayoun Sheikholeslami, Mahsa Mirdamadi, Amir Ziaee & Camellia Kani Boali Sina Hospital, Qazvin University of Medical Sciences, Qazvin, Polycystic ovary syndrome (PCOS) is a common reproductive endocrine Islamic Republic of Iran. disorder. The metabolic aspect of disorder is characterized by obesity-related risk factors for cardiovascular disease. The aim of this study was to determine in women with PCOS, indices of lipid metabolism and their oxidation, and to assess Objectives possible relation to insulin resistance. We investigated 75 women with PCOS Hirsutism is a common clinical condition in women during reproductive age and (age: 23.1G5.1 years, body mass index (BMI): 24.9G4.7 kg/m2) and 56 age and characterized by excessive growth of terminal hair in the androgen-sensitive skin BMI respective controls. In all subjects after an overnight fast, blood samples regions. Polycystic ovary syndrome (PCOS) and idiopathic hirsutism (IH) were collected in follicular phase of the cycle for basal glucose, total-, HDL- and account for most of the cases of hirsutism. Insulin resistance and hyperinsuli- LDL-cholesterol, oxidized LDL (OxLDL), triglycerides, apolipoprotein – A1, B nemia have been demonstrated in women with PCOS and IH. We intended to and E, nonesterified fatty acid (NEFA), insulin, testosterone and SHBG. investigate the degree of insulin resistance in women with PCOS compared to Homeostatic model (HOMA index) and free androgen index were determined. weight-matched women with IH. PCOS patients in comparison to controls had increased indices of insulin Methods resistance, basal insulin and HOMA index (14.3G8.7 vs 8.2G3.4 mU/l, Thirty women with PCOS (mean age, 31.2G3.7 years; body mass index (BMI), P!0.001 and 3.2G2.0 vs 1.7G0.7, P!0.001 respectively), and deteriorated 23.3G2.1 kg/m2) and 38 women with IH (mean age, 25.0G5.1 years; BMI, 2 insulin resistance-related dyslipidemia with decreased HDL-cholesterol (1.2G0.3 24.9G3.4 kg/m ) were included in the study. The presence of insulin resistance vs 1.5G0.3 mmol/l, P!0.01), elevated triglycerides (1.0G0.6 vs 0.8G was investigated by using basal insulin levels, the oral glucose tolerance test, and 0.4 mmol/l, PZ0.010), and pronounced LDL oxidation 66.9G33.0 vs 50.2G the homeostasis model assessment (HOMA) score in both groups. Written 14.6 ng/ml, P!0.001). In conclusion, PCOS women had characteristic informed consent was obtained after the procedure had been fully explained. dyslipidemia of insulin resistance. Elevated OxLDL, and relation to the insulin Results insulin (rZ0.389, P!0.01) and HOMA (rZ0.343, P!0.01), is suggestive on Patients with PCOS had significantly (P!0.05) higher basal insulin levels premature atherosclerosis in patients with PCOS. (26.9G6.1 vs 10.8G6.5 mU/l), HOMA scores (6.3G1.3 vs 2.3G1.7) and FBS (95.4G8.2 vs 82.4G8.9 mg/dl) than patients with IH. Twenty-seven normal- weighted patients (90%) with PCOS and 10 (26.3%) normal-weighted women with IH had HOMA scores of greater than 2.5. Six patients (20%) with PCOS and 2 women with IH (5.3%) had impaired glucose tolerance. P647 Conclusion PCOS and IH are associated with insulin resistance independent of total body Nonalcoholic fatty liver disease in women with polycystic ovary mass. In women with PCOS, insulin resistance appears more common in both syndrome obese and non-obese women compared to women with IH. Hyperinsulinemia Evangeline Vassilatou, Sophia Lafoyianni, Kostantine Tsarouhas, appears to play a key pathogenic role in the ovarian androgen overproduction, Stathis Papavassileiou & Ioanna Tzavara because of the stimulatory effect of insulin on ovarian steroid production. Amalia Fleming General Hospital, Melissia, Athens, Greece.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P649 parameters. Moreover, in the western immuno blot there was an increase in the Accumulation of dietary glycotoxins in the reproductive system of nitration of the tyrosine residues in the asthenozoospermic samples compared to normal female rats controls. The present data suggest a critical negative effect of peroxynitrite on Evanthia Diamanti-Kandarakis1, Christina Piperi2, Eleni Kandaraki2, sperm motility when spermatozoa concentration is normal. Tyrosine nitration is Penelope Korkolopoulou3, Efstratios Patsouris3, Apostolos Papalois4 & enhanced by peroxynitrite that affects motility parameters. Thus, a possible Athanasios Papavassiliou2 pathogenic role in infertile men when asthenozoospermia is the main critical 1Endocrine Section, First Department of Internal Medicine, Medical School, problem may be suggested. University of Athens, Athens, Greece; 2Department of Biological Chemistry, Medical School, University of Athens, Athens, Greece; 3Department of Pathology, Medical School, University of Athens, Athens, Greece; 4Experimental Research Unit, ELPEN Pharma, Athens, Greece. P651 The present study aimed to investigate whether dietary advanced glycation end- Apoptosis related signaling in the reproductive system Ido Ben-Ami1,2 & Rony Seger1,2 products (AGEs) are detected in the ovarian tissue of normal female rats and 1 2 whether they affect metabolic or hormonal profile. The Weizmann Institute of Science, Rehovot, Israel; Assaf Harofeh Normal rats were randomly assigned to regular diet, high (H-AGE) or low Medical Centre, Zerifin, Israel. (L-AGE) content for 6 months. Age-matched rats fed with regular diet served as controls. Apoptosis is crucial in regulating many aspects of the reproductive system. Since ! 0 H-AGE rats, demonstrated higher levels of fasting glucose (P 0.001), mitogen-activated-protein-kinases (MAPKs) and phosphatidylinositol-3 -kinase Z ! insulin (P 0.069), and serum AGEs (P 0.001) and testosterone (PI3K)-dependent signaling systems play important roles in apoptosis regulation, ! (P 0.001), than control and L-AGE rats. In H-AGE rats body weight we undertook to study their involvement in the induction of apoptosis in the Z Z compared with normal (P 0.118) and L-AGE-fed rats (P 0.35) did not reproductive system. differ. H-AGE group showed increased AGE localization in the theca interna Two pro-apoptotic stimulants were investigated in two corresponding cell lines. Z cells of the ovarian tissue compared to control rats (P 0.003). Furthermore, One of them was prostaglandin F2a (PGF2a), which is known to be the principal increased receptor for AGE (RAGE) staining was also observed in both physiologic luteolytic factor in mammals. It was found to exert direct apoptosis in Z granulosa as well as in theca interna cells compared to controls (P 0.038 human luteinized granulosa cells, and thereby studied in SVOG-4O cell line. The Z and P 0.052 respectively). second stimulant was gonadotropin-releasing-hormone-analog (GnRH-a), which These results demonstrate for the first time that administration of high AGE is known to induce direct apoptotis in many malignancies, benign diseases and diet in normal female rats is associated with increased deposition of AGEs various cell lines. As a model system we used the mouse pituitary cell line, aT3-1, in the theca cells and of RAGE in the granulosa and theca interna cells of which was found here to undergo apoptosis upon GnRH-a treatment. the ovarian tissue compared with the corresponding ovarian compartments We report that PGF2a and GnRH-a directly induces apoptosis in SVOG-4O and of the control and low AGE-fed animals. The metabolic alterations in aT3-1 cell lines respectively in a dose and time dependent manner. The apoptotic conjunction with the increased deposition in ovarian tissues of dietary effect of PGF2a and GnRH-a is mediated by JNK and inhibited by the PI3K-PKB glycotoxins and elevated levels of testosterone in H-AGE-fed animals pathway. PKC activation induces the assembly of the catalytic and regulatory compared to the controls, suggest an additional impact of environmental subunits of PP2A, thus activating it. Activated PP2A binds to PKB causing its factors on ovarian function and these findings need further exploration. dephosphorylation. Furthermore, PKC activation induces inhibition of PI3K activity. Altogether, the reduction of PKB activity releases PKB-induced inhibition of MLK3, thus further stimulates JNK activity and accelerates PGF2a and GnRH-a apoptotic effect. We conclude that both PGF2a and GnRH-a exert pro-apoptotic effect via similar signal transduction pathways. Our results support a potential use of GnRH-a for the treatment of various diseases and suggest that the outcome of this treatment P650 can be amplified by using PI3K-PKB inhibitors. Finally, revealing the signal Reactive nitrogen species in the chemical biology of sperm functions transduction pathways governing apoptosis in luteinized human granulosa cells Arianna Vignini2, Eddi Bildreghini1, Laura Nanetti2, Francesca Raffaelli2, may help both in the diagnosis and treatment of various reproductive Francesca Paggi1, Laura Mazzanti2, Franco Mantero3, Marco Boscaro1 & abnormalities, using specific signal transduction modulators. Giancarlo Balercia1 1Clinica di Endocrinologia, Istituto di Medicina Interna, Universita` Politecnica delle Marche, Ancona, Italy; 2Istituto di Biochimica, Universita` Politecnica delle Marche, Ancona, Italy; 3Dipartimento di Scienze Mediche e Chirurgiche, Universita` di Padova, Padova, Italy. Signal transduction Inflammation activates a variety of inflammatory cells, which induce and activate P652 several oxidant-generating enzymes which are able to produce high concen- Insulin regulation of proliferation involves activation of akt and erk 1/2 trations of free radicals and oxidants which react with each other to generate other signaling pathways in vascular smooth muscle cells more potent reactive oxygen and nitrogen species such as peroxynitrite 1 2 1 1 K Esma Isenovic , Maxenence Fretaud , Goran Koricanac , Emina Sudar , (ONOO ) that can damage DNA, RNA, lipids, and proteins by nitration, Jelena Velebit1, Branislava Dobutovic1 & Pierre Marche2 oxidation, etc., leading to increased mutations and altered functions of enzymes 1 2 K $ Institute Vinca, Belgrade, Serbia, USA; 2CNRS UMR 7131, and and proteins. Spermatozoa generate small amounts of O2 and NO . Under University Pierre and Marie Curie, Hoˆpital Broussais, Paris, France. physiological condition these compounds exist at very low concentration; however their local concentrations become significant close the production sites and the formation of peroxynitrite appears likely. Moreover, tyrosine nitration is a This investigation used primary cultured rat vascular smooth muscle cells widely used marker of peroxynitrite. The nitration of protein residues gives rise to (VSMCs) to examine the effects of insulin (INS) on proliferation of VSMCs. In K 3-nitrotyrosine which represent a protein modification specific for ONOO this study, protein kinase B (Akt) and p42/44 mitogen-activated protein kinase K formation in vivo. In the present study we have determined ONOO production in (ERK 1/2) signaling pathways in mediating the mitogenic actions of INS in semen and its correlation with kinetic features in spermatozoa, and we set out to VSMCs was investigated. Incubation of a rat VSMCs with INS (100 nM) for determine whether protein tyrosine nitration takes place in the same sample. 10 min resulted in an increase of Akt phosphorylation by 6-fold (P!0.001) and Semen samples from 25 normal fertile donors (control group) and 40 infertile ERK 1/2 phosphorylation by 3-fold (P!0.001). Pretreatment for 15 min with patients affected by idiopathic asthenozoospermia were analysed according to 10 mM of P13 K/Akt inhibitor LY294002 or with 20 mM inhibitor of ERK 1/2 WHO 1999 criteria. After liquification one aliquot of semen diluted to 5! PD98059 significantly reduced INS-stimulated Akt and ERK 1/2 phosphorylation 106 spermatozoa/ml was stored at K80 8C until determinations. Peroxynitrite by 76% and by 75%, respectively. Incubation of a rat VSMCs with INS resulted in concentration was measured through the fluorescence of the DCFDA probe. an increase of VSMC proliferation (CONTZ100%, INSZ187G13%, Protein tyrosine nitration was determined with Western Immuno Blot. Curvilinear P!0.001.) The effect of INS on VSMC proliferation was significantly reduced velocity and straight line velocity of sperm cells were determined using a Motion by 68% by pretreatment with LY294002 (PO0.01) and by 71% (PO0.01) by K Analysis CASA system. The controls exhibited ONOO production significantly pretreatment with PD98059. These results indicate that INS acts through Akt and lower than asthenozoospermic patients (7.32G0.54 vs 27.16G1.58, P!0.001); ERK 1/2 signaling pathways to up-regulate proliferation of VSMC’s. furthermore, ONOOK exhibited a significant inverse correlation with the motility
Endocrine Abstracts (2008) Vol 16 jY gpA!d gdQ A gJ d:g2 \dg_gQ8 A _\d8 A b!d8 B
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d:g2 \dA ) !2 rBs g_ j 10th European Congress of Endocrinology, Berlin, Germany, 2008
P692 P694 Rosiglitazone in two patients with thyroglobulin-positive and Cyclin A and B1 are overexpressed in thyroid cancers which had been radioiodine-negative differentiated thyroid cancer operated for indeterminate, nondiagnostic, or suspicious fine-needle Tomas Martin1, Amaya Ferna´ndez-Arguelles1, Alberto Torres1, aspirate results Alfonso Gentil1, Juan Castro2 & Teresa Cambils2 Asli Nar Demirer1, Ozlem Ozen2, Aysegul Sengul1, Neslihan 1Endocrinology Service, Hospital Virgen Macarena, Seville, Spain; Bascil Tutuncu1, Alptekin Gursoy1 & Nilgun Guvener Demirag1 2Nuclear Medicine Service, Hospital Virgen Macarena, Seville, Spain. 1Baskent University Faculty of Medicine, Endocrinology, Ankara, Turkey; 2Baskent University Faculty of Medicine, Pathology, Ankara, Turkey. Thiazolidinediones have demonstrated some efficacy in promoting radioiodine uptake of previously poorly radioiodine-responsive thyroid cancers. We describe Objective the effect of rosiglitazone, in promoting uptake in thyroid metastatic tissue with Approximately 30% of patients with thyroid nodules have indeterminate, weak uptake in order to treatment with radioiodine in two patients. nondiagnostic, or suspicious fine-needle aspiration (FNA) biopsy results. These Case 1 patients usually undergo thyroidectomy because of cancer risk. Our aim was to A 62-year-old woman with thyroid cancer and negative I-131 body scan post determine diagnostic markers to distinguish benign from malignant thyroid therapy (150 mCi) with presence of recurrent disease (PET positive in neck, neoplasms, so we focused on G2-M boundary regulators of the cell cycle and pulmonary and mediastinum and persistently elevated serum thyroglobulin investigated the expression of two proteins, cyclin A and cyclin B1. concentrations). The patient received 8 mg rosiglitazone daily for 3 months. Methods Serum thyroglobulin stimulated before initiation of therapy with rosiglita- We studied the expression of cyclin A and B1 in resection specimens of 168 zone was 37.5 ng/ml. After differentiation treatment, she received 150 mCi indeterminate, nondiagnostic, or suspicious FNA biopsy results retrospectively I-131 and the posttherapy scan showed marked uptake in the neck and Tg using immunohistochemistry. elevation after rTSH to 172.4 ng/ml in contrast to the predifferentiation Results treatment scan. Sixty-four of resection specimens were consisted of malignant histopathology. Of Case 2 64 cases of thyroid cancer (58 papillary, 4 follicular, 1 medullary, and 1 hu¨rthle A 63-year-old woman with thyroid cancer and negative I-131 body scan post cell carcinoma), cyclin A was overexpressed in 33 cases (51.5%) in contrast to 33 therapy (150 mCi) with presence of recurrent disease (PET positive in neck and cases (31.7%) of 104 benign pathology specimens (PZ0.025). Tweny-five mediastinum and serum antibody antithyroglobulin elvated 395.8 UI/ml). The (39.1%) of thyroid cancer cases were positive for cyclin B1 in contrast to 16 patient received 8 mg rosiglitazone daily for 3 months. After differentiation (15.4%) of 104 benign cases (PZ0.001). Cyclin A overexpression was not linked treatment, she received 150 mCi I-131 and the posttherapy scan showed marked to cyclin B1 overexpression. No association was found between overexpressions uptake in the neck and Ac-antTg elevation to 436.1 UI/ml. of cyclin A, cyclin B1 and TNM stage in malignant cases. Both patients tolerated treatment well without symptoms of hypoglycemia or Conclusions change in liver function tests. In this study, we have demonstrated that cyclin A and B1 may be important Conclusion biomarkers in predicting malignancy in indeterminate, nondiagnostic, or Our two patients showed uptake augmentation of I-131 after pretreatment suspicious FNA biopsies. The use of these biomarkers may allow an accurate differentiation with rosiglitazone. It might encourage the use of TZDs in preoperative diagnosis of thyroid cancer. The value of these biomarkers warrants patients with radiotherapy resistant differentiated thyroid cancers. further evaluation in a prospective study on fresh cytological samples of indeterminate, nondiagnostic, or suspicious FNA biopsies.
P695 P693 Semiquantitative evaluation of E-cadherin immunoexpression in the Effects of 8-Cl-cAMP on growth and apoptotic process in poorly thyroid neoplasms differentiated thyroid cancer cell lines Mariusz Klencki1, Stanislaw Sporny2, Bozena Popowicz1, Simona Lucchi2, Tiziana de Filippis2, Davide Calebiro1, Patrizia Porazzi1, Andrzej Lewinski1 & Dorota Slowinska-Klencka 1 Anna Spada1 & Luca Persani1 1Medical University of Lodz, Chair of Endocrinology and Metabolic 1Department of Medical Science, University of Milan, Milan, Italy; 2Lab of Diseases, Lodz, Poland; 2Medical University of Lodz, Chair of Experimental Endocrinology, IRCCS Istituto Auxologico Italiano, Milan, Pathomorphology, Lodz, Poland. Italy. Cadherins are proteins important for regulation of cell to cell adhesion. It has been Tools that are highly effective in the treatment of differentiated thyroid cancer postulated that the loss of cadherins may be an essential step in progression of (DTC) loose their therapeutic potentials in poorly differentiated tumors. The cancer cell dedifferation, leading to increased metastatic potential. In the present synthetic analog 8-Cl-cAMP has been known to have an antiproliferative effect in study, the immunoexpression of E-cadherin was examined in various types of a variety of cancer cells and is tested as antineoplastic agent in clinical trials. The thyroid neoplasms and compared with that expression in normal thyroid tissue. signaling mechanisms that govern the 8-Cl-cAMP-induced growth inhibition are The histopathological slides from 138 thyroid carcinomas (90 papillary, still uncertain and data in thyroid neoplasia are lacking. Therefore, we tested the 8 follicular, 15 oxyphilic cell type, 14 poorly differentiated, and 11 effects of 8-Cl-cAMP on the growth and apoptotic process in anaplastic (ARO), undifferentiated), 16 follicular adenomas and 26 normal thyroids were papillary (NPA) and follicular (WRO) thyroid carcinoma cell lines. Our immunostained with the use of anti E-cadherin antibody. The intensity of staining proliferation data show that growth of ARO, NPA and WRO was inhibited by was assessed semiquantitatively by evaluation of 1000 cells in each lesion. The more than 50% after the treatment with 8-Cl-cAMP in a time- and dose-dependent results were expressed in an ordinal scale from 0 to 4 (0 – staining present in !5% manners. To test whether apoptosis occurs in 8-Cl-cAMP treated cells, we of cell, 1 – 6–30% of cells, 2 – 31–60% of cells, 3 – 61–90% of cells, and 4 – more analyzed cell cycle, DNA fragmentation and caspase activity. We found induction than 90% of cells). Statistical significance was tested with Mann-Whitney U test. of apoptosis in all the cell lines with different sensitivities. Since MAPKs The lowest mean expression of E-cadherin was found in undifferentiated are involved in the regulation of proliferation and apoptosis, we investigated carcinomas (1.63) and the second lowest (2.07) – in poorly differentiated modification of ERKs, that are preferentially activated in response to mitogens, carcinoma. All other examined lesions showed significantly higher expression of and p-38 MAPKs, that are activated in response to cell stresses. Following the E-cadherin (the highest expression was observed in follicular adenomas – 3.25 – treatment with 8-Cl-cAMP, no modification of ERK phosphorylation was found P!0.005). There was no significant difference between undifferentiated and while a marked and progressive induction of p38-MAPK phosporylation was poorly differentiated carcinomas. Interestingly, there was a significant difference seen in all the cell lines. We also evaluated the Akt phosphorylation, as a marker in immunoexpression of E-cadherin between follicular adenoma and papillary of the PI3K proliferative pathway that as been implicated in thyroid cell carcinoma (2.47, P!0.05) as well as normal thyroid tissue (2.69, P!0.05). The proliferation, and we found poor modifications of Akt phosphorylation state after correlation between TNM classification and the level of E-cadherin immunoex- 8-Cl-cAMP treatment. pression was also examined. In the group of poorly or undifferentiated carcinomas In conclusion, 8-Cl-cAMP has a potent inhibitory effect on WRO, NPA and ARO there was a very weak negative correlation between the lymph nodes involvement cell growth which is accompanied by a pro-apoptotic effect via p38-MAPK. and the level of E-cadherin immunostaining (Spearman coefficientZK0.25). No Therefore, 8-Cl-cAMP has a potential to be tested in vivo as a therapeutic agent such correlation was observed in the groups of differentiated carcinomas. There for poorly DTC. was no correlation between the presence of metastases and the E-cadherin expression in none of the examined groups of cancers.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Conclusions females (PZ0.06). Thyroid ophtalmopathy was diagnosed dominantly in TRAB The loss of E-cadherin expression can be observed in poorly differentiated and positive disease (41% vs %24 PZ0.05). The recurrence of disease in radioactive- undifferentiated carcinomas. However, it seems that prognostic value of iodine or anti-thyroid drug treated subjects was more common in TRAB positive E-cadherin immunoexpression is rather weak. subjects (%25 vs %7). TRAB titers were found to be correlated with FT4, FT3, ATPO, thyroid volume and radioiodine uptake. Conclusion TRAB negative Graves disease is not a clinical entity on which the endocrinologists have fully agreed. It has been suggested that technical difficulties P696 in TRAB assays might contribute to lower levels. Furthermore, some authors Pronostic value of serum thyroglobulin measured before thyroid suggest that Hashitoxicosis should be the proper diagnosis in patients with TRAB ablation with I131 in patients with papillary cancer meta-analysis negative thyrotoxicosis. Jorge Sapunar, Marcela Jime´nez & Eugenia Ortiz Our results demonstrate that TRAB negative Graves disease is associated with a La Frontera University, Temuco,Cautı´n/Araucanı´a, Chile. milder form of thyrotoxicosis. However, either the clinical presentation of our patients or their laboratory data are distinguishable from Hashimato Thyroiditis. We suggest that TRAB negative Graves disease is a real clinical subtype of Objective Graves disease. It must be kept in mind that, despite low TRAB levels, To know the pronostic value of serum thyroglobuline (Tg), obtained before ophtalmopaty or recurrence of disease may occur. thyroid ablation with I131, in order to predict cancer recurrence risk in patients treated with total thyroidectomy due to differentiated thyroid carcinoma (DTC). Methods We conducted a computed search of the published literature in Medline. We included diagnostic test studies that evaluated the relationship between Tg before I131 ablation, with local or distance tumoral recurrence. Selection criteria were Tg P698 measurement method description and the explicit exclusion of patients with Absence of sonic hedgehog mutations in a large cohort of children with positive thyroglobuline antibodies. To express the accumulate diagnostic test thyroid dysgenesis pronostic value, we applied likelihood ratio (LR). To obtain accumulate 1 2 4 3 likelihood ratio we introduced our data in the Revman 4.2 program (Cochrane Marina Muzza , Tiziana de Filippis , Roberto Gastaldi , Giovanna Weber , Renata Lorini4, Paolo Beck-Peccoz1, Luca Persani2 & Laura Fugazzola1 Initiative) and selected the accumulated OR function. Statistical heterogeneity 1 2 Endocrine Unit, Department of Medical Sciences, University of Milan, across the studies was tested with the use of Cochrane Q statistic and Higgins’s I 2 coefficient in a randon effect model. Ospedale Maggiore IRCCS, Milan, Italy; Department of Medical Sciences, Results University of Milan and Istituto Auxologico IRCCS, Milan, Italy; 3Department of Pediatrics, San Raffaele Scientific Institute, Vita-Salute San The mean recurrence rate was 20.39%. Next table shows accumulate LR by Tg 4 value ranges: Raffaele University, Milan, Italy; Department of Pediatric Endocrinology, Ospedale Gaslini, Genova, Italy.
Tg (ng/ml) LRC CI 95% LRK CI 95% Thyroid dysgenesis accounts for 75% of all cases of congenital hypothyroidism (CH), and includes thyroid agenesis or hemiagenesis, thyroid hypoplasia, and 2.0K2.25 6.8 3.9K11.8 0.2 0.1K0.3 thyroid ectopy. Thyroid transcription factors TTF-1, TTF-2 and Pax-8, which are 5.0K5.05 9.7 5.9K15.9 0.1 0.06K0.17 involved in the development of the thyroid gland and its normal migration, have 10.0K11.05 16.2 9.9K26.1 0.06 0.04K0.10 been indicated as the best candidate genes but have been found to be mutated in a 27.5K30.25 38.8 20.2K74.3 0.03 0.01K0.05 minority of cases. Sonic Hedgehog (Shh) protein is involved in several key events 37.5K38.10 39.3 22.3K69.3 0.03 0.01K0.04 during vertebrate embryogenesis, as well as left-right axis determination and organ development. In mice, Shh is expressed in cardiac bud and indirectly Conclusions governs the symmetric bilobation of the thyroid. Shh knockout mice develop a The best range of values of Tg before I131 ablation in order to predict recurrence single unilateral thyroid mass and ectopic thyroid tissue remnants from the in DTC’s thyroidectomized patients is 27.5–30.25 ng/ml. presumptive trachea. The aim of this study was to investigate if mutations of SHH For a recurrence rate of 20.39% the positive predictive value of Tg before ablation gene could be implicated in human thyroid dysgenesis. is 91% and the negative predictive value 0.76%. The SHH gene has been analyzed in 23 cases of CH associated with thyroid ectopy. Three cases were of particular interest due to a particular dysgenetic phenotype: sublingual ectopy was associated with a thyroglossal duct cyst in one and with hemiagenesis in the second, the third patient was euthyroid with an in situ thyroid gland and an incidentally discovered intracardiac thyroid ectopy. The three coding exons of SHH have been amplified and directly sequenced, but no mutations have been detected. A novel silent polymorphism at codon 299 P697 (CTG/CTC) has been found in one patient with isolated thyroid ectopy. Clinical features of TRAB negative Graves disease: a prospective study In conclusion, no germline mutations of SHH gene have been found in a large Serkan Yener1, Nergiz Bayrakci2, Tevfik Demir1, Firat Bayraktar1, group of children with CH and thyroid ectopy. Though a key role in mouse Abdurrahman Comlekci1 & Sena Yesil1 thyroid development has been proposed, SHH defects may be rarely involved in 1Division of Endocrinology and Metabolism, School of Medicine, Dokuz the pathogenesis of isolated thyroid dysgenesis in humans. Eylul University, Izmir, Turkey; 2Department of Internal Medicine, School of Medicine, Dokuz Eylul University, Izmir, Turkey.
Objective It is well-established that hyperthyroidism of Graves disease is caused by P699 generation of TSH-receptor stimulating autoantibodies. However, in some Thymic hyperplasia presenting as a neck mass in Graves’ disease patients TRAB titers may be in normal levels. The rate and the burden of Serkan Yener1, Mustafa Secil2, Mehmet Ali Kocdor3, Ozhan Ozdogan4, TRAB negative disease vary between studies. In this study, we compared the Abdurrahman Comlekci1 & Sena Yesil1 clinical and laboratory parameters of 170 patients (85 TRAB positive and 85 1Division of Endocrinology and Metabolism, School of Medicine, Dokuz TRAB negative) that were diagnosed to have Graves disease in our department. Eylul University, Izmir, Turkey; 2Department of Radiology, School of Methods Medicine, Dokuz Eylul University, Izmir, Turkey; 3Department of General Diagnostic criteria for Graves disease; i) Elevated free T3 or free T4 ii) Typical Surgery, School of Medicine, Dokuz Eylul University, Izmir, Turkey; thyroid inferno pattern in ultra-sonography iii) Elevated radioiodine uptake 4Department of Nuclear Medicine, School of Medicine, Dokuz Eylul (I-131). TRAB was measured with radioreceptor assay (RRA)-(RIAZEN- University, Izmir, Turkey. Belgium). Results Mean age of study group was 46.7 and female dominance was present (72%). Introduction FT4, FT3, ATPO, thyroid volume and radioiodine uptake was significantly Thymic hyperplasia is a rare manifestation of Graves disease. In this report, we elevated in TRAB positive disease. Mean age or the presence of thyroid nodules describe a female with Graves’ disease and a neck mass that was associated with did not differ between groups. TRAB negative disease was more common in thymic hyperplasia.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Case report P701 A 28-year-old woman was referred to our division for the evaluation of Thyronamines are isozyme specific substrates of deiodinases palpitations. Thyroid function tests were associated with thyrotoxicosis. Thyroid 1 2 2 3 O Susanne Piehl , Thomas Heberer , Gabor Balizs , Thomas Scanlan , receptor antibody (TRAb) was found to be 22.3 U/l (positive: 14 U/l). Rene´ Smits4, Beate Koksch4 & Josef Ko¨hrle1 Sonography showed bilateral enlargement of thyroid lobes, typical ‘thyroid 1 ! ! Institut fu¨r Experimentelle Endokrinologie und Endokrinologisches inferno’ pattern and also a homogenous mass of 10 15 25 mm in dimensions, Forschungszentrum der Charite´ EnForCe´, Charite´ – Universita¨tsmedizin at the inferior of the thyroid. Magnetic resonance imaging demonstrated that the Berlin, Berlin, Germany; 2Federal Institute for Risk Assessment, Berlin, mass was a homogenous anterior mediastial lesion plunging to the neck, Germany; 3Department of Physiology and Pharmacology, Oregon Health compatible with hyperplasia of the thymus. Thymic hyperplasia related to GD and Science University, Portland, Oregon, USA; 4Department of Chemistry was suggested and follow up was recommended. She was treated with and Biochemistry – Organic Chemistry, Free University of Berlin, Berlin, metimazole. At the 3rd month of therapy euthyroidism was obtained but there Germany. was no significant change in either the size or the sonographic characteristics of the mass. At the 6th month of therapy neck ultrasonography did not reveal any regression of the mass. Total thyroidectomy and mass extirpation were performed 3-iodothyronamine (3-T1AM) and thyronamine (T0AM) are novel endogenous and pathological examination was consistent with chronic lymphocytic thyroiditis signaling molecules that exhibit great structural similarity to thyroid hormones and thymic hyperplasia. but apparently antagonize classical thyroid hormone (T3) actions. Their Conclusion proposed biosynthesis from thyroid hormones would require decarboxylation Elevations in circulating thyroid hormones are suggested to cause thymus and more or less extensive deiodination. Deiodinases (Dio1, Dio2 and Dio3) hyperplasia in Graves disease. It must be noted that microscopic changes in catalyze the removal of iodine from their substrates. Since a role of the thymus can be detected in one third of patients but massive enlargement deiodinases in thyronamine biosynthesis requires their ability to accept is rare. This presented patient has two different features when compared thyronamines as substrates, we investigated whether thyronamines are with the previously reported cases. First, she presented with a neck mass converted by deiodinases. instead of a mediastinal mass. This is probably due to a different growth Thyronamines were incubated with isozyme specific deiodinase preparations. pattern of thymus from mediastinum towards the cervical area Second, the Deiodination products were analyzed using a newly established method hyperplastic thymus did not regress after anti-thyroid treatment. We suggest applying liquid chromatography and tandem mass spectrometry (LC- that additional factors rather than the level of circulating thyroid hormones MS/MS). Phenolic ring deiodinations of 3,30,50-triiodothyronamine 0 0 0 0 0 may be involved in the pathogenesis of thymic hyperplasia in Graves’ (rT3AM), 3 ,5 -diiodothyron-amine (3 ,5 -T2AM), 3,3 -diiodothyronamine 0 0 disease. (3,3 -T2AM) as well as tyrosyl ring deiodinations of 3,5,3 -triiodothyrona- mine (T3AM) and 3,5-diiodothyronamine (3,5-T2AM) were observed with Dio1. These reactions were completely inhibited by the Dio1 specific inhibitor 6n-propyl-2-thiouracil (PTU). Dio2 containing preparations also 0 0 deiodinated rT3AM and 3 ,5 -T2AM at the phenolic rings but in a PTU- insensitive fashion. All thyronamines with tyrosyl ring iodine atoms were 5(3)-deiodinated by Dio3 containing preparations. In functional competition assays, the newly identified thyronamine substrates inhibited an established iodothyronine deiodination reaction. By contrast, thyronamines which P700 had been excluded as deiodinase substrates in LC-MS/MS experiments, failed to show any effect in the competition assays, thus verifying the Cigarette smoking but not the TSHR germline polymorphism D727E is former results. associated with toxic multinodular goitre (TMNG) and the thyroid These data support a role for deiodinases in thyronamine biosynthesis volume and contribute to confining the biosynthetic pathways for 3-T1AM and Jakob Jo¨rn, Konstanze Miehle, Claudia Schmidt, Juliane Wicht & T AM. Ralf Paschke 0 Third Department of Medicine, University of Leipzig, Saxony, Germany.
Objective There are contradictory results regarding the possible association of the TSHR polymorphism D727E with TMNG. Furthermore the influence of smoking on the thyroid volume has been reported by several authors. A possible association of smoking with thyroid nodules and particularly TMNG has not been investigated up to date. P702 Methods The outcome of radioiodine therapy of hyperthyroidism: comparison of In this study, 88 patients with TMNG were included. Diagnosis was verified by patients with a toxic nodular goiter and with Graves’ disease ultrasonography, scinthiscan, and measurement of TSH, f T4 and f T3. Patients Jolanta Kijek, Jerzy S Tarach, Maria Kurowska & Bozena Szymanek were age- and sex-matched to 88 controls without any thyroid disorders. The Medical University, Lublin, Poland. polymorphism was detected by denaturating gel electrophoresis (DGGE). Results The prevalence of polymorphism D727E in the TMNG population (23.9%) did Introduction not deviate significantly (PZ0.355) from the control group (18.2%). There was Hyperthyroidism is one of frequently encountered clinical syndromes appearing no significant (PZ0.601) difference for thyroid volumes between polymorphism in about 2% of adult population. The aim of this study was to evaluate the efficacy carriers (PC) (16.5 ml) and wildtype probands (WP) (18.5 ml). Moreover, also of radioiodine treatment in relation to the form of hyperthyroidism. within the TMNG group (nZ88) and the control group (nZ88) there was no Material and methods significant (TMNG: PZ0.603; controls: PZ0.332) difference for thyroid The study investigated 300 patients: 150 with Graves’ disease and 150 with a volumes between PC and WP (TMNG: PC 36 ml, WP 36.5 ml; controls: toxic adenoma goiter (109 with a solitary nodule and 41 with a multinodular PC 13.9 ml, WP 11.6 ml). Compared to nonsmokers (nZ132, 44.7%) the goiter). In all the cases, the estimation of FT3, FT4, TSH, TSI concentrations, prevalence of TMNG was significantly higher (P!0.05) for smokers (nZ44, radioiodine uptake and technetium-99m pertechnetate scans were carried out. The 65.9%) in the entire population (TMNG and controls). Smokers also had a radioiodine dose was calculated on the basis of Marinelli’s formula. significantly higher thyroid volume than nonsmokers in the entire population Results (TMNG and controls, nZ176) (smokers: 34 ml, nonsmokers: 15.7 ml, P!0.05). After a year long observation period, 31.35% of the patients with Graves’ disease Moreover, also within the TMNG group thyroid volumes of smokers (43 ml) were found to be euthyroid, 31.35% hypothyroid and 37.3% hyperthyroid, differed significantly from nonsmokers (31 ml, P!0.05) and in the control group whereas among the patients with a toxic nodular goiter 84% were euthyroid, 2% smokers tended to have a higher thyroid volume (smokers: 15.8 ml, nonsmokers: hypothyroid, and 14% were hyperthyroid. The results of radioiodine therapy for a 11.6 ml, PZ0.119). solitary nodule and a multinodular goiter were similar. Conclusion Conclusion Neither an association of the polymorphism with TMNG nor its association with The radioiodine therapy revealed a significantly higher efficacy with a lower rate the thyroid volume was evident in this study. However, smoking clearly showed a of hypothyroidism in the therapy of a toxic nodular goiter than in Graves’ disease, positive association with the thyroid volume. Furthermore, our results suggest an but its efficacy in the patients with a solitary nodule and a multinodular goiter was association of smoking with TMNG. comparable.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P703 P705 Results of thyroxine therapy on thyroid nodules size in children with Thyroid function of pregnant women hospitalized in a section of Hashimoto’s thyroiditis gestational pathology Vassiliki Skarpa, Athanasia Tertipi, Vassilios Petrou, Eleni Kostakioti, Zsuzsanna Szanto, Imre Zoltan Kun & Bela Szabo Elvira Posaghidou, Eleni Kousta, Petros Papachilleos, Aphroditi University of Medicine and Pharmacy, Targu Mures, Mures, Romania. Kitsopoulou, Marina Vakaki, Aspasia Fotinou, Dimitris Ioanidis, Asteroula Papathanasiou & Charalambos Hadjiathanasiou Department of Endocrinology, Children’s Hospital ‘P.and A. Kyriakou’, In our previous studies, we determined the incidence of thyroid dysfunctions in Athens, Greece. pregnant women in endocrinological out-patient departments, comparing the frequency and nature of gestational complications in hypothyroid pregnant women versus pregnants without thyroid disturbances. In the present study, we Aim proposed to appreciate thyroid dysfunctions in a clinical section of pregnant To study the effect of thyroxine treatment on the size of thyroid nodules in women with gestational pathology. We investigated 75 pregnant women children with Hashimoto’s thyroiditis hospitalized in the Clinic of Obstetrics and Gynecology Nr. I. Tg.Mures¸, Patients and methods gestational pathology section, during September–November 2006. We Twenty-two girls and 6 boys (78.6/21.4%) were followed for 2 years under determined the TSH in all women, and in addition FT4,T3 and anti-TPO thyroxine therapy, at mean dose 1.6G0.4 mg/kg per day. Diagnosis of antibodies in those patients whose gestational complications couldn’t be Hashimoto’s thyroiditis was based on the high value of either antithyroid explained by obstetrical–gynecological (placental or organic genital pathology), G antibodies, ATPO or ATG. Age at presentation was 10.6 2.0 year (6.2–13.6). general or acute infectious diseases. In 11 cases (14.7%), we obtained Nineteen patients were pubertal and 9 prepubertal (67.9/32.1%). Thirteen (46.4%) pathological hormone values, detecting in 6 women (8%) hypothyroidism and were euthyroid, 12 (42.9%) with subclinical hypothyroidism and 3 (10.7%) G in 5 (6.7%) hyperthyroidism. Among these patients 10 were hospitalized for hypothyroid. The size of thyroid nodules was 0.97 0.38 cm (0.6 – 2.2). All serious gestational complications, without any other trigger factors. In half of the nodules R1 cm were examined by FNA that confirmed Hashimoto’s thyroiditis. For the statistical analysis, t-test and Mann–Whitney test were used. women with hypothyroidism (3), we observed a normal TSH-level with a decreased FT -value, situation described by other authors in 2/3 of pregnant Results 4 At presentation, there was not any significant difference in nodule size between women. From the 6 hypothyroid women 5 (83.3%) presented considerable gestational complications: those 3 with normal TSH had tardive dysgravidia, euthyroid children and children with hypothyroidism or subclinical hypothyroi- imminent abortion or history of precocious neonatal mortality, while the other dism, 0.9G0.2 vs 1.0G0.4 cm, respectivelly, PO0.05. Nodule’s size R1 cm had 42.9% of children (NZ12). Decrease in nodule size R0.3 cm after 2 years with 2 were hospitalized for imminent abortion and pregnancy induced arterial hypertension, respectively. All the 5 hyperthyroid women presented serious thyroxine was observed in 75.0% (NZ21). Overall, nodule size showed significant decrease, from 0.97G0.38 cm at start of thyroxine to 0.64G gestational complications: 2 imminent abortion, one imminent premature delivery, one gestational hyperemesis and a woman had 3 spontaneous 0.48 cm, P!0.001, after 1 year and to 0.65G0.47 cm, P!0.001, after 2 years of treatment. Separately, in euthyroid children nodule size decreased from 0.96G abortion in anamnesis. In conclusion, among the 44 pregnant women having 0.30 cm at start of thyroxine, to 0.58G0.48 cm, PZ0.027, after 1 year and to gestational complications with unknown etiology, in 11 (25%) was detected a thyroid dysfunction. 0.63G0.46 cm, PZ0.045, after 2 years under treatment. In children with hypothyroidism or subclinical hypothyroidism, nodule size decreased from 1.00G0.43 to 0.69G0.49 cm, PZ0.024, after 1 year and to 0.68G0.49 cm, PZ0.007, after 2 years under treatment. Conclusions Treatment with thyroxine in children with thyroid nodules due to Hashimoto’s thyroiditis can significantly decrease the size of the nodules, in children with P706 euthyroidism and in those with hypothyroidism or subclinical hypothyroidism, Assessment of cobalt status: a comparison between goiterous children as well. and healthy control subjects Mojgan Sanjari1, Ahmad Gholamhosseinian2, Nouzar Nakhaee1 & Mahdieh Mashrooteh1 1Physiology Research Center/Kerman University of Medical Science, Kerman, Iran, Islamic Republic of Iran; 2High Technology and Environ- P704 mental Sciences, Kerman, Islamic Republic of Iran. Refetoff syndrome associated with other congenital diseases (case report) Imre Zoltan Kun, Zsuzsanna Szanto, Ildiko Vicsi & Zsuzsanna Reti Introduction University of Medicine and Pharmacy, Targu Mures, Mures, Romania. Cobalt is a relatively rare magnetic element with properties similar to iron and nickel. Cobalt is an essential element necessary for the formation of vitamin B12; however, excessive administration of this trace element produces goiter and We report the case of a 25-year-old woman (K.Cs.) hospitalized in our clinic for reduced thyroid activity. This study was done to compare the prevalence of cobalt endocrinological investigation, presenting a spontaneous abortion 3 weeks before excess (as a cause of goiter) between goiterous and non goiterous children and to hospitalization. From medical history, we mention a cerebral thrombophlebitis assay the relationship between serum cobalt and thyroid hormones too. with intracranian hypertension syndrome, appeared after oral contraceptive drug Methods (Diane 35R) used for 5 months.The clinically asymptomatic patient presenteddiffuse This cross sectional study was carried out on 5380 randomly selected children goiter (I. gr.), overweight and virilism, without other clinical signs (pulse 68/min). aged 8–11 years. Anthropometric measurements and thyroid exam were done on The hormone determinations showed an elevated TSH-level (6.43 mIU/l, normal all of them. Serum concentration of T4, T3, thyroid stimulating hormone (TSH), range: 0.44 – 3.45), free T4 at the upper normal limit (1.94 ng/dl, normal range: 0.8– serum cobalt and urine iodine were analysed from a subsample of 169 goiterous 2.0), and T3 close to the upper normal value (3.4 ng/ml, normal range: 2.02 – 4.43). children who were selected randomly. All above data were collected in an age and The repeated investigations gave similar results. Based on these data and on the sex matched control group too. clinical euthyroidism, we suspected a thyroid hormone resistance syndrome. Results The TRH-stimulation test (200 mg i.v.) showed an increased response to thyrotropin: The serum cobalt level was significantly lower in case group (4.3G2.9 mg/l in the basal TSH (4.63 mIU/l, normal range: 0.44 – 3.45) increased after 20 min to case versus 6.3G2.7 mg/l in control group (P!0.0001)).The urine iodine level 25.69, being high also after 40 and at 60 min (24.1 and 25.01 mIU/l, respectively). was significantly lower in case group. (19.8G10.9 mg/l in case versus 25.8G This result and the negative cranial MRI excluded the possibility of a hypophyseal 10.9 mg/l in control group (P!0.0001)).There was 12(7.1%) cases of cobalt TSH-secreting adenoma. Similarly, the lack of clinical signs of hypothyroidism deficiency and no one has cobalt excess. There was not a significant difference Z and FT4 at the upper normal limit excluded the possibility of a deficient trans- between Cobalt deficiency and goiter (P 0.07), but there was a significant membrane transport of thyroid hormones, due to a mutation of the MCT8-gene difference between iodine deficiency and goiter (PZ0.01). The total goiter rate (mono-carboxylate transporter-8). At the same time, this syndrome has been was 34.8%(GII) and 100% of cobalt deficient children were goiterous. There was described only in the men, women being just carriers of the mutation. The T3 not a significant correlation between cobalt concentration and height, weight, suppression test and other laboratory examinations are in course. Besides the BMI, T4, TSH and urine iodine, but there was a weak correlation with T3 Refetoff syndrome the patient was diagnosed with catastrophic antiphospholipidic (PZ0.04, rZ0.1). syndrome (incomplete form, having only 2 criteria present), although the levels of Discussion antibodies weren’t high (IgG anti-cardiolipin antibody, anti-DNAds, antiSm/RNP This study shows that goiterous children had lower serum cobalt concentration. In antibody, cryoglobulines absent). Further investigations detected a congenital most of previous studies, cobalt excess was known as a cause of goiter. Further hypercoagulability syndrome, too. studies for detecting the effect of cobalt replacement on goiter size may be needed to establish the cause and relationship between cobalt deficiency and goiter.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Conclusion P709 Serum concentration of cobalt and urine iodine was lower in goiterous children Cinacalcet reduces serum calcium in intractable primary hyperpara- and it may be a cause of goiter in our region (Kerman–Iran). thyroidism (PHPT) Claudio Marcocci1, Laureano Ferna´ndez-Cruz2, Cheng Sunfa3, Lulu Ren3 & Munro Peacock4 1Department of Endocrinology, University of Pisa, Pisa, Italy; 2Department of Surgery, University of Barcelona, Barcelona, Spain; 3Amgen Inc., 4 P707 Thousand Oaks, California, USA; Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA. Lack of apparent association of TSH receptor mutations in vitro activity with the clinical course of patients with sporadic non-autoimmune hyperthyroidism Patients with persistent PHPT after parathyroidectomy (PTX) or contraindica- Julia Lueblinghoff, Sandra Mueller, J Sontheimer & Ralf Paschke tions for PTX often require chronic treatment for hypercalcemia, representing an III Medical Department, University of Leipzig, Leipzig, Germany. unmet medical need. In an open-label, single-arm study in the US and EU, 17 patients underwent a variable length titration phase (maximum 16 weeks) with a maintenance phase (MP) of up to 3 years. Patients were eligible if they had Up to date, 12 patients with sporadic non-autoimmune hyperthyroidism (SNAH) (1) persistent PHPT following PTX or were considered contraindicated for PTX, caused by sporadic germline mutations in the TSHR gene have been reported. and (2) serum calcium (sCa) O3.1 mmol/l (12.4 mg/dl). Possible dose increases Nearly, all case reports discussed possible associations of the TSHR mutations occurred every 2 weeks during a titration phase until sCa %2.5 mmol/l in vitro activity (IVA) with the clinical course (CC). Therefore, we analyzed this (10.0 mg/dl), or the patient reached the highest dose (90 mg qid) allowed, or question in a systematic review of the case reports and investigated the TSHR adverse events (AEs) precluded further dose increases. The primary endpoint of mutation’s IVA in selected cases. sCa reduction by R0.25 mmol/l (1 mg/dl) at the end of titration (EOT) was Recently, linear regression analysis (LRA) of constitutive activity as a function of reached by 15 patients, while 9 reached the secondary endpoint of sCa reduction TSHR expression determined by 125I-bTSH binding or FACS analysis compared to %2.6 mmol/l (10.3 mg/dl) at the EOT. Mean values (SE) for sCa and iPTH to the wt TSHR was described as a more reliable way of characterizing the IVA of showed a decrease in sCa and a rise in iPTH. However, median iPTH (Q1, Q3) a constitutively activating TSHR mutation. Therefore, we determined the LRAs decreased from 29.3 pmol/l (14.9, 33.0) at baseline to 19.0 pmol/l (14.4, 32.4) at for all sporadic germline mutations which had not previously been reported. EOT. Three patients were treated for up to 72 weeks in the maintenance phase, at Moreover, we systematically evaluated all case reports of SNAH for evidence of which point mean (SE) sCa was 2.5 (0.23) mmol/l and mean (SE) iPTH was 11.9 an association of the CC with the IVA of the mutated TSHR. The LRAs (4.5) pmol/l. The most frequent treatment-related AEs were nausea, vomiting, and determined were: M453T (5.2G0.8), L512Q (4.5G0.7), I568T (25.6G6.3), paresthesia. Only 1 patient had a treatment-related adverse event that led to F631L (45.9G9.4), T632I (14.5G2.7), D633Y (16.4G6.4). Only 4 of 10 withdrawal from the study. investigated clinical signs namely prematurity, early onset of goiter (!15 months), eye signs (proptosis and eyelid retraction) and craniosynostosis are associated with a high LRA (O10). Furthermore, mental retardation, Baseline End of titration craniosynostosis and eye signs are associated with an early onset (!1.5 months) and a long duration (O3 years) of insufficiently treated hyperthyroidism. The Mean sCa (S.E.M.) 3.2 (0.05) mmol/l, NZ17 2.6 (0.08) mmol/l, NZ17 Mean iPTH (S.E.M.) 26.7 (2.9) pmol/l, NZ16 43.5 (17.4) pmol/l, NZ15 comparison of the CCs of patients harboring the same mutation (M453T, S505N) showed no relation of the clinical activity with a high LRA. Considering the different diagnostic circumstances, therapeutic strategies and the limitations of a systematic analysis of case reports due to the restricted number of In conclusion, cinacalcet addresses an unmet need in patients with PHPT and case reports and limited follow-up we found no consistent relation of the TSHR hypercalcemia for which no approved therapy exists. mutation’s IVA determined by LRA with the CC of patients with SNAH.
P708 P710 Phenotypic profiling of MCT8 deficient mice Eva Katrin Wirth1, Stephan Roth1, Petra Ambrugger2, Heike Biebermann2, Josef Ko¨hrle1, Annette Gru¨ters-Kieslich2 & Ulrich Schweizer1 1Institute for Experimental Endocrinology, Charite´-Universita¨tsmedizin Berlin, Berlin, Germany; 2Institute for Experimental Pediatric Endo- crinology, Charite´-Universita¨tsmedizin Berlin, Berlin, Germany. Abstract withdrawn
Thyroid hormones are essential for the proper development of a variety of tissues, especially the nervous system. Their transport into target cells is mediated by specific thyroid hormone transporters like the monocarboxylate transporter 8 (MCT8). Mutations in this X-chromosomal gene in humans lead to a severe phenotype characterized by psychomotor retardation, hypotonia, and a striking derangement of P711 serum thyroid hormone levels: high T3 in the presence of low T4, and no significant changes in TSH. Interestingly, despite high serum T3 the patients do not show tachycardia. Here, we present data on the expression of MCT8 in various human and mouse tissues, as well as on clinical phenotypes of MCT8 knock-out mice. To this end, we submitted MCT8-deficient mice to a comprehensive phenotypical screen at the German Mouse Clinic, located at the GSF in Munich. MCT8-deficient mice Abstract withdrawn replicated the hormonal phenotype of the patients, but did not exhibit neurological deficits and hypotonia. No obvious neuroanatomical changes were observed in MCT8 knock-out mice as analyzed by immunohistochemistry. Nevertheless, the loss of the transporter causes behavioral changes that need further investigation. T3 transport is significantly impaired in MCT8-deficient primary cortical neurons. Systematic analysis of candidate thyroid hormone transporters in primary cortical P712 neurons identified several other transporters that may be involved in compensation of the neurological phenotype almost absent in mice. Since some organs show either a hypothyroid, normal, or hyperthyroid phenotype, we speculate that every organ and tissue may be equipped with different thyroid hormone transporters and their differential response may depend on whether MCT8 is limiting T3 transport or not. Supported by grants of the DFG. Abstract withdrawn
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P713 P715 Subclinical hyperthyroidism, a retrospective study for 11 years Genetic predisposition for goiters analysed by a case control study Isobel Martinez & P Giralt Juliane Wicht, Joerg Singer & Ralf Paschke Hospital S. Bernabe´, Bernabe, Spain. III Medical Department, University of Leipzig, Leipzig, Saxony, Germany.
Our hospital has a referent population of 50 000 people in a rural area. We have Background made a retrospective study about ambulatory outpatients who had been diagnosed Iodine deficiency is the most important exogenous factor for the development of with subclinical hyperthyroidism. goiters and thyroid nodules. In addition, family and twin studies as well as linkage Objectives analyses and a genome-wide scan in 18 euthyroid goiter families suggest a genetic To describe and analyze the characteristics of these patients, the treatment they predisposition for euthyroid goiters. However, data about the inheritance of received, the relationship beween TSH and goiter, complementary image tests goiters are still contradictory. Therefore, we investigated goiter predisposition by and evolution. a matched case control study. Material and methods Patients and methods This is a descriptive study about patients registered as subclinical hyperthyroid- Three hundred and seventy-six patients providing written consent were included ism during the period from 1995 to 2006: sex, BP, BMI, CF, age at diagnosis, in the study. All of them were anti-TPO negative. We matched 188 patients with symptoms, TSH and T4L levels, antithyroidal antibodies, sonography and euthyroid or subclinically hyperthyroid goiter (TSH 4.20–0.05 mU/l) with 188 scintingrathy, treatment and evolution. Patients taking thyroid hormone, with euthyroid controls without thyroid enlargement for age and gender. Family subcute thyroiditis, post-partum thyroididtis or administration of iodine products history of the patients was recorded using a standardised questionaire and thyroid were excluded from the study. ultrasound was performed for patients with goiter and controls. Results Results NZ57, m age 64, O65 years 50.87%. About 85.5% women. m BMI 27.6, 508% About 50.5% of patients with goiters showed a positive family history for SBPR140, 52.6%, DBPZO80 m CF 82.6, TSH!0.1, 73.7% (40% of them had goiter. In contrast, only 25% of patients with normal thyroids had a positive multinodular goiter, 16% uninodular; rate no significant) TSHZO0.1, 26.3%. family history for goiter (P!0.001; ORZ3.1). Patients with goiters had a Antithyroglobulyn antibodies 8.7%, TPO 7%. Multinodular goiter 36.7%, significantly higher proportion of parents (P!0.001; ORZ3.6) or siblings Nodular 14.28%. Heterogeneus 37.8% Sonography 98.24%, Scintigraphy (PZ0.004; ORZ2.5) with goiters. Children of parents (mother and/or father) 45.61%. About 52.8% suffered from symptoms. We had registered 21.42% with goiters showed a 2.7-fold increased risk for goiter development and had a patients with HBP, 10.52% osteoporosis, 8.7% arrhythmia, all of them had goiter prevalence of 73.3%. The primary diagnosis of goiter was made 10 years TSH!0.1. Initial dose of methimazole between 5 and 30 mg. All patients taking earlier in patients with a positive family history as compared to goitrous patients 20–30 mg had TSH!0.1. Radioiodine treatment 8.77%. A patient undertook with a negative family history. surgery. About 31% stopped treatment. The rest maintained the treatment but with Conclusion a lower dose. Exitus 4. Follow-up by their GP 8, didn’t come back 4. The significantly higher rate of positive family histories in patients with goiters as Normofuntion at one year: 35 patients, 16% without treatment. Mean follow-up compared to the matched control patients as well as the increased goiter time, 3.6 years. prevalence in children of parents with goiters indicate the importance of genetic Conclusion factors in goiter development. The majority of patients were women. About 42.1% aged O65. About 80.7% had Additionally, the earlier onset of thyroid enlargement in case of a positive family goiter. About 52.6% had symptoms. When lowering medication TSH disminishes history for goiter further supports a genetic predisposition in the aetiology of and treatment is manteined at a low dose. TSH levels aren’t associated with type goiters. of goiter. All patients taking doseR20 mg had TSH!0.1.
P714 Giant subcutaneous hemorrhage mimicking anaplastic thyroid P716 carcinoma Effects on bone mineral density of supraphysiological levothyroxine Igor Tauveron1, Marie Batisse1, Frederic Somda1, Pascal Chabrot2, doses in patients with differentiated thyroid carcinoma Eugenio Rosset3, Philippe Thieblot1, Jean-Louis Kemeny4 & Louis Boyer2 Miguel Angel Mollar-Puchades, Antonia Perez-Lazaro, Juan 1Endocrinologie CHU, Clermont-Ferrand, France; 2Imagerie Medicale Francisco Merino-Torres, Monica Mun˜oz-Vicente, Raquel Segovia-Por- CHU, Clermont-Ferrand, France; 3Chirurgie Vasculaire CHU, Clermont- toles, Vicente Campos-Alborg, Ma Soledad Navas-de Solis & Ferrand, France; 4Anatomie Pathologique CHU, Clermont-Ferrand, France. Francisco Pin˜on-Selles Unit of Endocrinology, University Hospital La Fe, Valencia, Spain. A 63-year-old woman was referred by her cardiologist because of rapid growth of an anterior cervical mass. The patient had a history of severe vascular Introduction atherosclerotic disease, requiring multiple prosthetic vascular surgery, among The treatment of differentiated thyroid carcinoma exposes most patients to which thoracic aorta surgery, atrial fibrillation requiring coumadin and chronic chronic supraphysiological doses of thyroid hormone which seems to have several respiratory failure. On admission, the patient presented with a 7 cm firm mass, negative effects for the patient. The goal of the present study was to assess the regularly growing for 2 months, adherent to the cervical skin, highly suggestive of consequences of these doses on the bone mineral density (BMD). thyroid anaplastic carcinoma. Immediately performed, a CT scan demonstrated Patients and methods an anterior cervical lesion, possibly related to an old hematoma. Fine needle We performed a cross-sectional study on 64 female patients followed up between biopsy aspiration revealed after thin prep filtration inflammatory cells 1972 and 2007. We registered the levothyroxine doses over the last 3 years and (macrophages, neutrophil leukocytes and lymphocytes), but no tumor cell. the anthropometric parameters. All patients were tested for their hormonal Needle evacuation was poorly successful, and further, regular follow up was situation and underwent a BMD study on hip and lumbar spine by DXA. For the decided. No change in the cervical mass volume was observed. statistic analysis, we performed the corresponding parametric and nonparametric Discussion tests to compare means and establish correlations. A firm rapidly and regularly growing anterior cervical swelling is highly suggestive Results of anaplastic thyroid carcinoma. Lymphomas and Riedel’s thyroiditis may also be Out of 64 patients, 71.4% (nZ45) were menopausal and 28.6% (nZ19) were evoked. By contrast, intrathyroidal hemorrhage is usually acute and painful. premenopausal. The time of evolution was higher in the menopausal patients Hematomas of the thyroid region (except after thyroidectomy) are rather unusual. In (15.9 vs 8.8 years, P!0,05) and the levothyroxine dose was higher in the our case, it was induced by venous flow changes as a consequence of surgical ligation premenopausal patients (2.45 vs 2.15 mg/kg, P!0,05). According to the of left innominate vein following aortic replacement, leading to highly increased levothyroxine dose, those patients receiving over 2.2 mg/kg or 100 mg/m2 showed subcutaneous straining of turgescent collateral veins. Blood leakage was probably a decrease in their T and Z Scores, compared with those who were receiving a enhanced by antivitamin K treatment (especially when irregularly controlled and lower dose. The results were significant in the premenopausal women, in both excessive) and an initial muscular effort (carrying a sofa). areas, whereas in the menopausal ones, the significant results were those in the Conclusion lumbar spine. The menopausal patients who had received a dose over 100 mg/m2 Regularly growing cervical hematomas may occur months after aortic surgery, due had osteopenia in the lumbar spine (Spine T Score K1.54). to venous straining rearrangement and enhanced by anticoagulation, and therefore The dose of levothyroxine in premenopausical patients had a negative clinically mimic anaplastic thyroid carcinoma. and significant correlation with hip T Score (rZK0.692) and spine T Score (rZK0.470).
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Conclusion were only measured in two patients, one was negative and the other was antibody In our study, those patients receiving higher doses of levothyroxine showed a positive. decrease in the BMD parameters. In the menopausal patients, this decrease The high prevalence of hypothyroidism after TACE should lead to enhanced resulted in osteopenia in the lumbar spine. clinical suspicion of this disorder in these patients.
P719 P717 Alterations of the circulating selectin, intercellular adhesion molecule-1, Autoantibodies to thyroid peroxidase and hypothyroidism in patients and vascular cell adhesion molecule-1 in patients with non-immune with type 1 diabetes nodular thyroid disease Homayoun Sheikholeslami, Amir Ziaee, Camellia Kani & Siamak Vahedi Kristine Ducena, Peteris Tretjakovs, Antra Jurka, Inga Bormane & Boali Sina Hospital, Qazvin University of Medical Sciences, Qazvin, Valdis Pirags Islamic Republic of Iran. 1University of Latvia, Riga, Latvia; 2Pauls Stradins Clinical University Hospital, Riga, Latvia. Objective Genetic susceptibility to autoantibody formation in association with auto- Cytokines, including adhesion molecules, are a family of protein mediators that immune thyroid disease and type 1 diabetes mellitus has been described with are important in transducing information between various cell types, were non- varying frequencies. We have, therefore, investigated the prevalence of anti- immune cells may also be important sources of certain cytokines. thyroid peroxidase (anti-TPO), overt and subclinical hypothyroidism in type 1 Aim diabetic patients. Aim of this study was to evaluate of soluble intercellular adhesion molecule-1 Methods (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and soluble Sixty-five subjects with type 1 diabetes mellitus and 65 unrelated normal E-selectin (sE-selectin) in patients with non-immune nodular thyroid disease. controls were recruited for the detection of anti-TPO and Thyroid-stimulating Materials and methods hormone (TSH). Written informed consent was obtained after the procedure We formed two study groups: 32 patients with non-toxic, non-immune nodular had been fully explained. thyroid disease (P) and 32 healthy subjects were selected as controls (C). The Results histological examination revealed follicular adenomas in all of the cases. All Among 65 type 1 diabetic patients, 18 (27.7%) were positive for anti-TPO and 18 patients were without autoimmune diseases, cancer and coronary heart disease. (27.7%) had abnormal serum TSH level. Among these patients 11 (16.0%) had The study groups were matched for age, sex, and body mass index. sICAM-1, overt hypothyroidism and 7 (10.8%) had subclinical hypothyroidism. Compared sVCAM-1 and sE-selectin were measured by xMAP technology (Luminex-200 with those without thyroid autoimmunity, there was a female preponderance for analyzer). the type 1 diabetic patients with thyroid autoimmunity (female:male, 24:23 vs Results 11:7 respectively). Patients with thyroid antibodies were older, had a longer sICAM-1, sVCAM-1 and sE-selectin levels were statistically significantly G G duration of diabetes (17.6 9.3 vs 10.8 7.8 years), and developed diabetes later elevated in patient group compared to healthy subjects (P versus C, P!0.05). in life than those without antibodies. The mean anti-TPO levels were higher in Conclusion G patients with overt hypothyroidism (238.18 223.69 U/ml) than in patients with Our findings show that patients with non-immune nodular thyroid disease have G subclinical hypothyroidism (36.38 22.46 U/ml). Among 11 patients with overt significantly elevated sICAM-1, sVCAM-1 and sE-selectin levels. hypothyroidism 9 (81.1%) had abnormal anti-TPO levels, whereas positive anti- TPO were detected in 57% of patients (4:7) with subclinical hypothyroidism. Conclusion The presence of anti-TPO in 27.7% of our type 1 diabetic patients confirmed the strong association of autoimmune thyroid disease and type 1 diabetes mellitus. For early detection of autoimmune thyroid disease in patients with type 1 diabetes mellitus, measurement of anti-TPO and TSH preferably at type 1 diabetes P720 mellitus onset is recommended. Level of von Willebrand factor in thyrotoxicosis of a various genesis Alina Babenko, Margarita Cadinskaya & Elena Grineva Saint-Petersburg Medical State University named after I.P.Pavlov, Saint- Petersburg, Russian Federation.
In several studies, the state of the endothelial function is analyzed in clinical thyrotoxicosis. Increased level of von Willebrand factor is detected. Many events P718 of association of trombosis at these patients with high level of VWF are described. Hypothyroidism after transarterial chemoembolization for hepatocel- An association between autoimmune thyroid disease and pulmonary arterial lular carcinoma hypertension (PAH) has been reported too. We have studied factors which Felix Flohr, Jan Harder & Jochen Seufert influence on level of VWF at patients with a clinical thyrotoxicosis of a various Department of Internal Medicine II, University Hospital of Freiburg, genesis. The present study includes 74 normotensive patients with a Freiburg, Germany. thyrotoxicosis of Graves’ disease (GD) and 15 patients with a thyrotoxicosis of not immune genesis (TNIG) (toxic nodular goitre) without any CVD. The level of von Willebrand factor was mesured by the immunoturbidimetric method (the Transarterial chemoembolization (TACE) is widely used for treatment of normal range – 50–160%). The patients were examined echocardiography by hepatocellular carcinoma (HCC). During this procedure approximately 20 g of standard method. The mean level of VWF had been increased (181.6G13.57%) iodide is applied by radiopaque material. There is usually high awareness before the therapy. The mean level of VWF has been increased (192.95G regarding hyperthyroidism in association with contrast enhanced imaging studies 13.74%) in group of patients with GD in comparison with group TNIG (120.5G and TACE. To date, however, there are no reports regarding the frequency of 11.29%) (P!0.01). Correlation analysis detects the relationship between VWF hypothyroidism after this procedure, although high doses of iodide can also and a level of thyroid hormones: fT3 (rZ0.38, P!0.01), fT4 (rZ0.27, P!0.05) inhibit the synthesis of thyroid hormones (Wolff Chaikoff effect). and an antibody to TSH (rZ0.26, P!0.05) and an antibody to TPO (rZ0.32, We retrospectively evaluated a cohort of patients with HCC treated by TACE at P!0.01). From EchoCG parameters the moderate correlation with pressure in our center from 1997 to 2007. Out of 107 patients with histologically proven pulmonal artery (PPA) (rZ0.27, P!0.05) is noted and very strong relationship is HCC, 65 had TSH measured before and after at least one TACE. Treatment was detected between level of VWF and PPA at the dynamic control over year (rZ performed one to seven times. Twelve out of 65 patients (18.5%) had a suppressed 0.86, P!0.001). After treatment level of VWF has been decreased (97.8G TSH. Two were treated for hyperthyroidism, 10 had subclinical hyperthyroidism, 6.85%) in comparison with first examination (P!0.01). These results either before or after TACE. demonstrated, firstly, that rising of a level of a VWF is associated with an Surprisingly, 8 out of 65 patients (12.3%) developed an elevated TSH after the autoimmune genesis of a thyrotoxicosis, secondly, that these changes can be a TACE (mean TSH 19.96 mU/ml, range 4.59–76.66). Two of them displayed predictor/marker of a PAH. Immune system dysfunction may underlie this transient hypothyroidism with normalization of TSH within months. The course association. of hypothyroidism in the other 6 patients was lost to follow-up. TPO antibodies
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P721 Conclusion Clinical impact of positron emission tomography/computed Mutational analysis of the TRß gene allows definitive diagnosis of RTH, tomography in the follow-up of well differentiated thyroid carcinoma potentially avoiding the need for protracted and expensive pituitary function with elevated anti-thyroglobuline auto-antibodies testing. Slimane Zerdoud1, Lawrence Dierickx1, Adil Benlyazid2,Je´roˆme Sarini2, Samir Dahimene3, Delphine Bastie´4, Antoine Bennet5,Fre´de´ric Courbon4 & Philippe Caron5 1Department of Nuclear Medicine, Institut Claudius Regaud, Toulouse, France; 2Department of Surgery, Institut Claudius Regaud, Toulouse, P723 3 France; Department of Biology, Institut Claudius Regaud, Toulouse, Prevalence of antibodies to thyroid peroxidase (TPO) and postpartum France; 4Department of Nuclear Medicine, CHU Rangueil, Toulouse, 5 thyroiditis (PPT) in a cohort of 1700 pregnant women with gestational France; Department of Endocrinology, CHU Larrey, Toulouse, France. diabetes mellitus (GDM) Azriel Sharona1, Caman˜o Isabel2 & Garcı´a-Burguillo Antonio2 1Department of Endocrinology, Hospital Universitario Doce de Octubre, Aim 2 Assessment of the clinical impact of a positron emission tomography/computed Madrid, Spain; Department of Obstetrics, Madrid, Spain. tomography (PET/CT) with FDG in the management of differentiated thyroid cancer (DTC) in patients with increased or positive thyroglobulin The prevalence of antithyroid autoantibodies in pregnant women ranges between autoantibodies (AbTg). 6 and 10%, like in the general population. PPT, a syndrome of transient or Methodology permanent thyroid dysfunction occurring in the first year after delivery, is Retrospective study involving 15 patients seen in the follow-up with confirmed associated with the presence of TPO in gestation. The prevalence varies from 5 to DTC primarily treated with total thyroidectomy and Iodine 131. Patients 10%, with higher frequency in patients with DM1. The aim of this study is to presenting with increased AbTg and a negative or non informative conventional estimate TPO frequency during gestation and its relationship with PPT in a group evaluation were included. Inclusion was independent of presence or not of of women with GDM. metastatic lymph nodes at time of diagnosis. The results of the PET/CT were Methods correlated with histology and/or clinical follow up. The clinical impact was GDM was diagnosed in a cohort of 1700 pregnant women (mean age 32.7G6.5 determined on a change of intention to treat, which was decided upon in years; mean gestational week: 26.2G5.1), excluded patients with previous multidisciplinary meetings, based on the PET/CT result. thyroid dysfunction. In 1053 patients (60.3%) a follow-up of thyroid function Results after delivery was performed (3.5G3.3 months). We observed in 14 out of 15 eligible patients: 10 true positive examinations Results (confirmed by histology in 7 patients and clinical follow up in 3) 7 patients with The 22.7% of the patients were TPO positive (O11.9 U/ml). A clear association cervical uptake, 1 cervical and mediastinal uptake, 1 cervical and lung uptake and between the presence of TPO and recurrent pregnancy loss (R3 miscarriages) 1 liver uptake, 4 true negative examinations with negative follow up of on the was found (RR: 2.41; CI 95%: 1.17–4.97). The prevalence of hypothyroxinemia average 22 months (18–36 months) and no false positive or false negative results. in the cohort was 5.1%, regardless of autoantibodies levels. Positive TPO The intention to treat was modified in 73.3% (11/15 patients). The variation in the frequency postpartum was 39.9%. Women with positive TPO during pregnancy values of the AbTg of the true positive and the true negative group was similar had a greater risk to maintain a positive titer in postpartum (RR: 2.63; CI 95%: and did not allow for a threshold value. 2.30–3.01). The PPT prevalence in pregnant with positive TPO during gestation Conclusion was higher (RR: 3.76; CI95%: 2.61–5.42). PET/CT with FDG seems to be very useful in the therapeutic management of Conclusions recurrence of DTC in the case of increased or positive AbTg, in particular for the Considering the high prevalence of positive TPO in women with GDM and the patients with N1 at the initial staging. Further studies are suggested to confirm the increased risk of developing PPT in this group, a screening of thyroid function very promising negative predictive value and specificity of this study in a larger during pregnancy and a postpartum follow-up is recommended in this women. number of patients with longer follow up. There is a significant association between the presence of thyroid autoimmunity and a higher miscarriage rate.
P722 P724 Thyroid hormone receptor beta gene mutation (P453A) in a family Subclinical hyperthyroidism and insulin resistance in women with producing resistance to thyroid hormone simple goiter 1 2 1 1 Taner Bayraktaroglu , Janet Noel , Faruk Alagol , Nese Colak , Nahhit Constantinos Tzioras, Andromachi Vryonidou & Constantinos Phenekos 3 4 Motavalli Mukaddes & Samuel Refetoff Department of Endocrinology, Red Cross Hospital, Athens, Greece. 1Istanbul Faculty of Medicine, Endocrinology and Metabolism, Istanbul University, Istanbul, Fatif/Capa, Turkey; 2Departments of Medicine, JP Kennedy Mental Retardation and Developmental Disabilities Center, The Introduction University of Chicago, Chicago, Illinois 60637, USA; 3Department of Child Thyrotoxicosis has been shown to cause deterioration of glucose levels in patients Psychiatry, Istanbul Faculty of Medicine, Istanbul University, Istanbul, with DM 2 while return to euthyroidism results in better glycaemic control. Fatif/Capa, Turkey; 4Departments of Medicine, and Pediatrics and the Studies in normal subjects suggest that increased thyroid hormones may Committees on Molecular Medicine and Genetics and the JP Kennedy aggravate insulin resistance and decrease pancreatic secretion of insulin but the Mental Retardation and Developmental Disabilities Center, The University exact underlying mechanisms have not been completely elucidated. The purpose of Chicago, Chicago, Illinois 60637, USA. of this study was to investigate if this also occurs in subclinical hyperthyroidism as in the case of thyroxin suppression therapy in women with simple goiter. Patients and methods Background We prospectively studied 32 premenopausal women with simple goiter: 16 Resistance to thyroid hormone (RTH) is a dominantly inherited syndrome normal cycling women (Group A) and 16 women with polycystic ovary syndrome characterized by decreased responsiveness of target tissues to thyroid hormone. (PCOS) (Group B) matched for age and weight. We measured T3, T4, TSH, Two members of a Turkish family, a mother and son, had thyroid function tests Insulin, C-peptide and glucose levels, before and 3 months after suppression suggestive of resistance to thyroid hormone (RTH). treatment with thyroxin 2 mg /kg per day. For the assessment of insulin resistance Methods HOMA-IR was calculated. Comparisons between groups were made with The clinical presentation was, however, different. The mother (proposita) had Wilcoxon matched pairs test. palpitation, weakness, tiredness, nervousness, dry mouth and was misdiagnosed Results as having multinodular toxic goiter which was treated with antithyroid drugs and As expected, there was a significant increase in T4 and a significant decrease in partial thyroidectomy. Her younger son had attention deficit hyperactivity TSH in both groups (P!0.0001). In Group A, glucose and C-peptide levels and disorder and primary encopresis, but normal intellectual quotient. Both had HOMA-IR were significantly decreased after thyroxin therapy while insulin elevated serum iodothyronine levels with nonsuppressed thyrotropin. levels remained unchanged (glucose 94.4G3.0 vs 80.8G2.4 mg/dl P!0.004, Results C-peptide 2.92G0.27 vs 1.76G0.14 ng/dl, P!0.0004, HOMA-IR 4.1G0.27 A mutation in one allele of the thyroid hormone receptor beta gene (P453A) was vs 3.5G0.1, P!0.004). In Group B, only insulin levels and HOMA-IR identified, providing a genetic confirmation for the diagnosis of RTH. were significantly reduced (insulin 20.1G10.6 vs 11.1G4.2 mIU/ml, P!0.02,
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
HOMA-IR 4.8G1.2 vs 2.5G0.25, P!0.05) after thyroxin therapy. No significant T4L 7.5. Patient 3: HIV, chronic hepatitis, chronic renal failure, arterial change was noted in body weight as well in T3 levels during the study. hypertension, moderate aortic stenosis, PAF. Treatment: antithyroid and Conclusions corticosteroids. Two months of hyperthyroidism. T4L 6.5. Patient 4: vascular In contrast to primary hyperthyroidism, suppression thyroxin therapy in women encephalopathy, heart failure (double mitral valve, tricuspid failure valve, with simple goiter as well as women with simple goiter and PCOS results in pulmonary hypertension), PAF. Treatment: antithyroids, corticoids and potassium reduction of insulin resistance and better glucose tolerance. perchlorate. Two months of hyperthyroidism. T4L 7.7. Results Patient 1: thyroidectomy without peri-postoperative complications. Median hospital stay 2 days. TSH 0.1 mcU/ml and T4L 1.7 ng/dl. Patient 2: thyroidectomy without peri-postoperative complications. Median hospital stay 2 days. TSH 0.1. T4L 1.6. P725 Patient 3: not surgical indication (severe plaquetopenia). TSH 4.3. T4L 1.5. Patient 4: Treatment with thyroxine reduces thyroid volume in euthyroid children not surgical indication (comorbidities). TSH 5.8. T4L 1.1. with Hashimoto thyroiditis Conclusions Vasiliki Scarpa, Eleni Kousta, Athanasia Tertipi, Dimitris Ioannidis, 1. Although comorbidities involve a high cardiovascular surgery risk, total Vasilis Petrou, Charalambos Chatziathanasiou & Asteroula Papathanasiou thyroidectomy doesn’t mean more difficulties and a higher rate of complications Department of Endocrinology, P & A Kyriakou Children’s Hospital, shouldn’t be expected. Athens, Greece. 2. Surgical treatment arises when it is not possible to discontinue treatment with amiodarone, when complications appears from the use of antithyroids and when is necessary an early symptomatic control. Introduction 3. There is a need for an assessment of each patient in order to establish a safer There is no concensus whether euthyroid children with Hashimoto’s thyroiditis therapeutic approach. (HT) need treatment with thyroxine. Aim of the study To assess whether thyroxine influences goitre progression (calculated thyroid volume on U/S scan) in euthyroid children with HT. Subjects and methods We studied 50 euthyroid children with HT for a 2-year period. Children with a P727 multinodular goitre were not included in the study. Twenty-five children (17 girls Hashimoto’s thyreoiditis is associated with an increased occurrence of and 8 boys, median age (IQR) 12.1 (11.1–13.4) years) were randomised to receive deficits in attention testing compared to patients with other thyroid thyroxine and 25 children (20 girls and 5 boys, age 12.2 years (11.1–13.0)) did not illnesses receive treatment and were followed-up. There were no significant differences in Karsten Mu¨ssig1, Thomas Leyhe2, Claudia Weinert1, Ralf Saur2, sex, age, height, height SDS, weight, weight SDS, BMI, BMI SDS, thyroid Stefan Klingberg2 & Baptist Gallwitz1 volume (7.7 (6.6–9.1) ml and 7.3 (6.2– 8.4) ml, respectively and thyroid volume 1Division of Endocrinology, Diabetes, Angiology, Nephrology and Clinical SD (1.1 (0.7–1.5) and 0.9 (0.4–1.4)) between the two groups. Chemistry, Department of Internal Medicine, University Hospital of Results Tu¨bingen, Tu¨bingen, Germany; 2Department of Psychiatry and Following one year there was no significant difference in the thyroid volume (7.1 Psychotherapy, University Hospital of Tu¨bingen, Tu¨bingen, Germany. (5.8–10.2) and 9.0 (7.9–10.6) ml, respectively, PZ0.128) and thyroid volume S.D. (1.0 (0.0–1.4) and 1.7 (0.8–2.0), PZ0.075) between the treated and the non treated group. Three children of the non treated group who developed Objectives hypothyroidism and were treated were excluded from further analysis. Following Experimental and clinical data point to an involvement of the central nervous 2 years, the children on thyroxine had significantly smaller thyroid volume (7.6 system in Hashimoto’s thyroiditis (HT) independent of thyroid dysfunction. The neuropsychological function of patients with HT has not been systematically (6.3–9.2) vs 10.6 (8.2–12.1) ml, PZ0.016) and thyroid volume S.D. (0.6 (0.3–1.0) vs 2.0 (1.1–2.3), PZ0.001) compared to the children that did not receive evaluated yet. treatment. When each group was studied separately and comparisons within Design groups were made, there was no significant difference in the thyroid volume nor in In the present prospective study, neuropsychological testing was performed in 26 euthyroid patients with HT compared to 25 euthyroid patients with hormonal the thyroid volume S.D. before and after 1 year of treatment, however thyroid treatment for goitre or after thyroid surgery. volume S.D. was significantly lower two years following treatment compared to the thyroid volume before treatment (PZ0.002, Wilcoxon signed rank test). In Results Investigating executive function, cognitive flexibility, attention, figural and the non treated group, thyroid volume and thyroid volume S.D. increased after the 1st year (P!0.0001 and PZ0.007 respectively) and 2nd year (PZ0.001 and verbal memory as well as acoustic working memory with established PZ0.016) of follow-up. neuropsychological tests no significant differences between the two groups Conclusion could be detected. However, comparing the number of patients with conspicuous Treatment with thyroxine is beneficial for the further progression of goitre test results we found significantly more patients with a performance below the because it reduces thyroid volume significantly in euthyroid children with HT. cut-off point in the d2 attention test regarding carefulness (GZ-F, HT versus control group: 12 vs 5, P!0.05) and attention (KL, HT versus control group: 12 vs 2, P!0.01) than in the control group. Comparison of the demographic and endocrine data of the HT patients revealed a significantly increased mean value of the anti-thyroid peroxidase antibodies (TPO-Abs) in the group with conspicuous results in the d2 attention test (371.4G187.2 vs 69.3G28.7, P!0.05). P726 Conclusions Surgical management of amiodarone-associated thyrotoxicosis The results of the present study point to subtle cerebral dysfunction in a part of Silvia Maraver, Isabel Serrano, Cristobal Morales, Guillermo Martı´nez de patients with HT even in the euthyroid state. These patients might have an Pinillos, Juan Manuel Garcia-Quiros, Monica Tome, Antonio Jimenez- increased risk to develop a neuropsychiatric disease. Disturbances of cerebral Garcia & Angel Sendon thyroid hormone metabolism by the anti-thyroid antibodies or an association with Virgen Macarena Hospital, Seville, Spain. an unknown autoimmune disorder affecting the central nervous system could possibly explain the findings. Introduction Amiodarone is an excellent antiarrhythmic with a high use although it isn’t free from complications. Most of patients stay euthyroid (80%), inducing thyroid dysfunction in the remaining 20% (thyrotoxicosis, 1.5–3%). Objective We analyze amiodarona-associated hyperthyroidism surgical management according to the associated pathology and patients clinical evolution. P728 Subjects and methods The impact of changed body image on social relations and interpersonal We report four patients with amiodarona-associated hyperthyroidism occurred behavior for patients with thyroid associated orbitopathy between September 05 and March 07, two women and two men from 44 to 74. Annesofie Lunde Jensen1 & Ingegerd Harder2 Patient 1: chronic bronchitis, paroxysmal atrial fibrillation (PAF). Treatment: 1Department of Medical Endocrinology, Aarhus Hospital, Aarhus antithyroids and corticosteroids. Toxic hepatitis induced by metimazol. 1 month University Hospital, Aarhus, Denmark; 2Department of Nursing Science, of hyperthyroidism. T4L 6.1 ng/dl. Patient 2: Arterial hypertension, FAP. Faculty of Health Sciences, Institute of Public Health, University of Aarhus, Treatment: antithyroids and corticosteroids. Four months of hyperthyroidism. Aarhus, Denmark.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Objective Conclusions Altered appearance and changed visual function characterize thyroid associated Zones of iodine deficiency still exist in western Andalusia which means that a orbitopathy (TAO). TAO affects face and eyes and influences social function. It is sanitary intervention is necessary to prevent the upheavals associated to this well documented that thyroid disease influences the patient’s quality of life situation in order to its clinical importance. negatively and TAO aggravates the situation. Recently, attention has been directed towards the impact of the patient’s body image and studies show how body image dissatisfaction is a significant psychosocial complication. Although TAO is a disfiguring disease the impact of change in body image on social function has not been investigated using qualitative methods. This study explores P730 how patients with TAO experience the impact of a changed body image on their A poly A(K) RNA transcript (Heg) in human blood mononuclear cells is social relations and interpersonal behavior. Methods inversely related to TSH receptor autoantibodies in patients with untreated Graves’ disease: gene expression of CD14 and inhibition of An ethnographic approach using interviews and participant observation. Thirteen Cdk1 patients diagnosed with moderate to severe TAO and receiving treatment in a thyroid clinic were included. Grounded theory methodology was used to analyse Niels Juel Christensen, Gurli Habekost & Palle Bratholm data. The local ethics committee approved the study. Herlev Hospital, University of Copenhagen, 2730 Herlev, Denmark. Results The participants’ ability to maintain their social function was connected with Objective changed body image. ‘Eyes out of control’ was the dominating experience, We studied a previously uncharacterized poly A(K) RNA transcript (designated including 4 dimensions; deviating appearance, deviating visual function, Heg) in blood mononuclear cells and its relationship to TSH receptor deviating visual sensibility and deviating disease. TAO made it difficult to autoantibodies and to CD14, Nucks, Cdk1, GCRa, NF-kB and CK2 mRNA. make eye contact with other people and use the eyes for communication. The Subjects and methods participants witnessed how people stared at them, acted unpleasantly, avoided The main study groups were a) normal subjects b) patients with early and them, and misunderstood their facial expression. TAO made the participants untreated Graves’ disease and c) patients with Graves’ disease studied after change their social function with regard to reduced contact with others and treatment. Quantification of mRNA was done by RT-PCR-HPLC. The protocol everyday activities such as shopping, reading, driving and working. study was approved by the local Ethics Committee. Conclusion Results TAO is a challenging disease, hard to treat and unpredictable, making it difficult The sequence of the transcript was localized to a clone from the HUGO project. for patients and others to understand the meaning of TAO. The findings of this The 30 end of the Heg gene overlaps the 30 end of the Nucks gene. In 18 study contribute to clarification of essential elements of living with TAO and normal subjects, mean basal levels of specific RNA/mRNA were 0.15G0.01 development of guidelines for supporting and informing patients with TAO. (meanGS.E.M.), 1.3G0.07 and 30G3 amol/mg DNA for Heg, Nucks and CD14, respectively. In 17 patients with untreated Graves’ disease, concentrations of TSH receptor autoantibodies were negatively correlated to Heg RNA amol/mg DNA (P!0.001) and positively correlated to Cdk1 mRNA zmol/mg DNA (P!0.002) (rZ0.83). In the combined group of treated patients with Graves’ disease and P729 normal subjects CD14 was negatively correlated to Heg RNA amol/mg DNA (P!0.001). Nucks and CK2 mRNA were closely correlated (P!0.001). Valuation of iodine deficiency in Western Andalusia by means of the Inhibition of Cdk1 by a cyclin-dependent kinase inhibitor, Roscovitine, decreased neonatal screening of congenital hypothyroidism CD14 mRNA markedly (P!0.001). Heg and Nucks siRNA elicited an immune Juan Manuel Garcia-Quiros, Cristobal Morales, Silvia Maraver, reaction. Guillermo Martinez de Pinillos, Monica Tome, Carmen Cuesta, Conclusions J M Guerrero & Angel Sendon TSH receptor autoantibodies may be regulated by nuclear kinase activity (Cdk1) Virgen Macarena Hospital, Seville, Spain. and the degree of apoptosis (Heg) in mononuclear cells. Drugs which inhibit Cdk1 may be of interest in the treatment of autoimmune disease. Introduction The accomplishment of screening neonatal congenital hypothyroidism allows the use of the determination of TSH in new born (NB) like indirect marker of the iodine ingestion of the pregnant woman and the nutritional iodine deficiency in the population. In populations with a sufficient iodine ingestion, the proportion of children with TSH superior to 5 U/ml is smaller of 3%. P731 Primary target Rate of thyroid cancer in a cohort of thyrotoxic patients treated with To make the iodine deficiency map in the studied area (western Andalusia). radioactive iodine Method Fares Haddad1, Omar Malkawi1, Ahmad Omari1, Abdallah Abdelaziz1, The NB studied were selected by measuring TSH levels in heel dry blood from the Abdelkareem Khawaldih1, Khalid Khawaldih2, Mais Halaseh2, provinces of Cadiz, Huelva and Seville during years 2000–2004 (188, 616 RN). Luma Fayyad3 & Nazmi Kamal3 O The percentage will take shelter of NB that in each population has a value of TSH 1King Hussein Medical Center, Amman, Jordan; 2Nuclear Medicine Center, 5 uU/ml., indicative according to the WHO/UNICEF/ICCIDD of iodine deficiency. Amman, Jordan; 3Prince Iman Lab and Research Center, Amman, Jordan. It was used only samples of heel with a stagger between the birth and extraction of O48 h to avoid the slant of confusion of transitory physiological TSH elevation. Results Radioactive iodine treatment for thyrotoxicosis had been introduced since Percentage of RN with TSHO5 uU/ml (we frequently presented/displayed in the 1940(s). The association of thyroid cancer and radioactive iodine (RAI131) single summary the ZBSO3%) treatment for thyrotoxicosis is rare. Rate of thyroid cancer in Jordan is 3 per PROV. HUELVA 4.11% 100 000 (according to Jordan National Registry).The latest population is DISTRICT COUNTY COUNTRYSIDE 2.72% estimated to be 5.6 million in 2006. DIST. HUELVA COST 4.55% Aim DIST. MOUNTAIN RANGE OF CENTRAL HUELVA ANDEVALO 12.50% To look for rate of thyroid cancer in a cohort of patients who received RAI131 and PROV. SEVILLE 1.06% to report the index cases’ characteristics and management. DIST.ALJARAFE 1.19% Patients and methods DIST SEVILLE CITY 1.20% A cohort of 227 patients who received RAI131 over period of 10 years DIST EAST SEVILLE AREA OSUNA 0.74% (1997–2007) for different causes of thyrotoxicosis were followed up by physical DIST NORTH SEVILLE 0.83% exam and serial thyroid function tests. DIST SOUTH SEVILLE 0.94% Results PROV. CADIZ 2.48% We found two cases of thyroid cancer during this follow up period giving a DIST BAY OF CADIZ JANDA 2.10% prevalence of 0.88% of cases who received RAI131. Relative riskZ39.32 (95% DIST FIELD OF GIBRALTAR 1.76% confidence limits for RR 9.88ORR!156.46) PZ0.0012. DIST SHERRY COSTA NE 3.56% First case is a 75-year-old female patient who was diagnosed to have DIST MOUNTAIN RANGE OF CADIZ 2.90% thyrotoxicosis due to toxic multinodular goiter in 1990 who received 25 mCi CEUTA 1.85% RAI131 in June 1998. She became clinically and biochemically euthyroid. In May MELILLA 8.94% 2006, she noticed progressive neck swelling causing compressive symptoms and
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 hoarseness of voice. Thyroid FNA revealed medullary versus anaplastic cancer. Results Serum calcitonin level was elevated at 11.3 pg/ml (normal value: 0–5) favouring Mean basal and Pg-stimulated CT concentrations were 20.6G8.1 (range 10.2–39) medullary thyroid carcinoma. An emergency surgery to relieve obstruction was and 119.5G77.7 (range 21–281) in nonMTC-group and 28.6G8.9 (range 13.4– attempted, but unfortunately she succumbed immediately postoperatively. 41.5) and 685.7G593 (range 116–1600) in MTC-group. In nonMTC-group, Histopathological diagnosis confirmed medullary thyroid carcinoma with Pg-stimulated CT levels were higher in cases with pathological evidence of anaplastic changes and positive calcitonin stain. Second case is 65-year-old C-cell-hyperplasia (CCH) than in cases without CCH (172.3G69.2 vs 66.7G lady, known case of bronchial asthma and toxic multinodular goitre. She received 42.5, P!0.05). 15 Mci RAI131 in 2003 and became euthyroid within 6 months. In April 2007, she At ROC-analysis a Pg-stimulated CT valueO193 pg/ml showed the best accuracy presented with neck discomfort and sensation of suffocation. Thyroid FNA biopsy in detecting MTC with 77.8% sensitivity, 92.9% specificity; positive and negative revealed papillary thyroid cancer. The diagnosis was confirmed histologicaly likelihood ratios were 87.5 and 84.6%. after total thyroidectomy. She is due for ablative RxI131. Conclusions Conclusion On considering the large orverlap of PG-stimulated CT in patients with and The prevalence of thyroid cancer post RAI131 is 0.88%. Despite no direct cause without MTC, any cut-off value chosen as a criterium to recommend surgery in effect relationship between RAI131 and thyroid cancer could be established in patients with nodular thyroid disease remains fallible and possibly bound to these cases nevertheless they highlight the importance of lifelong surveillance of change over time. patients who receive RAI131.
P734 P732 Resistance to thyroid hormones (RTH): study of a family Correlations between lipids and thyroid hormones in primary Jacinta Santos1, Isabel Paiva1, Carla Baptista1, P Beck-Peccoz2 & hypothyroidism Manuela Carvalheiro1 Slavica Savic, Bozo Trbojevic, Jasmina Ciric, Biljana Beleslin, 1Endocrinology, Diabetes and Metabolism Department, HUC, Coimbra, Djordje Marina, Mirjana Stojkovic & Milos Zarkovic Portugal; 2Unita Operativa di Endocrinologia – Dipartimento di Scienze Institute of Endocrinology, Belgrade, Serbia. Mediche, Milano, Italy.
The aim of the study was to assess the influence of thyroid hormones on Resistance to thyroid hormones (RHT) is a rare syndrome, with autosomic lipid profiles in primary hypothyroidism, in order to determine the most dominant transmission, due to mutations in thyroid hormones beta-receptor gene. influential one for the clinical follow-up. Study group included 15 subjects Clinical presentation is variable for the same mutation. This hypothesis must be (3 male, 12 female, age 46G13 years/meanGS.D.), and total and free T4, considered in presence of high levels of thyroid hormones and TSH not total and free T3 and TSH, total, HDL and LDL cholesterol, triglycerides, suppressed. ApoA, ApoB and Lp(a) were determined. The diagnosis of primary The evaluation of a 15-year-old female patient, in 1990, harbouring a thyroid hypothyroidism was based on increased TSH and decreased FT4 nodule, secondary amenorrhea and visual and auditory impairment showed concentrations. We found that only FT3 was inversely correlated with slightly elevated thyroid hormone levels but normal TSH. She started total cholesterol, triglycerides and ApoB concentrations. Other assessed levothyroxine treatment and resumed menses. She was lost to follow up. Three hormones were not significantly correlated with any of the measured years later, returned to consultation with a multinodular goiter, high levels of parameters. Therefore, FT3 should be assessed in patients with patients with thyroid hormones and high TSH, in spite of levothyroxine treatment. After TRH primary hypothyroidism and lipid disorders. stimulation and pituitary MRI, resistance to thyroid hormones was diagnosed. Treatment was tried with tri-iodotironine and TRIAC, with slight reduction of TSH. In 2004, a new radiologic evaluation suggested a pituitary microadenoma, fully described with 10 mm in 2006. No other hormonal disorders were detected. A not yet described mutation in exon 9 (G344R) was identified by Professor Beck-Peccoz team. We studied patient’s family – mother, two brothers and two sisters (one of them is a non-identical twin sister of our patient). Father was P733 already deceased. We found abnormalities in thyroid hormone levels in both brothers, who also have the mutation. MRI of one of them suggests a pituitary The role of pentagastrin stimulated calcitonin in nodular thyroid microadenoma. disease: will we be able to minimize false positive results? Conclusions Erika Grossrubatscher1, Paolo Dalino Ciaramella1, Emanuela Carioni1, We describe a family with Resistance to Thyroid Hormones Syndrome due to a Renato Cozzi1, Daniela Dallabonzana1, Fabrizio Muratori1, new mutation in thyroid hormone receptor beta – G344R. Until now, a pituitary Giuseppe Oppizzi1, Angela Riolo1, Giuseppe Verde1, Marco Boniardi2, microadenoma was diagnosed in two of the affected patients, which is a rare Raffaele Pugliese2, Ornella Rossetti2, Teresa Burla3 & Paola Loli1 pathological situation that can occur in the natural history of RTH. 1Endocrinology, Ospedale Niguarda Ca’ Granda, Milan, Italy; 2Surgery, Ospedale Niguarda Ca’ Granda, Milan, Italy; 3Biochemistry, Ospedale Niguarda Ca’ Granda, Milan, Italy.
An increase in basal and Pentagastrin (Pg) stimulated calcitonin (CT) concentration is a specific feature of medullary thyroid carcinoma (MTC). Routine basal CT measurement in nodular thyroid diseases is controversial. Pg stimulation is expected to increase the basal CT specificity in MTC screening, P735 although false positive responses in patients without MTC have been reported. Onset of thyrotoxicosis in patients over 65 years is associated with Aim increased risk of skeletal and heart disease To report the diagnostic accuracy of Pg-stimulated CT in surgically treated Ileana Duncea, Carmen Georgescu & Ioana Ilie patients with nodular thyroid diseases and basal CT in the high-normal range or University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca, Cluj, ! slightly supranormal ( 42 pg/ml). Romania. Patients and methods We studied 12 pts (11 M, 1 F, aged 55.7G24.1), without evidence of MTC at pathological examination (nonMTC-group) and 9 pts (1 M, 8 F, aged It has been shown that aging is associated with ‘physiological’ alterations in both 37.1G26.3) with pathologically proven MTC (hereditary in 6 cases) the hypothalamo–pituitary–thyroid axis and at the peripheral level such as (MTC-group). Tumor size in MTC-group was comparable in hereditary and elevation of basal TSH levels, often with normal T3 and T4 levels and decreased non-hereditary cases (PZ0.129). Serum CT was measured (Immulite 2000 nuclear binding of thyroid hormones, particularly of T3. The frequency of nodular Calcitonin, Medical Systems, normal values 0–15 pg/ml) in basal condition and 1, goiter and of an altered thyroid status increases with advancing age. The aim of 2, 4 and 10 min after i.v. injection of Pg (0.5 mcg/kg). ROC curve was performed our study was to analyze the clinical and paraclinical features of thyrotoxicosis in by MedCalc-package. patients over 65 years of age, hospitalized at the Clinic of Endocrinology Cluj-
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Napoca, Romania. The study was performed on 51 patients (9 men and 42 Trspfl/fl mice. Application of tamoxifen resulted in a significant decrease of women) with a mean age of 67.6G0.62 years. Aside from clinical data, thyroid thyroidal Dio1 activity providing a model in which to study the role of ultrasonography, radionuclide imaging of the thyroid, thyroid hormone levels and intrathyroidal deiodinase activity for circulating T3 levels. In pilot experiments, other laboratory examinations were performed. Graves’disease was observed in we observed a reduction of plasma T3 levels in these mice. Thus, it may be only 10 patients while toxic nodular goiter/adenoma was noticed in 41 patients. possible that thyroidal Dio directly contribute to circulating T3 levels. This notion The majority of hyperthyroid patients over 65 presented with cardiovascular is compatible with reports on physiological variations of the T3/T4 ratio released symptoms (96%), followed by tremor (84%) and weight loss (78%). Of the 51 from the thyroid gland under conditions of stimulation of the TSH receptor by patients, 8 presented with atrial fibrillation. Nervousness, anxiety and TSH or TSHr autoantibodies or during severe iodine deficiency. Supported by hyperkinetic motor activity were seen in only 40% of patients. The most DAAD and DFG grants. sensitive laboratory test for the diagnosis of hyperthyroidism was the concentration of basal TSH. Serum alkaline phosphatase concentrations were slightly increased (56.1G4.1 U/l) probably due to an enhanced rate of bone remodeling. Screening for osteoporosis by ultrasonography revealed the presence of the disease in 30% of patients while 60% had osteopenia. In 17 patients, radioiodine therapy or surgical ablation of the gland was decided. Conclusions The study suggests that at the time of presentation hyperthyroidism in elderly is P738 associated to a distinct clinical pattern. With regard to the complications of hyperthyroidism, aged patients are more likely to develop cardiovascular and Iodine excretion and prevalence of thyroid dysfunction in the Western skeletal abnormalities. Part of Germany: results of the Heinz Nixdorf Recall study Martina Broecker-Preuss1, Harald Lahner1, Susanne Moebus2, Stefan Moehlenkamp3, Ulla Roggenbuck2, Karl-Heinz Joeckel2, Raimund Erbel3, Klaus Mann1 & on behalf of the Heinz Nixdorf Recall Investigator Group1 1Department of Endocrinology, University Hospital Essen, Essen, Germany; 2Institute of Medical Informatics, Biometry and Epidemiology, University Hospital Essen, Essen, Germany; 3Department of Cardiology, West-German P736 Heart Center Essen, University Hospital Essen, Essen, Germany. Evolution of thyroid autonomy in iodine sufficient environment Josip Zmire, Kresimir Martinac, Kristijan Peros, Kristina Kljajic, Objective Bozo Colak & Lea Sokolic While Germany was considered to be an iodine deficient area grade I to II in 1993, Vuk Vrhovac University Clinic, Zagreb, Croatia. iodine supply has increased. With higher iodine uptake, prevalence of autoimmune thyroiditis may increase. Poor data exist on iodine supply and the occurrence of thyroid dysfunction in middle-aged adults in the western part of Last 10 years, we are living in iodine sufficient environment. To clarify natural Germany. The aim of our study was to analyze iodine status, prevalence of TPO- course of thyroid autonomy in this conditions, we investigated 100 consecutive antibodies (TPOab), TSH and fT4 levels in a large population-based sample in the patients in last three months – 93 female and 7 male aged 19–86 years. Included western part of Germany. were patients with scans showing thyroid autonomy, and patients with nodular or Methods diffuse goiter with low or suppressed TSH. We followed them from their first Between 2001 and 2003 serum and casual urine samples were drawn from 4814 visit. Thirty patients were hyperthyroid – one spontaneously cured, 50 had low or participants (50.2% women, 49.8% men, age 45–75 years) of the Heinz Nixdorf suppressed TSH, and 20 had normal both TSH and thyroid hormones. Twenty- Recall study and analyzed by routine laboratory tests. Assay reagents for TSH, five patients presented with mild hyperthyroidism from the very beginning, in 5 fT4 and TPO-Ab were provided by Roche Diagnostics. patients hyperthyroidisnm developed in next 1–5 years. In two patients, thyroid Results autonomy developed after cure od autoimmune hyperthyroidism. One patient had We excluded participants with known thyroid disease, thyroid medication papillary thyroid carcinoma and hyperthyroidism in nodular goiter. Considering (including iodine-containing drugs) and elevated serum creatinine. Of the the fact that hyperthyroid patients have at least one visit in 3–4 months, that those remaining 3527 persons, TSH and fT4 data were available from 3150 (89.3%). with low TSH, we follow twice a year, and that those with normal hormones, we About 96.7% of men and 94.2% of women were euthyroid. Subclinical and overt see once a year, we approximate that 18% of our patients with thyroid autonomy hyperthyroidism was detected in 1.5 and 0.4% of male and 2.4 and 0.4% of female are hyperthyroid. participants, respectively. About 1.2 and 0.2% of men and 2.2 and 0.8% of women exhibited subclinical and overt hypothyroidism. The median iodine excretion was 128 mg iodine/g creatinine (men: 113 mg/g, women: 152 mg/g; P!0.05). Iodine deficiency (!100 mg/g) was significantly more frequent in men than in women (37.9 vs 13.0%). High iodine excretion (more than 200 mg/g) was detected in 24.3% of women and 9.0% of men (P!0.01). Elevated TPOab (O200 U/ml) were also found significantly more frequent in women (5.4%) than in men (1.5%). In men, high TPOab titres were found particularly in those individuals with high P737 iodine excretion (TPOab O200 U/ml in 2.9% of men with 200–250 mg/g). Interestingly, in women TPOab O200 U/ml (6.8%) were detected primarily Role of deiodinases in the thyroid for the maintenance of circulating T3 in individuals with an excretion of 100–150 mg/g. About 69.6% (16/23) levels of women and 41.2% (7/17) of men with TSH levels O5 mU/l exhibited Jazmin Chiu, Eva Wirth & Ulrich Schweizer TPOab O200 U/ml. Neither in men nor in women iodine excretion was ´ ¨ Charite-Universitatsmedizin Berlin, Berlin, Germany. associated with TSH or fT4 levels. Conclusion Deiodinases (Dio1-3) are selenium-dependent enzymes that catalyze the Our data demonstrate that iodine supply in the Western Part of Germany has reductive removal of iodine from iodothyronines. Depending on the substrate normalized. In men, elevated TPO antibodies were associated with high iodine and the position of the iodine removed, deiodination can generate T3 from T4 or excretion. inactivate T3 and T4. Local expression of Dio can help to adjust the intracellular levels of T3 to the physiological needs of the organ without changing circulating T3 concentrations. It has been suggested that hepatic Dio1 generates circulating T3. However, we have shown that mice with a hepatocyte-specific inactivation of selenoprotein expression do not display altered serum T3, T4, or TSH levels (Streckfuss et al. Biochem Biophys Res Comm 2005). In addition, classical gene disruption of Dio1 in the mouse did not reduce circulating T3 values (Schneider et al. Endocrinology 2006). Since Dio2-deficient mice are also not deficient in P739 circulating T3 levels, the question for the source of circulating T3 remains open. Interleukin-6 is not essential for bone turnover in hypothyroid mice Since Dios are expressed in the thyroid, we speculated that T3 may also be Janusz Mysliwiec, Robert Zbucki, Maria Winnicka, Boguslaw Sawicki, produced intrathyroidally by 50-deiodination of T4. In order to investigate this Agnieszka Nikolajuk, Karol Kaminski, Piotr Mysliwiec, possibility, we have generated mice with a tamoxifen-inducible inactivation of Wlodzimierz Musial, Zofia Bondyra, Jerzy Walecki & Maria Gorska selenoprotein-specific tRNA (gene symbol Trsp) in thyrocytes: Tg-CreER; Medical University, Bialystok, Poland.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Interleukin-6 (IL-6) has been shown to be involved in the pathogenesis of several P741 bone diseases characterized by an imbalance between bone resorption and Pharmacokinetics of digoxin in hyperthyroidism: effect of methimazole formation. Lately we have published our data suggesting an important role of IL-6 and acebutolol in thyrotoxicosis-related osteoporosis in mice (Horm Metab Res 2007 39 1–5). Teresa Gasinska1, Maria Izbicka1 & Renata Dec2 Aim 1Department of Internal Diseases, Silesian Medical University, Katowice, The aim of the study was to estimate serum markers of bone turnover: osteoclast- Poland; 2Department of Nuclear Medicine, Silesian Medical University, derived tartrate-resistant acid phosphatase form 5a (TRACP 5b) and osteocalcin Katowice, Poland. in IL-6-deficient mice to assess the role of IL-6 in bone metabolism in hypothyroidism in mice. Material and methods Hyperthyroid patients show an impaired response or even resistance to digoxin C57BL/6J (wild-type; WT) and C57BL/6JIL6-/-Kopf (IL-6 knock-out; IL6KO) treatment. mice randomly divided into 4 groups with 10 in each one: 1/WT mice in Objectives hypothyroidism (WT-ht), 2/WT controls, 3/IL6KO mice with hypothyroidism 1. Are there any differences in the pharmacokinetics of a single oral dose of (IL6KO-ht) and 4/IL6KO controls. Experimental model of hypothyroidism was digoxin between hyperthyroid and euthyroid patients? 2. Does simultaneous induced by intraperitoneal injection of propylthiouracyl. The serum levels of administration of digoxin and methimazole or digoxin and acebutolol affect the TRACP 5b and osteocalcin were determined by ELISA. pharmacokinetics of a single oral dose of dogoxin? 3. Does methimazole-induced Results euthyroidism change the pharmacokinetics of a single oral dose of digoxin? Serum concentrations of TRACP 5b (median and interquartile ranges) were 4. Does acebutolol, which ameliorates symptoms of hyperkinetic circulation significantly decreased in both groups of mice with hypothyroidism: change the pharmacokinetics of a single oral dose of dogoxin? WT (3.2 (2.5–4.7) U/l) and IL6KO (2.6 (1.8–3.5) U/l) as compared to the Design and method respective controls. Similarly, serum osteocalcin levels were significantly The subject of the study were 28 patients with hyperthyroidism and 15 healthy reduced in both groups of mice in experimental hypothyroidism: WT (25.8 persons.We evaluated the pharmacokinetics of a single oral dose of digoxin. (23.0–28.2) ng/ml) and IL6KO (21.5(19.0–24.6) ng/ml) in comparison to the Twelve methimazole treated patients were re-assessed once they had become respective controls. There were no significant differences in bone turnover euthyroid. Sixteen acebutolol-treated patients were re-asessed once symptoms of markers between IL6KO and WT mice both in hypothyroid and control hyperkinetic circulation had subsided.Moreover we evaluated pharmacokinetics animals. of a single dose of digoxin after simultaneous administration of digoxin and Conclusions methimazole or digoxin and acebutolol. The results of the present study suggest that IL-6 does not play an important role Results in bone turnover in both euthyroid and hypothyroid mice. Hyperthyroid patients showed significantly lower serum digoxin concentrations, 1 shorter T 2⁄beta and a significantly smaller area under the concentration curve that the control group. Administration of methimazole did not affect digoxin pharma- co-kinetics, administration of acebutolol resulted in an increased serum digoxin concentration and in a longer time to the peak serum level of digoxin in comparison with the control group. Conclusions In hyperthyroid patients the pharmacokinetics of a single oral dose of digoxin does differ from that observed in healthy subjects. Acebutolol but not methimazole do alter digoxin pharmacokinetics in hyperthyroid patients. P740 Serum ghrelin levels are increased in hypothyroid patient and become normalized after L-thyroxin treatment Signe Gjedde1, Esben Thyssen Vestergaard1, Lars Christian Gormsen2, Anne Lene Riis1, Jorgen Rungby3, Niels Moller1, Jorgen Weeke1 & Jens Otto Jorgensen1 P742 1Medical Department M (Endocrinology and Diabetes), Aarhus University Iodine metabolism and effect of 131I therapy in Graves’ disease Hospital, Aarhus, Denmark; 2Department of Clinical Physiology and Jolanta Kijek, Jerzy S Tarach & Maria Kurowska Nuclear Medicine, Aarhus University Hospital, Aarhus, Denmark; 3Medical Medical University, Lublin, Poland. Department C and Department of Pharmacology, Aarhus University Hospital, Aarhus, Denmark. The factors influencing the final outcomes of 131I therapy are indefinitely known, besides its practical use since more than 60 years. One of the considered factors Context affecting the results of 131I therapy is iodine metabolism. An interaction between gut-derived ghrelin, which is implicated in the regulation Aim of short- and long-term energy balance, and thyroid function has previously been The aim of the study was the evaluation of the iodine uptake and the effective reported in patients with hyperthyroidism, in whom ghrelin levels are reversibly half-life of 131I influence on the result of radioactive iodine therapy in patients suppressed. In the present study, we measured total serum ghrelin levels and treated due to Graves’ hyperthyroidism. pertinent metabolic indices in hypothyroid patients before end after L-thyroxin Material and methods replacement. A hundred subjects (84 females and 16 males) aged 27–76 with diagnosed Patients and methods Graves’ disease, were enrolled. In all patients, the thyroid technetium-99m scan Eleven patients were examined twice: 1) in the hypothyroid state, and 2) after at and determination of the serum levels of FT3, FT4, TSH, TSHRAb were least 2 months of euthyroidism. Ten healthy subjects served as a control group. performed. Iodine uptake was measured at 24 h, 48 h, then the half-life has been Ghrelin was measured in conjunction with indirect calorimetry and a determined. The therapeutic activity of 131I was calculated according to Marinelli hyperinsulinemic euglycemic clamp. formula. After the 12th months follow up period, the thyroid function has been Results estimated. Serum ghrelin levels were increased by 32% under basal conditions in Results the hypothyroid state (PRE) as compared to post treatment (POST) (pg/ml): The levels of thyroid hormones and TSH before therapy were: FT3 976.4G80.8 vs 736.8G67.1 (P!0.001). This difference prevailed during the 5.7–74.8 pmol/l, FT4 10.3–90 pmol/l, TSH 0.02–0.08 mIU/l. clamp but a decline was observed in both states: 641.4G82.2 vs 444.3G After 24 h, radioiodine uptake ranged between 18 and 89%, but after 48 h between 66.8 mg/ml (PZ0.005). The hypothyroid state was associated with decreased 17 and 83%. The effective half-life range was from 1.2 to 8.1days. resting energy expenditure, increased respiratory quotient and insulin resistance. The administered therapeutic activities ranged between 148 and 1113.7 MBq. Serum ghrelin levels as well as the metabolic aberrations became normalised after After 1 year follow-up, the effective 131I therapy was confirmed in 60 patients (29 L-thyroxin replacement as compared to the control subjects. euthyreosis, 31 hypothyreosis), but in 40 patients hyperthyreosis still remained. Conclusion Statistical analysis revealed no correlations between 24-h and 48-h radioiodine Serum ghrelin levels are reversibly increased in hypothyroid patients. It remains uptake as well as T1/2 and the result of 131I therapy. to be investigated whether this represents a direct effect of iodothyronines or a Conclusions compensatory response to the abnormal energy metabolism in hypothyroid The iodine uptake as well as the effective half-life of 131I did not influence the patients. result of 131I therapy.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P743 P745 Analysis of concomitant thyroid pathology in patients with thyroid Surgery, antithyroid drugs, or glucocorticosteriod in amioadarone- hemiagenesis induced hyperthyroidism (AIH) in patients with low iodine uptake: that Marek Ruchala, Ewelina Szczepanek, Hanna Zamyslowska, is the question Agata Czarnywojtek & Jerzy Sowinski Agata Czarnywojtek, Marek Ruchala, Rafal Czepczynski, Department of Endocrinology and Metabolism, Poznan, Poland. Ewelina Szczepanek & Jerzy Sowinski Department of Endocrinology and Metabolism, Poznan, Poland. Introduction Thyroid hemiagenesis (TH) is a rare inborn anomaly of unclear importance. The Amiodarone is frequently used in cardiac patients but has side effects which aim of the study is to describe clinical, hormonal and autoimmunological profile effects the thyroid due to its high iodine content. The use of radioiodine in AIH of patients with TH. with low iodine uptake is controversial. In these patients therapeutic choices Material and methods for refractory cases include either: surgery, antithyroid drugs, or glucocortico- The studied group consisted of 20 subjects (4 men), diagnosed of having TH at the steriods. age from 15 to 63. Laboratory tests, including measurement of serum What are the treatment choices in elderly patients which can’t be operated on, concentration of thyroid-stimulating hormone (TSH), free thyroxine (FT4), free agranulocytosis is present, or have toxic liver failure after methimazol therapy? triiodothyronine (FT3), thyrotropin receptor antibody (TRAb), antithyroid Aim peroxidase antibody (aTPO), antithyroglobulin antibody (aTg) as well as thyroid The aim of study was the evaluation of radioiodine therapy results in AIH patients scintigraphy and ultrasound examination (US), were performed. The data were with low radioactive iodine uptake (RAIU). analyzed with regard to the circumstances and the age of establishing diagnosis, Patients and methods gender, side of agenesis, associated thyroid developmental anomalies, US We examined 9 patients with AIH, 1 female (11.1%), and 8 males (88.9%) aged abnormalities, thyroid volume, hormonal function, concomitant thyroid diseases, from 63 to 78 years. (xGS.D.: 69.2G5.5 years). The therapy including administered therapy and the follow-up period. amiodarone was essential for the underlying heart disorder. Radiotherapy was Results the necessary medical choice because of: in two cases – agranuloccytosis post The left to right sided agenesis ratio was 4:1, with associated isthmus agenesis in 7 antythyroid drugs, additionally in two cases with diabetes mellitus (against (35%). Compensatory enlargement of thyroid lobe was found in 14 cases (70%) glucocorticoid therapy), and five hepatic failure. In all of them, surgical and was not correlated to TSH concentration. Thyroid volume was significantly intervention was excluded. The diagnostic procedure included baseline thyroid lower in the young (!25 years); PZ0.0035. US performed in 17 patients, function test (fT3, fT4 and TSH levels), thyroid autoantibodies (TgAb, TPOAb, revealed abnormal echogenity in 13 (76.5%) and focal lesions (nodules and/or TRAb), thyroid ultrasound, thyroid scan, and RAIU. RAIU in all cases was below cysts) in 8 (47.1%), all benign by fine-needle aspiration biopsy and significantly 10% at 24 h. less often found in younger subjects (!25 years); PZ0.044. At diagnosis, 8 Results patients (40%) were biochemically euthyroid (TSHZ2.0G0.38 mIU/ml), 7 Serum values of TSH, TgAb, TPOAb, TRAb were undetectable. Serum fT4, fT3 (35%)-hypothyroid and 5 (25%)-hyperthyroid. Thyroid autoantibodies were were as follows: fT4 12.4 to 49 pmol/l (mean: 28.4G13.6); fT3 3.9 to 6.8 pg/ml detected in 10 subjects (50%), more frequently among patients O40 years (mean: 5.7G1.4). Mean thyroidal 5-h and 24-h RAIU values were 5.1G1.0 and (PZ0.069). 8.2G1.4%, respectively. In every patient, an ablative dose of 131I (22 mCiZ Conclusions 814 MBq) was administered. The study indicates high prevalence of US abnormalities and thyroid Conclusion autoimmunological disorders of frequency increasing with age, in subjects Iodine therapy can be a useful therapeutic method in every case with low RAIU presenting TH, probably as a consequence of prolonged TSH overstimulation. and in which other treatments (surgery, antytyroid drugs, glucocorticoid) are Therefore, systematic observation and hormonal treatment, if required, is contraindicated if the dose used is ablative. recommended in all detected cases.
P746 Incidental thyroid carcinomas: do they have a different clinical aggressiveness? P744 Anna Ciampolillo1, Maria Bellacicco1, AnnaLisa Natalicchio1, Assessment of VEGF, VEGF receptor, EGF and endostatin Luciano Grammatica2, Gaetano Achille2, Paolo Trerotoli3, concentrations in patients with endemic goiter Riccardo Giorgino1 & Francesco Giorgino1 Wieslaw Zarzycki, Anna Zonenberg, Anna Modzelewska, 1Section of Internal Medicine, Endocrinology and Metabolic Disease, Bari, Agnieszka Nikolajuk & Maria Gorska Italy; 2ORL Unit, IRCCS Oncologico, Bari, Italy; 3Medical Statistic Unit, Department of Endocrinology, Diabetology and Internal Medicine, Medical Bari, Italy. University of Bialystok, Bialystok, Poland. With the increasing use of thyroid ultrasound (US), the recognition of thyroid Tumor angiogenesis is believed to result from an imbalance of pro- and anti- nodules in a large proportion of apparently healthy subjects has become common. angiogenic factors. Angiogenesis is an important component in the development Moreover, some autopsy series have shown that papillary cancer measuring of thyroid goitre. Vascular endothelial growth factor (VEGF) and epidermal 10 mm or less, the so-called papillary thyroid microcarcinoma (PTMC), is a very growth factor (EGF) represents a family of specific endothelial cell mitogens frequent incidental finding. Because PTMC is being increasingly discovered, it is involved in normal angiogenesis and in tumor development. Consequently, a important to ascertain whether PTMC may exhibit heterogenous clinical and panel of anti-angiogenic factors was addressed in a representative sample of pathological features, associated with different aggressiveness. To test this VEGF receptor-2 (VEGFR-2) and endostatin. Mechanism through which hypothesis, we examined 122 consecutive cases of thyroid cancer (31 incidental endostatin and VEGFR-2 suppressed angiogenesis was induction of endothelial and 91 non incidental) to find potential clinical and pathological findings that cell apoptosis and inhibition of endothelial migration. The aim of our study was to could be predictive of their aggressiveness behaviour. The cancers are considered evaluate the concentrations of VEGF, its soluble receptor, EGF and endostatin in invasive in the presence of the following conditions: capsular infiltration, stage N peripheral blood of patients with endemic goitre. The study comprised 91 patients or M more or equal to 1. To identify clinical and histological factors related to with nodular goiter, 34 with parenchymatous goiter and 51 persons without more invasive cancer, a logistic regression model was performed. All independent pathology of thyroid (control group). VEGF, VEGFR-2, EGF and endostatin were variables were considered in the multivariate logistic regression with stepwise determined by Human Immunoassay – Quantikinew ELISA (R&D Systems, selection; variables entered in the model at significance level 0.05. Minneapolis, USA). The highest concentrations of VEGF and EGF was Results demonstrated in nodular goitre in the medium level in parenchymatous goitre In the group of 31 patients with true incidental cancer, 20 of them (64.5%) had a and the lowest level in subjects with normal thyroid. Respectively, VEGFR-2 and diameter !10 mm (PTMC) with a statistically significant difference (P!0.0001) endostatin were lower in patients with goiter than in the control group, but without as compared to the group of non incidental thyroid carcinomas. When size and significant differences. In the group with goiter, significant Spearman correlation incidental discovery were examined in relation to the invasiveness, after adjusting between concentration of endostatin and iodine urine excretion was observed for multiple comparisons, a statistically significant difference (PZ0.027) was (P!0.02). In conclusion, the observed misbalance between inhibitors and found between PTMC incidentally discovered (4/20), which were less invasive, accelerators of angiogenesis could be an element of goitrogenesis. and the group with non incidental discovery and diameter O10 mm (39/71), which were more invasive. The logistic regression analysis showed both in
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 univariate and in multivariate analysis that the papillary histotype and the Conclusion diameter %10 mm (incidental or non incidental) resulted less aggressive. Although it is not clearly supported by our study, considering the burden of Conclusions comorbidity of thyroid dysfunction, we recommend TSH screening for patients We have demonstrated that the papillary histotype and the diameter %1cm with diabetes and cardiovascular disease, especially for women. resulted as the only protective factors in term of invasive behaviour. It is likely that in the near future molecular studies will be able to discriminate aggressive PTMC from those with an indolent clinical course.
P749 ProEGF cytoplasmic domain (proEGFcyt)-mediated up-regulation of P747 SNAP25 decreases cathepsin-L secretion and elastinolytic activity in Thyroid disorders in pregnancy human thyroid carcinoma cells. Sanjay Saraf, Sanchita Saraf & Sharon Jones Aleksandra Glogowska1, Astrid Kehlen4, Ekkehard Weber5, Marek Los2, Good Hope Hospital, Sutton Coldfield, UK. Cuong Hoang-Vu6, Thomas Klonisch1 & Thomas Klonisch3 1Department of Human Anatomy and Cell Science, Winnipeg, MB, Canada; 2Manitoba Institute of Cell Biology Cancer Care Manitoba, Winnipeg, MB, After diabetes, thyroid disorder is the second most common endocrine disorder in Canada; 3Medical Microbiology and Infectious Diseases, Winnipeg, MB, women of reproductive age. Thyroid disorders in pregnancy have been proven to Canada; 4Medical Immunology, Martin Luther University Halle-Witten- have adverse maternal and foetal outcome if not treated adequately and timely. berg, Halle, Germany; 5Physiological Chemistry, Martin Luther University Aim Halle-Wittenberg, Halle, Germany; 6Clinics of Surgery, Martin Luther The aim of this audit was to assess management and therapeutic interventions and University Halle-Wittenberg, Halle, Germany. outcomes of pregnancies complicated by thyroid disorders. Method A retrospective case notes analysis of 35 pregnancies with thyroid disorders The cytoplasmic domains of EGF-like ligands have important biological booked in antenatal clinic at Good Hope Hospital, Sutton Coldfield in 1996 was functions. Stable transfectants of the human follicular thyroid carcinoma cell performed. Parameters included were prepregnancy counselling, thyroid function line FTC-133 over-expressing the cytoplasmic domain of proEGF (FTC-133- tests assessment, change in treatment instituted, outcome of pregnancy. Standard proEGFcyt) demonstrated a transcriptional up-regulation of the lysosomal laboratory non-pregnant reference ranges were used for thyroid function test hydrolases cathepsin- (cath-) B and -D and alterations in the processing of interpretation in all three trimesters. cath-L protein. Cath-L has strong elastinolytic activity and was the only of the Result three cathepsins to be secreted by FTC-133 transfectants. FTC-133-proEGFcyt Of 35 pregnancy 32 (91%) had hypothyroidism and 3 (9%) had hyperthyroidism. clones displayed a markedly reduced ability to migrate through elastin matrices Prepregnancy counselling was provided to 13% of pregnant women with thyroid when compared with mock transfectants (empty plasmid) or a natural disorders. In hypothyroid group medication increased in 21% and decreased in proEGFsplice mutant construct. Decreased migration through elastin matrix 3%. In hyperthyroid group, Propylthiouracil started in 2 (66%) and decreased and coincided with a reduction of cath-L secretion in FTC-133-proEGFcyt clones. stopped in 2 (66%). When incubated with a specific cath-L inhibitor, FTC-133-proEGFsplice and Conclusion mock transfectants showed a similar reduction in elastinolytic activity implicating With appropriate and timely adjustment in therapy majority of pregnancy had cath-L to be largely responsible for the elastinolytic activity in our elastin good outcome. Usually in pregnancy with hypothyroidism, the dose of micration assays. Down-regulation of cath-L in FTC-133-proEGFcyt coincided levothyroxine needs increasing but in one of our pregnant woman it was with an upregulation of the t-SNARE component SNAP25 as determined by decreased. We need consensus on reference range for interpretation of thyroid specific siRNA knock-down of SNAP25. Incubation of FTC-133-proEGFcyt with function test in different trimesters of pregnancy. soluble EGF reduced SNAP25 protein levels in proEGFcyt transfectants and, thus, reversed the inhibitory actions of proEGFcyt on elastinolytic migration. This antagonistic EGF action was mediated by the EGFR. In summary, we have identified proEGFcyt as a novel regulator of the function of the t-SNARE membrane-vesicle fusion complex involved in the exocytosis/secretion of P748 elastinolytic cath-L. This mechanism facilitates the suppressive role of TSH screening and thyroid disease comorbidities proEGFcyt domain on thyroid carcinoma cell elastinolytic activity and Fusun Erdenen, Cuneyt Muderrisoglu, Mustafa Boz, Esma Altunoglu, invasiveness. Partly supported by Krebshilfe. Sukran Turkes, Zeynep Gurcan, Pinar Demir, Alper Doventas & Hale Aral Istanbul Education and Research Hospital, Istanbul, Turkey.
Background Thyroid diseases are commonly encountered in the population though it is P750 unanswered for whom screening tests are useful. We aimed to see the value of Impact of Cinacalcet treatment on health related quality of life TSH screening and to find out comorbidities of any thyroid diseases among these (HRQOL) in patients with primary hyperparathyroidism (PHPT) who patients who were diagnosed by screening. have failed or in whom parathyroidectomy (PTX) is contraindicated Method Philippe Chanson1, Dolores Shoback2, John Lu3, Sunfa Cheng3, Lulu Ren3 All consecutive patients (n: 796) who admitted to outpatient Clinics of Internal & John Bilezikian4 Medicine, between 1 and 31 January 2007 were recruited in the study. Age, 1Hoˆpital de Biceˆtre and Universite´ Paris-Sud, Paris, France; 2Veterans gender, final diagnosis were recorded. TSH levels were measured by Affairs Medical Center, University of California, San Francisco, California, chemiluminesance method (Roche Diagnostics GmbH, Mannheim, Germany). USA; 3Amgen Inc, Thousand Oaks, California, USA; 4College of When they were found out of reference values, after two weeks, TSH levels were Physicians and Surgeons, Columbia University, New York, New York, repeated and FT3 and FT4 levels were also measured by the same method. USA. Results Data were collected from 796 patients (393 male, 403 female). Thirty-seven patients had been followed up with known thyroid disease. Among these 10 were Hypercalcemic complications of PHPT include renal, cardiovascular, gastro- hyperthyroid, 10 were hypothyroid despite treatment and 17 were euthyroid. 55 intestinal, neuromuscular and neuropsychiatric issues, all potentially impacting (7.2%) subclinical hyperthyroidism (TSH: 0.12G0.08 mIU/ml), 48 (6.3%) negatively on HRQOL. As control of the hypercalcemia associated with PHPT subclinical hypothyroidism (TSH: 6.24G2.76 mIU/ml) and 4 (0.5%) overt might improve HRQOL, the SF-36 and a 6-item scale on cognitive functioning thyroid disease (3 hypothroidism and 1 hyperthyroidism) were diagnosed. (CF) were included in a phase 2, single-arm study evaluating the ability of Subclinical hyperthyroidism and hypothyroidism rates were found similar with cinacalcet to control serum calcium levels in 17 patients with intractable PHPT. overt thyroid disfunction. Subclinical hypothyroidism was more common among MeanGS.E.M. calcium in these patients fell significantly from 3.2G0.05 to 2.6G women than men (68 vs 32%, PZ0.001) although there was not such a relation 0.08 mmol/l after up to a 16-week titration phase. The SF-36 scales are for subclinical hyperthyroidism (PZ0.919). With regard to comorbidities we standardized so that the general population mean is 50. The CF scale is scored could not find a significant relation between cardiovascular disease or from 0 to 100. Higher numbers indicate better HRQOL. Mean change from hypertension in both subclinical thyroid diseases (PO0.05). There was a slight baseline to end of the treatment phase for these patients was calculated for each increase of diabetes mellitus in subclinical hyperthyroid group (PZ0.08), scale. Numerically scores for all scales improved during treatment. For the SF-36, compared to subclinical hypothyroid group (PZ0.367). the gain ranged from 3.0 to 7.7 points. For the CF, it was 11.8 (Table).
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Previously, we demonstrated an inverse correlation between CoenzymeQ10 (CoQ10) and thyroid hormones, suggesting its usefulness as index of thyroid Mean (S.E.M.) Mean change from hormone tissue effect. A low-T3 syndrome, observed in chronic diseases, is score at baseline considered an adaptive mechanism and its treatment is still debated. To HRQOL scales baseline (95% confidence interval) evaluate the metabolic status of these patients and antioxidant vs energetic role of CoQ10, we studied 32 patients, with chronic obstructive pulmonary Physical functioning (PF) 34.3 (3.2) 4.6 (2.0, 7.2) disease (COPD), comparing respiratory indexes, thyroid hormones, CoQ10 Body pain (BP) 42.8 (3.1) 5.1 (0.7, 9.6) (also corrected for cholesterol levels) and Total Antioxidant Capacity (TAC) Role limitations-physical (RP) 35.0 (2.6) 3.3 (K1.1, 7.7) in patients with low (nZ12)ornormal(nZ20) fT3 concentrations. Another General health (GH) 40.9 (2.5) 3.0 (K2.3, 8.3) low-T3 model was represented by five patients studied after major heart Social functioning (SF) 36.7 (3.6) 6.9 (K2.1, 15.9) surgery (HS). Twenty-one normal subjects were studied as controls. CoQ10 Vitality (VT) 37.8 (2.6) 5.6 (K2.7, 13.8) were assayed by HPLC; TAC was determined using the system Role limitations-emotional (RE) 37.4 (3.4) 7.7 (0.6, 14.9) metmyoglobin-H2O2, which interacting with the chromogen ABTS generates Emotional well being (EW) 38.5 (3.3) 7.5 (K0.1, 15.1) a radical spectroscopically revealed; the latency time (Lag) in the Cognitive functioning (CF) 61.2 (5.7) 11.8 (K2.4, 25.9) appearance of radical species is proportional to the antioxidant content. CoQ10/Cholesterol ratio values were significantly higher in COPD with low- vs normal-fT3 (CoQ10: 0.88G0.06 vs 0.83G0.07 mg/ml; CoQ10/Cholesterol 239.7G28.5 vs 185.1G14.0 nmol/mmol, P!0.05); TAC showed opposite Treatment with cinacalcet may lead to improvement in HRQOL and pattern (54G6vs64G2 s). Similarly in post-surgical cardiac patients, all functioning in patients with PHPT who have failed parathyroidectomy or in exhibiting low values of fT3, CoQ10 levels were in the hypothyroid range whom surgery is contraindicated. Larger, randomized studies are needed to (CoQ10: 0.97G0.01 mg/ml; CoQ10/Cholesterol: 216.6G3.85 nmol/mmol) confirm these findings. despite the fact cardiac diseases are well known to be associated with low CoQ10. These data suggest that low fT3 levels are accompanied by indexes of true hypothyroidism in COPD and HS, supporting the need for replacement therapy. The different TAC pattern suggests that elevated CoQ10, despite P751 oxidative stress, expresses a reduced tissue utilization. Same aspects regarding immunohistochemical diagnosis of papillary thyroid carcinoma Ioana Zosin, Ioana Golu, Marioara Cornianu, Daniela Amzar & Melania Balas University of Medicine and Pharmacy ‘V Babes’, Timisoara, Romania.
The study evaluates the expression of same immunohistochemical (IHC) markers (Ki-67, PCNA, CK-19, HBME-1 and Galectin 3, in the diagnosis of differentiated P753 thyroid carcinomas. Material and methods Thyroid function and glucose tolerance in pregnancy: THYROMOBIL The study group comprised 57 patients with thyroid tumors; aged 17–71 years pilot study in Poland 1 1 (mean age 48.96 years). All cases were evaluated before surgical treatment by Zbigniew Szybinski , Grzegorz Sokolowski , Aleksandra Gilis- 1 1 1 means of clinical examination, thyroid ultrasonography and fine needle aspiration Januszewska , Alicja Hubalewska-Dydejczyk , Agnieszka Stefanska , 1 2 2 biopsy (FNAB). Monika Buziak-Bereza , Irena Kaim & Antoni Basta 1 IHC staining was performed (on formalin fixed paraffin-embedded tissue) in 37 Chair and Department of Endocrinology, Medical College, Jagiellonian 2 cases of papillary thyroid carcinoma – PTC (classical form, variants and University, Krakow, Poland; Chair and Department of Gynecology and microcarcinomas), 6 cases of follicular adenoma – FA, 4 cases of follicular Obstetrics, Medical College, Jagiellonian University, Krakow, Poland. thyroid carcinomas – FTC, 5 cases of neoplasia with uncertain malignant potential and 5 cases of Hurthle cell tumors (carcinomas and adenomas). Aim of the study was The obtained results were expressed semi quantitatively. 1. To assess the thyroid function in pregnancy in the course of effective iodine Results prophylaxis model introduced in 1997, based on obligatory salt iodization. All studied markers were expressed in the tumor cytoplasm, with no or weak 2. To exam glucose tolerance and insulinemia in pregnancy. expression in benign tumors and diffuse and strong in malignant ones. Methods Twenty-two cases with carcinomas were positive for Ki67 and 27 for PCNA. TSH, fT4, aTPO, urine iodine concentration, usg thyroid volume and CK19 was detected in all PTCs, 2/4 FTCs and 2/6 FAs. homogeneity, glucose and insulin during OGTT, blood pressure, BMI, and Galectin 3 expressed in 32/37 PTCs, all FTCs and 4/5 neoplasms with uncertain thyroid function and glucose metabolism family history questionnaire, use of malignant potential. HBME-1 showed a highly specificy for PTC. iodine supplements questionnaire were examined in healthy pregnant women Conclusions (npilotZ103, recruited from the patients of Department of Gynecology and HBME-1 and CK19 proved to be helpful markers in diagnosis of PTC.HBME-1 Obstetrics, pregnancy trimester I-37%, II-47%, III-16%) in THYROMIBIL helps the differential diagnosis between follicular variant of PTC (FVPTC) and FTC. action. Galectin 3 was helpful in the differential diagnosis between FTC and FA and in the Results diagnosis of tumors with uncertain malignant potential. Goiter prevalence was 3.1%. Solitary thyroid nodules and abnormal The combined use of HBMB1, Galectin 3 and CK19 seems to increase the specificity homogeneity were detected in 17.5 and 20.5% of pregnant women respectively. and diagnostic accuracy of the IHC method. TSH over 2.5 mj/ml, decreased fT4 and increased aTPO were detected in 18.7, 14.1 and 9.6% of probants respectively. Sixty percent of pregnant women supplemented diet with 150–200 mg of iodine, only 26% had no supple- mentation. Family history of thyroid dysfunction was observed in 28.9%. Increased fasting glucose was found in 5%, and impaired glucose tolerance was P752 observed in 3.3% of pregnant women. Mean fasting and after glucose load Low-T3 syndrome in chronic obstructive pulmonary disease and heart insulin was 12.1 mj/ml (S.D.Z12) and 37 mj/ml (S.D.Z22) respectively. surgery patients: evaluation of plasma antioxidant systems Increased systolic and diastolic blood pressure was found in 5.2 and 12.4% Antonio Mancini1, Giuseppe Maria Corbo2, Andrea Scapigliati3, of probants. Erika Leone1, Mirella Conti3, Gian Paolo Littarru5, Elisabetta Meucci4, Conclusions Laura De Marinis1 & Alfredo Pontecorvi1 In spite of obligatory model of iodine prophylaxis still high incidence of nodules 1Chair of Endocrinology, Catholic University of the Sacred Heart, Rome, in thyroid was observed. More than 70% of women had additional iodine Italy; 2Department of Respiratory Physiology, Catholic University of the supplementation. Sacred Heart, Rome, Italy; 3Institute of Anaesthesia and Intensive Care, Abnormal glucose metabolism and hypertension in pregnancy requiring medical Catholic University of the Sacred Heart, Rome, Italy; 4Institute of consultation was observed in more than 5% of women. Biochemistry of Clinical Biochemistry, Catholic University of the Sacred Our study confirms usefulness of THYROMOBIL model in assessment of thyroid Heart, Rome, Italy; 5Institute of Biochemistry, University ‘Politecnica delle function and glucose metabolism in pregnancy. Marche’, Ancona, Italy.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P754 half-life of 10.5 h. In comparison, tumoral accumulation of 188Re, which is also Interference in assay of thyroid hormones due to auto-antibodies transported by NIS, was 15%ID/g with a biological half-life of approximately 15 h and an effective half-life of 8.2 h. After administration of a therapeutic dose against thyroxine and triiodothyronine: report on two patients with 131 188 Hashimoto’s thyroiditis of 55.5 MBq, Ior Re NIS-expressing tumors showed an average tumor Oscar Moreno-Pe´rez1, Joaquin Serrano1, Rocio Alfayate2, Maite Lo´pez2, volume reduction of approx. 50 and 20%, respectively, while control tumors 1 1 2 continued their rapid growth exponentially. Sandra Martinez-Fuster , Nieves Arias , Monsrrat Mauri & Antonio 131 188 Miguel Pico´1 In conclusion, a significant therapeutic effect of Iand Re has been 1 demonstrated in melanoma cells following tyrosinase-promoter-directed NIS Department of Endocrinology and Nutrition, Alicante General University 131 Hospital, Alicante, Spain; 2Department of Hormone Laboratory, Alicante gene transfer in vitro and in vivo with higher efficacy of I. This study General University Hospital, Alicante, Spain. demonstrates the potential of NIS-mediated radionuclide therapy of melanoma following tumor-specific NIS gene transfer offering an innovative strategy for melanoma therapy.
TSH FT4 FT4 AAcT4 FT3 FT3 AAcT3 Sub-a SHBG (EQLA) (EQLA) (CMIA) (%125I-T4) (EQLA) (CMIA) (%125I-T3) (IRMA) (QLA)
1 25 2.3 0.9 57.3 3.6 3.22 31.8 0.5 75 2 98.4 3.08 0.55 67.5 3.16 1.53 10.4 0.68 59 nv 0.38– 0.8–2 0.7– !1.6% 1.8– 1.71– !2% 0–0.9 11–124 P756 4.84 ng/dl 1.48 4.6 3.71 mU/ml nmol/l mU/ml ng/dl pg/ml pg/ml The role of elevated microvessel density in the metastatic potential of papillary thyroid carcinoma Marioara Cornianu, Ioana Golu, Elena Lazar, Alis Dema, Sorina Taban, Simona Costi, Aurora Milos & Ioana Zosin Introduction University of Medicine and Pharmacy ‘V BAbes’, Timisoara, Romania. Characteristically the discordant thyroid function test has been attributed to TSH- producing hypophyseal adenoma, familial dysalbuminemic hyperthyroxinemia and thyroid hormone resistance syndrome. We presented 2 cases with raised Introduction peripheral thyroid hormones with detectable TSH due to the presence of The value of microvessel density (MVD) as a prognostic factor in thyroid auto-antibodies against the peripheral thyroid hormones (PTAAb). carcinomas, and its role in the development of metastasis, remain controversial. Subjects and methods Aim A 24-year-old woman (1) and a 79-year-old woman (2) with auto-immune Determination of the relationship between MVD, the histological subtype of PTC, primary hypothyroidism diagnosed 4 and 3 years ago, with symptoms and signs of the presence or absence of metastasis in cervical lymph nodes (LN), the clinical hypothyroidism and without levothyroxine treatment was referred to our recurrence of the disease and AMES prognostic index. centre after a finding of discordant thyroid function values (Table). Hormonal Material and method and radioimmunoprecipitation studies. Subunit-a was determined by IRMA The study included 32 patients with PTC (mean age of 48.8 years) divided into 2 q q (Immunotech de Beckman Coulter ), SHBG by QLA (Immulite 2000 (DPC ), risk groups, depending on AMES prognostic index. TSH was determined by EQLA, following series dilution (1/2, 1/5) of the sample. Tissue sections fixed in formalin 10% and paraffin-embedded were colored with Samples were sent to another laboratory for determination of TP by ‘two-step’ monoclonal antibody anti-CD31, clone JC/70A, using the LSAB technique and q immunoassay (CMIA, Architect (Abbott Lab ). TPAAb was determined by visualization with DAB. incubating samples with I125-T4 and I125-T3, followed by precipitation in Results polyethylene–glycol. Precipitate count was obtained using a gamma-counter We noted: 1) Classic PTC in 20 cases (62.5%), follicular variant of PTC (FVPTC) (Packard Cobra). Euthyroid patients with no auto-immune pathology were used as in 6 cases (18.75%), PTC with diffuse sclerosis (PTCDS) in 2 cases (6.25%) and controls. PTC with tall cells in 4 cases (12.5%); 2) 17% micropapillary carcinomas Results (%1cm f), 75% with f between 1 and 4 cm and 8% with fO4 cm; 3) The presence of PTAAb was detected in both cases (table), confirming the initial extrathyroid extension in 8 cases (25%), vascular invasion in 8 cases (25%), diagnosis of primary hypothyroidism. perineural invasion in 4 cases (12.5%), lymphatic invasion in 42% and Conclusion multicentric dissemination in 45%; 4) mean MVD of 84 (64–114) in PTC The presence of PTAAb is an unusual cause of discordant thyroid function values without LN metastasis and 104 in PTC with positive LN; 5) a higher mean MVD that it must have in mind to the correct management of thyroid disease. in FVPTC (independent of metastasis) compared with classic PTC (98 vs 84), PTC with tall cells (80) and PTCDS (68); 6) mean MVD of 84 in patients %45 years and of 93 in those O45 years; 7) slightly higher mean MVD in the group of patients with recurrences. Conclusions P755 Elevated mean MVD in PTC with LN metastasis and in patients with recurrent disease indicates the metastatic potential of these tumors; we did not note a Image-guided radionuclide therapy of malignant melanoma following relationship between MVD and the AMES prognostic index. tumor-specific sodium iodide symporter (NIS) gene transfer Michael Willhauck1, Anne Kessel1, Katrin Klutz1, Bibi Rana Sharif Samani1, Nathalie Wunderlich1, Franz Josef Gildehaus2, Christian Zach2, Carola Berking3, Richard Vile4, Burkhard Go¨ke1 & Christine Spitzweg1 1Department of Internal Medicine II, Ludwig-Maximilians-University, Munich, Germany; 2Department of Nuclear Medicine, Ludwig-Maximi- lians-University, Munich, Germany; 3Department of Dermatology, Ludwig- P757 Maximilians-University, Munich, Germany; 4Molecular Medicine Program, Thyroglobulin measurement in fine-needle aspirates of cervical lymph Mayo Clinic, Rochester, Minnesota, USA. nodes in diagnosis of metastic differentiated thyroid cancer Rocio Alfayate1, Alicia Lo´pez2, Sandra Martinez-Fuster2, Montserrat Mauri1, Oscar Moreno-Pe´rez2, Santiago Gil3, Pedro De la In its early stages, malignant melanoma can be cured by surgical resection, but Iglesia3, Antonio Cabezas4 & Antonio Miguel Pico´2 once it has progressed to the metastatic stage it does not respond to current 1Department of Hormone Laboratory, Alicante General University Hospital, therapies. Therefore, the development of novel treatment strategies, such as gene Alicante, Spain; 2Department of Endocrinology and Nutrition, Alicante therapy, is urgently needed. To investigate an alternative approach, we examined 3 131 188 General University Hospital, Alicante, Spain; Department of Radiology, the feasibility of NIS-mediated radionuclide therapy ( I, Re) of malignant Alicante General University Hospital, Alicante, Spain; 4Deparment of melanoma following human sodium iodide symporter (NIS) gene transfer using Pathology, Alicante General University Hospital, Alicante, Spain. a melanoma-specific tyrosinase-promoter construct to target NIS expression to melanoma cells. For this purpose, a human melanoma cell line (Lu1205) was stably transfected with hNIS cDNA under the control of the tyrosinase-promoter. Introduction The stably transfected Lu1205 cell line showed perchlorate-sensitive iodide Serum thyroglobulin (Tg) measurement is the marker of differentiated thyroid uptake activity which was sufficiently high for a therapeutic effect of 131Ias carcinoma (DTC) after total thyroidectomy, but its value is limited by the shown in an in vitro clonogenic assay. After injection of 18.5 MBq, 123I NIS- interference of anti-Tg antibodies (TgAb). Detection of Tg in fine-needle transfected Lu1205 xenografts in nude mice accumulated approximately aspiration biopsy (TG-FNAB) washout fluid is used recently to identify neck DTC 30% ID/g 123I with a biological half-life of approximately 11.1 h and an effective metastases, but the interference of TGAb-FNAB in the procedure is unknown.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Objectives processes involving eye balls. Changes in latency of P100 increased from 123 ms in To evaluate the utility of TG-FNAB for detecting cervical lymph node metastases mild, to 127 ms in intermediate, to 129 ms in intense GO. Referring to the control from DTC. To evaluate the presence of anti-Tg antibodies in this fluid. group a statistical change was observed in latency of P100 and N145. They were Patients and methods extended already in mild occurrence of GO which confirmed subclinical visual An ultrasound-FNAB was done in all patients with suspected recurrence or nerve involvement. metastasis of CDT treated at the Alicante General University Hospital since June Conclusions 2006 since November 2007. Tg and TgAb serum and liquid-FNAB was assayed VEP can be helpful in diagnosing visual nerve neuropathy in patients with GD. by chemiluminescent assays (IMMULITE 2000, Siemensq). The aspirated The clinical interpretation of changes of P100 latency is very important in patients material was cytologicaly examined and were reported by an experienced with GO. cytologist. Results: Table. Conclusions Tg-FANB could be a marker in the early diagnosis of DTC recurrent or metastatic. The clinical performance of Tg-FANB fluid appears to be not affected P759 by TgAb-FANB, on the observed data. Some data about the epidemiology of thyroid cancer in Albania Agron Ylli2, Zamira Ylli3, Entela Lamcaj2, Blertina Olldashi2, Medi Shehu4, 1 1 5 5 FANB washout fluid Serum Thanas Furreraj , Gerond Husi , Edmond Celiku , Medi Agolli , Arben Gjata5, Vladimir Titka6, Albert Nocka6 & Agim Karaj7 1 Tg TgAb Tg TgAb Department of Endocrinology, UHC ‘MOTHER TERESA’ Tirana, 2 3 (ng/ml) (UI/ml) (ng/ml) (UI/ml) Cytology Albania; Endocrinology Clinic Neo Style, Tirana, Albania; Department of Immunology, UHC ‘MOTHER TERESA’ Tirana, Albania; 4Department Group 1 3392 !5 !0.2 !5 Metastatic DTC of Anatomy – Pathology, UHC ‘MOTHER TERESA’ Tirana, Albania; nZ4 5Department of Surgery, UHC ‘MOTHER TERESA’ Tirana, Albania; 21 460 !51.1!5 Metastatic DTC 6Department of Nuclear Medicine, UHC ‘MOTHER TERESA’ Tirana, 1271 !50.3!5 Metastatic DTC Albania; 7Department of Oncology, UHC ‘MOTHER TERESA’ Tirana, 470 !50.8!5 Metastatic DTC Albania. Group 2 !0.2 !5 !0.2 6.2 No malignancy nZ4 !0.2 !5 !0.2 !5 No malignancy Introduction !0.2 !5 !0.2 6.8 No malignancy Aim: the aim of our study was to give some data about the epidemiology of !0.2 !5 !0.2 9.2 No malignancy thyroid cancer in our country. Group 3 !0.2 !5 0.3 13.1 Inadequate Material and methods nZ2 We studied patients diagnosed with thyroid cancer during January 1998–October !0.2 !5 !0.2 5.3 Inadequate 2007. Group 4 0.7 !5 18.1 9.3 No malignancy Results nZ2 We studied 179 patient from 13 to 80 years diagnosed with thyroid cancer 64 !5 16 20.3 No malignancy during January 1998–October 2007. Median age at dignoses was: 46.2G14.7 years. According to the gender: females were 139 (77.5%); males 40 (22.5%); ratio F/M 3.4: 1. Distribution according to the type were: papillary 95 (52.9%) folliculary 58 (32.7%) medullary 8 (4.4%) anaplastic 13 (7.2%) lymphoma 3 (1.7%) other type 2 (1.1%). Pre surgical diagnosis were: multinodular goitre 93 (51.9%); cold nodule 69 (38.8%); hot nodule 6 (3.5%); Graves disease 2 (1.1%); thyroiditis chronic Hashimoto 1 (0.5%); suspect thyroid cancer 7 (4%); lymphoma 1 (0.5%). Distribution according to the years of the study: cytological evaluation were done in 53 cases (29.60%) and the results were: negative 9 (16.9%); suspicious 13 (24.6); malignant 31 P758 (58.5%). Distribution of cases according to the years were: 1998 6 cases; 1999 13 cases; 2000 14 cases; 2001 14 cases; 2002 17 cases; 2003 16 cases; Visual evoked potentials in diagnosis of orbitopathy during the course 2004 12 cases; 2005 25cases; 2006 36 cases; 2007 25 cases. Distribution of Graves-disease according to the age group: 10–20 years old 7 cases 20–30 years old 18 Małgorzata Zgorzalewicz-Stachowiak1, Agata Czarnywojtek2, 1 3 3 cases; 31–40 years old 42 cases; 41–50 years old 37 cases; 51–60 years old Zuzanna Bartkowiak , Krzesislawa Komar-Rychlicka & Jerzy Sowinski 42 cases; O60 years old 33 cases. 1Laboratory of Medical Electrodiagnostics, Department of Health Prophy- 2 Conclusions laxis, Poznan University of Medical Sciences, Poznan, Poland; Chair and Thyroid cancer in Albania like in all over the world is increasing. There is a Department of Endocrinology and Metabolism, Poznan University of 3 female predominance 77.5% of thyroid cancer. Papillary type is the predominant Medical Sciences, Poznan, Poland; Outpatient Clinic of Ophthalmology, form 52.9% but the folliculary type has a high prevalence 32.7%, may be these is Poznan University of Medical Sciences, Poznan, Poland. related with iodine deficiency which predominate in our country. The most frequen presurgical diagnoses was multinodular goitre. In 2007, we had 4 new Graves disease (GD) is autoimmunological disorder leading most often to cases ages 13 years old. hyperthyroidism and invasive-edema opthalmopathy (Graves opthalmopathy – GO). Aim Estimation of the relation of visual evoked potentials (VEP) results with the indicators of activity and advancement of the progress of GO. Materials and methods P760 The examined group consisted of 45 patients between the age of 24 and 77, The influence of radioiodine therapy on some parameters of hospitalized in the Department of Endocrinology and Metabolism. Duration of GD oxidant/antioxidant balance in patients with subclinical from the first clinical signs to the start of treatment took between 3 months to 20 hyperthyroidism years. Changes of the eye due to GO occurred from 3 months to 6 years. VEPs were Saeid Abdelrazek1, Franciszek Rogowski1, Anna Zonenberg2, carried out according to recommendations of the International Federation of Malgorzata Szelachowska2, Adam Parfienczyk1, Agnieszka Nikolajuk2, Clinical Neurophysiology. Latencies and amplitudes of VEP components were Piotr Szumowski1, Emilia Wojno1 & Malgorzata Frackiel1 compared to normal values. 1Department of Nuclear Medicine, Medical University of Bialystok, Results Bialystok, Poland; 2Department of Endocrinology, Diabetology and Internal According to the NOSPECS scale 2 people showed no visual symptoms. In 5 cases, Medicine, Medical University of Bialystok, Bialystok, Poland. class 1 or 2 was diagnosed. Furthermore, in 38 patients classes between 3 and 6 were observed. Possible loss of vision due to visual nerve damage (class 6) was found in only 4 patients. The CAS criteria in 8 patients was equal to 0, and the Oxidative stress plays an important role in hyperthyroidism induced – tissue remaining 14 patients from 1 to 3. Active GO was diagnosed in 23 patients. In 35 damage. (77.8%) patients, abnormal VEPs were recorded. Normal parameters of VEP were We aimed to determine whether radioiodine therapy (RIT) has benefit effect on observed in only 10 (22.2%) patients. These were patients with inactive or mild the oxidant and antioxidant status in subclinical hyperthyroidism.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Material and methods reflects better socioeconomic status, although this was not identified. We studied 40 patients with untreated subclinical hyperthyroidism, (33 female, 7 Unrecognized subclinical hyperthyroidism probably due to thyroid autonomy is male), aged 23–78 years; 14 patients with multinodular goitre, and 25 patients quite common. with solitary autonomous nodule. Twelve normal adult volunteers as control group. Before the treatment all the patients has normal levels of serum fT3, fT4, low levels of serum TSH (!0.1 mU/l) and effective half-life was more than 3 days. Malignant changes were excluded in all nodules by fine needle P762 aspiration biopsy. In the investigated groups, we evaluate malondialdehyde (MDA) as a Case report: a case of diffuse large B-cell lymphoma presented by marker of oxidative stress, glutathione (GSH) and glutathione peroxidase instantaneous enlargement in a known thyroid nodule and diagnosed by (GPx) activity as a parameters of antioxidant system before and 6 months fine needle aspiration biopsy Bekir Cakir1, Reyhan Ersoy1,KamileGul1, Bulent Yalcin2, after RIT. 3 4 5 2 The serum fT4, fT3 and TSH were evaluated before and monthly up to 12 Birol Korukluoglu , Huseyin Ustun , Cemil Ekinci & Fikri Icli 1Department of Endocrinology and Metabolism, Ankara Ataturk Education months after RIT. Thyroid ultrasound, and thyroid scan were done before 2 131 and Research Hospital, Ankara, Turkey; Department of Oncology, Faculty and after12 months of I therapy. The activity dose was calculated by 3 Marinelli’s formula and ranged between 200 and 600 MBq. The absorbed of Medicine, Ankara University, Ankara, Turkey; Department of General dose ranged between 160 and 280 Gy. Surgery, Ankara Ataturk Education and Research Hospital, Ankara, Turkey; 4Department of Pathology, Ankara Education and Research Hospital, Results 5 Subclinical hyperthyroidism caused a significant increase in MDA level Ankara, Turkey; Department of Pathology, Faculty of Medicine, Ankara (P!0.05) as well as a significant decrease in GPx activities (P!0.05) and University, Ankara, Turkey. GSH level (P!0.05) compared to euthyroid controls subject. Achievement of euthyroidism after 6 months of radioiodine administration Primary thyroid lymphoma is an uncommon malignancy; it accounts for !2% of resulted in a significant decrease of MDA, significant increase of GSH and all extranodal lymphomas and !5% of all thyroid malignancies. non significant increase in GPx activities. Thyroid volume reduced to 45% Case report (average); 38 patient were in euthyroidism, two patients received 2 doses of A 52-year-old male patient who was known to have a nodule in his thyroid RIT. gland for many years presented with instantaneous enlargement of his Conclusions existing nodule and with appearance of ipsilateral cervical lymphadeno- Our results confirm the imbalance of the antioxidant/oxidant status in pathy. On thyroid ultrasonography, a giant nodule of 38.4!31.6!45.5 mm subclinical hyperthyroidism. RIT was more effective to improve these balances. size, and containing macro and microcalcifical areas was detected in the left lobe. In the ipsilateral anterior cervical region, a lymphadenopathy with ultrasonographically malign appearance, in size of 23.4!15.6!32 mm was observed. The patient was euthyroid in laboratory findings and his thyroglobulin and calcitonin values were in normal ranges. As cytomorpho- logical appearance was consistent with anaplastic carcinoma in ultrasono- graphy-guided aspiration biopsies of thyroid nodule and lymphadenopathy, immunohistochemical staining was performed for differential diagnosis of lymphoma. Diffuse large B-cell lymphoma cells showing CD20 involvement P761 were seen in cytological specimens. The histological specimens of the Thyroid volume, selenium levels and nutritional habits in Southwestern patient who underwent total thyroidectomy and cervical neck dissection Albania were examined. While normal thyrocytes were detected in thyroid gland, John Doupis2, Katerina Saltiki1, Emily Mantzou1, atypical lymphoid cells showing diffuse infiltration in thyroid tissue were Antonios Mastrokostopoulos2, Charalambos Stavrianos1 & observed in the nodule, which were stained diffuse, strongly positive for Maria Alevizaki1 CD20 and BcL and negative for CD45 RO. In the lymph node, diffusely 1Department of Endocrinology, Metabolism and Diabetes, Evgenideion infiltrating atypical lymphoid cells with similar immunohistochemical Hospital, Athens University School of Medicine, Athens, Greece; 2Military staining properties were observed. According to Revised European– Hospital of Gyrocaster, Gyrocaster, Albania. American Classification of Lymphoid Neoplasms, the diagnosis was diffuse large B-cell lymphoma. The patient was accepted as stage I-EB. Rituximab, Doxorubucin, cyclophosphamide, vinciristine, and prednisone chemotherapy Introduction was started. We introduce the case in order to emphasize that infiltration of Aim: it is known that environmental factors are involved in the development of diffuse large B-cell lymphoma should be recalled with instantaneous goiter. A high number of goitrous patients was identified among patients enlargement of nodules known to be benign previously, and when attending the general medicine outpatients’ in a mountainous region in Albania. cytological specimen is uncertain, immunohistochemical staining should be We examined possible associations of thyroid enlargement with nutritional performed for differential diagnosis. factors. Methods One hundred and twelve consecutive patients (mean age 52.8G12.1, 104 female) attending the outpatients of the General Military Hospital of Gyrocaster, Southwestern Albania, who either took thyroxine (nZ27) or were suspected to have thyroid disease based on symptoms and physical examination were studied. Thyroid parameters and selenium levels were determined. The P763 type and frequency of food consumption was recorded; thyroid ultrasound was Case report: percutaneous laser ablation (PLA) to a functional performed. euthyroid autonomous thyroid nodule, and histopathologic effects of Results PLA on nodule after thyroidectomy at 2nd year of procedure Thyroid volume was above median (20.35 ml) in 51% of patients. Thyroid Bekir Cakir1, Kamile Gul1, Serdar Nevzat Ugras2, Reyhan Ersoy1, volume correlated negatively with the frequency of lamb and goat meat and Oya Topaloglu1, Tuba Agac1, Cevdet Aydin1, Ahmet Dirikoc1, vegetables consumption (PZ0.01). Mean thyroid volume was significantly lower 3 4 4 O G G ! Mehmet Gumus , Birol Korukluoglu & Ahmet Kusdemir in those eating lamb or goat 1 times a week (21.4 13.3 vs 31.9 23, P 0.01). 1Department of Endocrinology and Metabolism, Ankara Ataturk Education There was no association between current selenium levels and thyroid volume. and Research Hospital, Ankara, Turkey; 2Department of Pathology, Ankara All consumed food was home produced. The association of thyroid volume with Ataturk Education and Research Hospital, Ankara, Turkey; 3Department of lamb meat consumption was independent of sex, educational status or occupation Z ! Radiology, Ankara Ataturk Education and Research Hospital, Ankara, (P 0.004, multivariate analysis). Forty-three percent had TSH 0.3 mU/ml Turkey; 4Department of General Surgery, Ankara Ataturk Education and (those on thyroxine were excluded). In this group, log TSH correlated negatively Research Hospital, Ankara, Turkey. with thyroid volume and fT4 levels (PZ0.008), indicating the presence of autonomy (TSHRab found positive in two subjects). Conclusions Objective Nutritional factors appear to be involved in the development of goiter in Percutaneous laser ablation (PLA) is a new procedure utilized to decrease nodule Southwestern Albania. No role of selenium deficiency was found. The higher volume in symptomatic thyroid nodules, to provide euthyroidism in autonomous consumption of lamb and goat meat and vegetables, all non-industrialized, hyperfunctioning nodules, and to decrease compressive symptoms palliatively in appears to be protective. One cannot exclude the possibility that this finding malignant nodules. Standard treatment in autonomous thyroid nodules is
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 radioiodine and surgery. In this report, we aimed to present this case to Radioiodine (131I) administration has been found to be effective in the demonstrate changes in nodule histopathology, which was undergone thyroid- treatment of hyperfunctioning and normofunctioning multinodular goiter. ectomy two years after PLA procedure. Moreover, lithium therapy has been shown to enhance the radioiodine Case report efficacy and to reduce the transient thyrotoxicosis induced by radioiodine. We applied PLA in a 25-year-old woman with euthyroid solitary autonomous Aim of the present study was to evaluate the long term efficacy of 131I with thyroid nodule due to compression symptoms. A total of 3000 J of energy was or without lithium administration in the treatment of non toxic multinodular applied in 600 s with a power of 5 W in single session. Initial nodule volume was goiter (NTMG). Eighty patients without thyroid auto-antibodies were 13.50 ml, which regressed to 4.20 ml within 6 months. However, nodule size randomized into two groups: # 1, treated with con I131C lithium began to grow at 9th month, and became 6.50 ml in 1 year. Nodule volume (900 mg/die for 6 days) and # 2, treated with 131I alone. The 131I activity increased to 10 ml at second year of procedure, and compression symptoms (MBq) was calculated according to thyroid volume (TV) (222–600 MBq, reappeared. Thyroidectomy was performed two years after PLA. Macro- with a mean dose/patient of 555 MBq). Ultrasonography and biochemical scopically, thyroidectomy material revealed a white–gray area at the procedure analyses were evaluated before and 1, 3, 6, 12 and 24 months after 131I. A site. Microscopically, there was minimal fibrosis, scarce amounts of old mean thyroid volume reduction of 49% was observed at two years of hemorrhagic findings, and multiple microfollicular structures containing colloid follow-up without significant differences between the two groups. Forty-five in their lumen. Lymphocyte infiltration was observed in thyroid tissue patients were re-evaluated after a longer follow-up (41–70 months). Thyroid surrounding the nodule. volume further decreased (mean reduction: 50.7%) in 61% of these patients, Conclusion and remained unmodified in the remaining cases, without significant We did not observe any histopathologic effect of laser on thyroid tissue except differences between the two groups. A permanent hypothyroidism was lymphoid infiltration. This is the most important histopathologic finding diagnosed in 21.4% of patients during the first two years of follow-up, indicating that PLA procedure was a minimally invasive and reliable technique. without differences between the 2 groups; no additional patients developed These are the first long-term data of histopathologic effects of PLA in a benign hypothyroidism in the following 3 years of follow-up. thyroid nodule which tended to re-grow after procedure. According to these data, In conclusion, present data confirm the efficacy of 131I in the treatment of PLA application on thyroid nodules is considered safe in long-term. non toxic goiter. The maximum thyroid volume reduction was achieved 2 years after the therapeutic administration and no relapse was observed in the following years. Permanent hypothyroidism developed in about 20% of cases during the first 2 years of follow-up. The association with lithium treatment neither enhanced the efficacy to 131I treatment nor influenced the development of permanent hypothyroidism. P764 Clinical features and outcome of papillary thyroid cancers !2cm: univariate and multivariate analyses Michela Perrino1, Guia Vannucchi1, Leonardo Vicentini2, Davide Dazzi3 & Paolo Beck Peccoz1 1Endocrine Unit and Department of Medical Sciences, University of Milan and Ospedale Maggiore IRCCS, Milan, Italy; 2Endocrine Surgery Unit, 3 Ospedale Maggiore IRCCS, Milan, Italy; Internal Medicine Unit, Ospedale P766 di Fidenza, Fidenza, Italy. Higher prevalence of nodular goiter and thyroid carcinoma in patients with familial adenomatous poliposis (FAP) An increasing prevalence of papillary thyroid carcinomas (PTC) of small size Lucia Zirilli1, Stefania Romano1, Bruno Madeo1, Cesare Carani1, have been recorded in recent years. These tumors have a favorable outcome in Piero Benatti2, Maurizio Ponz De Leon2, Luca Roncucci2 & most cases, and total thyroidectomy without radioiodine therapy is suggested for Vincenzo Rochira1 microcarcinomas (defined as %1 cm). The 6th edition of the TNM staging system 1Chair of Endocrinology, Integrated Department of Medicine, Endo- for thyroid cancers includes in the T1 category tumors %2 cm, limited to the crinology, Metabolism and Geriatrics, University of Modena and Reggio thyroid. Aim of the present study was to evaluate the clinical/pathological Emilia, Modena, Italy; 2Clinic of Internal Medicine, Department of Internal features and the outcome of 251 patients with PTC dividing them into 2 groups Medicine, University of Modena and Reggio Emilia, Modena, Italy. according to tumor size (A: %1cm, nZ156; B: O1%2cm, nZ95). No differences between the 2 groups were observed in the mean follow-up (70G44.2 and 66G44.2 months), in the age at the diagnosis (47.5G13.7 and 44.7G16.2), in FAP is a dominant autosomic syndrome, due to mutation of the APC the gender (female in 68 and 61% of cases, respectively) and in the multicentricity oncosuppressor gene, characterised by adenomatous polyps at the colon–rectal (58 and 54%). A higher prevalence of incidentally discovered carcinomas was level, that progres to malignant degeneration. FAP extraintestinal manifestations found in group A compared to group B (P!0.0001), while lymphnode metastases include, although rare, the thyroid nodules and tumours. Neck ultrasound (US) is and extracapsular invasion at surgery were significant more frequent in group B routinely useful to identify thyroid nodules, but the characterisation of their nature (PZ0.02 and P!0.0001, respectively). Concerning the outcome, no significant requires the cytology by a FNAb. The exact incidence of the thyroid tumours on differences were found between the 2 groups, and in particular disease remission FAP syndrome is unknown. was observed in 90% of patients of group A and 84% of patients of group B. Aim When multivariate analysis was applied to all tumors smaller than 2 cm, disease To evaluate the prevalence of thyroid nodules and tumours in a group of FAP persistence/recurrence resulted to be associated with multicentricity, lymphnode patients. metastases at diagnosis and extracapsular invasion (PZ0.02, PZ0.01, PZ0.04, Subjects and methods respectively), but not with tumor size. Forty-six consecutive FAP outpatients (25\–54%, 21 _–46%; mean age 46.76G In conclusion, T1N0 unicentric tumors has a favorable outcome independently DS 13.96 years) underwent neck US. The lesions above 5 mm of diameter from the tumor size (%1cmorO1 and %2 cm) and should be treated with a non- underwent FNAb. The control group was of 599 subjects who underwent FNAb aggressive approach, avoiding radioiodine ablation. because of thyroid nodules. Results From the 41 FAP patients included in the study, 18 (43.9%) (13\,5_) showed thyroid nodules. The FNAb was performed on 12 FAP patients with thyroid nodules (66%; 8\,4_): 2\ (16.67%; mean age 34.05 years) had a diagnosis of papillary thyroid carcinoma. From the 599 FNAb of the control group 23 (3.8%) P765 had a diagnosis of thyroid carcinoma (6_-1% and 17\-2.8%; mean age 48.88G DS 14.83 years). A prospective study on a large series of non toxic multinodular goiters Conclusion treated with radioiodine: results at long term follow-up The nodular goiter is very common in FAP (43.9%). Furthermore, cytology at Guia Vannucchi1, Deborah Mannavola1, Arturo Chiti2, Davide Dazzi3, 2 2 1 FNAb highlights as the prevalence of thyroid tumours is higher in FAP group Marcello Rodari , Sara Tadayyon , Paolo Beck-Peccoz & (16.67%), also when compared with a control group, selected from a iodine Laura Fugazzola1 1 deficient area with an high incidence for thyroid carcinoma (3.8%). These data Department of Medical Sciences, Fondazione Ospedale Maggiore IRCCS, show a possible correlation between the two diseases and suggest the need for a Milan, Italy; 2Nuclear Medicine Unit, Istituto Clinico Humanitas, Rozzano, 3 careful follow-up of thyroid lesions in patients with FAP, by means of both neck Italy; Department of Internal Medicine, Ospedale di Fidenza, Fidenza, US and FNAb. Italy.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P767 Conclusions Case report: subcapsular hematoma complication during percutaneous T3 increase in ID areas gives adaptation possibility. Increased sensitivity to TSH laser ablation (PLA) to a hypoactive benign solitary thyroid nodule, and may occur when ID is present. This explains relatively high, though normal, TSH literature review of PLA- related complications levels in pts with large goiter. Bekir Cakir1, Kamile Gul1, Reyhan Ersoy1, Oya Topaloglu1, Tuba Agac1, Cevdet Aydin1, Ahmet Dirikoc1, Mehmet Gumus2, Birol Korukluoglu3 & Ahmet Kusdemir3 1Department of Endocrinology and Metabolism, Ankara Ataturk Education and Research Hospital, Ankara, Turkey; 2Department of Radiology, Ankara P769 Ataturk Education and Research Hospital, Ankara, Turkey; 3Department of General Surgery, Ankara Ataturk Education and Research Hospital, Ankara, The influence of chronic GH excess upon thyroid gland morphology Turkey. evaluated by ultrasound Catalin Buzduga, Teodora Emiliana Ananie, Simona Mogos, Eusebie Zbranca, Corina Galesanu, Voichita Mogos & Dumitru Objective D Branisteanu Ultrasound (US) guided percutaneous laser ablation (PLA) is a new procedure University of Medicine and Pharma, Gr.T.Popa, Iasi, Romania. utilized to decrease nodule volume in symptomatic thyroid nodules, to provide euthyroidism in autonomous hyperfunctioning thyroid nodules, and to decrease It is known that thyroid pathology is generally more frequently found in women than compressive symptoms palliatively in malignant nodules. Standard treatment in men. The somatotroph axis stimulates skeleton growth, but also the development protocol in symptomatic benign hypoactive thyroid nodules is surgery, if needed of smooth tissues, including the thyroid gland. We investigated the effect of chronic LT4 suppression, and radioiodine treatment in certain applications. We applied GH excess upon ultrasound-evaluated (7.5 MHz linear probe) thyroid gland PLA to 42-year-old male patient with 16.8 ml volume solid hypofunctioning morphology of 74 patients (40 women s¸i 34 men) diagnosed with acromegaly. benign thyroid nodule. When compared to mean thyroid volume of age- and sex-matched non-acromegalic Case report controls, mean thyroid volume was found to be significantly increased in both male The procedure was planned to inferior and superior parts of the nodule. First and female acromegalic patients (24G8.8 vs 13.2G6.1 ml for males, 23.4G10.2 vs application to inferior part of nodule was performed in single session with 3 W 10.7G7.9 ml for females and 23.9G8.9 vs 11.1G3.2 ml for the whole group, power, and 720 J was applied in 240 s. Control US images after the procedure P!0.05 at t-test). The incidence of goiter (defined as thyroid volume of over 20 ml in showed formation of subcapsular hematoma in inferior anterior part of nodule. females and over 25 ml in males) and of thyroid nodules was higher in female than in Although patient had no complaints like dysphagia, dyspnea, or pain, 2nd part of male controls (5.5 vs 2.4% for goiter and 13 vs 4% for nodules, P!0.05 at the c2 procedure was cancelled. Patient was closely monitored in coordination with test). Goiter incidence was much higher in acromegalic patients (56% in acromegalic surgical team. Hematoma was absorbed largely within 48 h. It disappeared women vs 5.5% in healthy age and sex matched controls and of 43% in acromegalic completely at first month. men vs 2.4% in healthy controls, P!0.0001). The incidence of thyroid nodules was Conclusion again high both in acromegalic females (40 vs 13% in controls) and males (33 vs 4% Various complications have been reported after diagnostic and therapeutic in controls, P!0.005). No correlation between GH levels and thyroid volume or interventions to thyroid nodules. Cervical pain, hoarseness due to laryngeal nodular volume was found. IGF-1 was assessed only in a minority of our study group. injury, and hematoma are most frequent of these. PLA is applied as one of non- The only parameter correlated to the thyroid volume and to the incidence of thyroid surgical treatment methods in treatment of solid thyroid nodules in recent years. nodules observed in our group was the length of disease evolution (P!0.05). We did Pain, hoarseness, fever, and hyperthyroidism have been reported as complications not notice the appearance of thyroid neoplasias or of nodular autonomy in our after PLA in several case series, but hematoma has not been, up to now, reported patients. Chronic GH excess increases thyroid volume and nodule incidence both in as a complication of PLA. We considered publication of this case report because women and men, attenuating sex differences in thyroid morphology. development of subcapsular hematoma after PLA was not previously reported in literature.
P770 New mutations demonstrate intracellular iodine retention in Pendred P768 syndrome Thyroid size and thyroid function in children from iodine deficiency MER Garcia-Rendueles1, SB Bravo1, F Palos2, J Cameselle-Teijeiro3, regions B Czarnocka4, L Dominguez-Gerpe2, J Lado-Abeal2 & CV Alvarez1 Nino Abdushelishvili, Marine Gordeladze, Zurab Sekhniashvili & 1Department of Physiology, University of Santiago de Compostela, Santiago Marina Svanidze de Compostela, Spain; 2Unidade de Enfermedades Tiroideas e Metabo´licas Pediatric Clinic of the State Medical University, Tbilisi, Georgia. (UETeM), Department of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain; 3Department of Pathology, Complejo Hospitalario Universitario de Santiago (CHUS)-SERGAS, Santiago de Background and aims Compostela, Spain; 4Department of Biochemistry, Medical Centre for Diffused endemic goiter (DEG) development is not always explained by Postgraduate Education, Warsaw, Poland. increased TSH levels. Most DEG patients (pts) have normal TSH concentrations, with tendency to decreased T4 and normal or slightly elevated T3. In the present study levels of thyroid hormones (TH) in pts with various degrees of thyroid size Pendred syndrome is an autosomal recessive disorder with congenital- (TS) and weak iodine deficiency (ID) were analyzed. sensorineural deafness and goiter due to mutations in SLC26A4, that encodes a Material and methods transmembrane protein, Pendrin. In thyrocytes, Pendrin is proposed to act at the In total DEG 137pts, aged 2–16 years were studied: 100 girls (g) (73%), 37 boys apical pole to transport intracellular iodide into the follicular lumen. (b) (27%). TH-T3, T4, TSH were measured. Results were compared using A Galician Pendred compound heterozygous patient was studied; a c.297delT in Student’s criterion (t-test). For each pt ultrasound was performed and antithyroid exon 3 and a new splicing-mutation c.416-1G!A were found, introducing antibodies (TPO-Ab, Tg-Ab) were measured. For palpation assessment of TS premature stop codons in the protein. WHO classification (1980) was used. TS ultrasound data were compared to upper A thyrocyte primary cell-line, T-PS2, was obtained from the patient and volume limit (ml) in iodine sufficient areas (WHO-IDD Control International compared with primary thyroid lines from our BANTTIC (Bravo Oncogene 2003, Council, 1997). Thyroid volume increase expressed as percentage and palpation Bravo Clin Cancer Res 2005). NT (normal thyrocytes) and T-PS2 have similar results were compared and summarized: IA–increase from 0 to 10%, IB – from 10 epithelial appearance, with follicle-like structures and expressed thyroglobulin. to 50%, II – from 50 to 100%, III – above 100% increase. By western-blot, NT and T-PS2 showed similar levels of plasma-membrane NIS Results (NaC/IK symporter), while only NT showed high levels of plasma-membrane Hashimoto thyroiditis was excluded based on TPO-Ab, Tg-Ab. Sixteen pts, pendrin. Confocal immunofluorescence localized Pendrin in NT at a spot near the (g12/b4) with hypothyroidism (3 pts) and subclinical hypothyroidism (13 pts) nucleus, Golgi location, and in narrow lines typical of plasma-membrane were excluded T3 levels compared in pts with IB and III TS, were evidently higher localization. Opposite, in T-PS2 Pendrin positivity was located exclusively in in pts with III TS (2.43G0.12 and 3.18G0.14 nmol/l, P!0.001). Significant Golgi, indicating retention of truncated proteins. difference in T3 levels between IB, II TS was not observed. Besides there was no Iodine-uptake measurements were performed. Steady-state uptake was 3-times significant difference in T4 levels while comparing various TS. TSH was evidently higher in T-PS2 than in NT. Time-course uptake in NT showed a fast uptake higher in pts with large goiter both in IB – II and IB – III TS (2.13G0.2 vs 3.59G followed by a plateau after 5 min onward; T-PS2 showed a progressive increase in ! G G ! 0.54 mUI/ml, P 0.05 and 2.13 0.2 vs 3.49 0.35 mUI/ml, P 0.001). iodide level till 30 min; Vmax was twice as high in T-PS2.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Efflux was fast for NT: at 15 min all radioactivity had effluxed while 40% still revealed a high positive predictive value (PPV) of 92% for pattern 1 in the diagnosis remained intracellularly in T-PS2. of HT. The high negative predictive value for pattern 4 (82.73%) suggests that a We used dose–response curves to study Michaelis-Menten iodine-uptake kinetics. macronodule is rarely associated with HT. In GBD, pattern 5 had a medium PPV After 5 min, T-PS2 had already reached a Km similar to that described for NIS at (42%). Changing echographic pattern in evolution suggested that in HT, the pattern equilibrium (22G4.8 mM). Opposite, NT only achieved equilibrium after 1 h of changed in only 12 patients (2.5%). In subacute thyroiditis, the echographic shape incubation. changed suddenly from day to day. In GBD, in 24 patients without Hashimoto In summary, normal thyrocytes behave as a complex system with two opposite association (75%), the echographic shape changed from pattern 5 to quasi-normal transporters (NIS and Pendrin) that reach equilibrium slowly. Pendred thyrocytes (pattern 7), after 3–5 years. In IM, no change was registered. Only 25 benign nodules accumulate iodine through NIS, although iodine leaves the cell inefficiently through (2.5%) improved and changed their shapes. No changes were observed for malign other non-specific transporters. nodules during follow-up prior to surgery (1–6 months). Conclusions It seems that thyroid echography is performed 3–4 times more than needed.
P771 Thyroid hormone replacement using a combination of levothyroxine plus slow-release liothyronine: beyond proof of principle P773 Gerald JM Tevaarwerk Surprising: hyperlipidemia in subclinical hyperthyroidism! University of Western Ontario, London, Ontario, Canada. Ljiljana Marina, Svetlana Vujovic, Miomira Ivovic, Milina Tancic-Gajic, Milos Stojanovic, Marija Barac & Milka Drezgic Institute of Endocrinology, Diabetes and Metabolic Disorders, Belgrade, Objective Serbia. To assess if adding slow-release liothyronine (SR-T3) to levothyroxine (l-T4)reduces persistent hypothyroid symptoms and signs on replacement with l-T4 alone. Design Subclinical hyperthyroidism is a biochemical diagnosis defined with suppressed Open label, two-period cross-over, cohort comparison. The main outcomes were levels of TSH and normal levels of thyroid hormones. One of the main metabolic changes in the serum T3 concentration and residual clinical hypothyroid indicants. responses to thyroid hyperfunction is peripheral lipolysis and release of free fatty Each study period was 10 weeks. The sample size required was determined to be 9 acids (FFA). The aim of this study was to compare levels of cholesterol, LDL, HDL patients. and triglycerides in persons with subclinical hyperthyroidism to age and BMI Subjects matched euthyroid healthy control. We evaluated 45 persons in two groups: 1st Three men and 15 women, aged 31 to 72, with primary, autoimmune group: 30 patients (26 women and 4 men) with subclinical hyperthyroidism, mean hypothyroidism who had persistent hypothyroid indicants in spite of normal or age 49.13G10.21 years, mean BMI 25.18G4.04 kg/m2, with laboratory proven suppressed thyroid stimulating hormone (TSH) levels on l-T4 alone entered the subclinical hyperthyroidism. Second group: 15 healthy euthyroid controls, mean age study after giving informed consent. 49.40G9.84 years, mean BMI 23.74G4.09 kg/m2. None of them had a history of Methods coronary heart disease, signs of liver and/or renal dysfunction or were previously Subjective clinical indicants, scored as ordinals from 0 to 3, and objective clinical treated withlipid lowering drugs.Statistical analysis was performed with t-test. In the and biochemical indicants measured on a numerical scale, were compared during 1st group, mean cholesterol level was 6.15G1.10 mmol/l, mean LDL level was treatment with l-T4 alone to treatment with l-T4 plus SR-T3 titrated to an increase in 4.08G0.96 mmol/l, mean HDL level was 1.46G0.49 mmol/l and mean triglycerides the serum T3 of 0.50 pmol/l. level was 1.71G0.57 mmol/l. In the 2nd group, mean cholesterol level was 5.38G Main outcome 1.03 mmol/l, mean LDL was 3.16G0.68 mmol/l, mean HDL level was 1.37G Adding an average of 13 (range 5–20) mgperdayofSR-T3 elevated the serum T3 by a 0.37 mmol/l and mean triglycerides level was 1.29G0.55 mmol/l. There was a significant average (95% CI) of 0.80 (0.60–1.00) pmol/l. The mean clinical significant difference in levels of cholesterol (P!0.05; PZ0.035) and triglycerides hypothyroid indicant score (95% CI) of 13.9 (10.8–17) on monotherapy, fell by a (P!0.05; PZ0.0034) and the difference in LDL was high (P!0.01; PZ0.005). significant average of 10.8 (9.0–12.6) (84 (70.3–97.3) percent) to 3.3 (0.9–5.5). The There was no difference in HDL levels (PO0.05; PZ0.55). The clinical presentation T4/T3 ratio fell significantly from 4.0 (3.7–4.3) to 3.5 (3.1–3.7). There were no of subclinical hyperthyroidism is quite subtle which points to not so high metabolic significant changes in the initial mean l-T4 dose of 88 (74–102), or mean TSH of 1.5 rate of this condition and no real metabolic need for utilization of released FFA’s. (0.9–2.1) mU/l and T4 of 16.3 (15.2–17.4) pmol/l. No patient exhibited evidence of This may be the possible explanation for unexpected and surprising result of over-replacement. hyperlipidemia in subclinical hyperthyroidism. Conclusion Treating primary, autoimmune hypothyroid patients with persistent hypothyroid symptoms and signs using a combination of l-T4 plus SR-T3 resulted in a significant rise in the serum T3 level and decrease in the persistent hypothyroid indicants. P774 The variation intercellular adhesion molecule-1 level in primer and postoperative hypothyroid patients with treatment P772 Mesut Ozkaya1, Erman Cakal2 & M Fatih Yuzbasioglu3 Usefulness of thyroid echographic pattern description: predictive value 1Department of Endocrinology and Metabolism, Sutcu Imam University at onset and in the evolution of thyroid diseases Medical Faculty, Kahramanmaras, Turkey; 2Department of Endocrinology Dan Peretianu1, Daniela Cristea Staicu1 & Mara Carsote2 and Metabolism, Yuksek Ihtisas Hospital, Ankara, Turkey; 3Department of 1SCM Povernei, Bucharest, Romania; 2Department of Endocrinology, Carol General Surgery, Sutcu Imam University Medical Faculty, Kahramanmaras, Davila University of Medicine and Pharmacy, Bucharest, Romania. Turkey.
Objectives Background and aims The study of the real indications for thyroid ultrasound and in which pathological It is reported that intracellular adhesion molecule-1 (ICAM-1) is important in conditions the echography is of real use and not for abuse. autoimmune thyroid diseases also it is an important point that ICAM-1 level is highin Material and methods postoperative hypothyroid cases. In literature, it is said that the level of plasma In the last 10 years, over 13 000 echographies were performed in 5136 soluble ICAM-1 can be used as a evidence immune system activation and consecutive patients for ‘thyroid disturbances’. In a previous paper we described inflammation, and also it can be used for the diagnosis of some inflammatory and 7 echographic patterns for thyroid ultrasound (9th ECE). The diagnosis of autoimmune diseases. The aim of our was to compare the level of ICAM-1 in Hashimoto’s thyroiditis (HT) was considered if antithyroperosidase antibodies hypothyroid cases who have different ethiologic origins and was to investigate the (ATPO) were above 34 IU/ml. Idiopathic myxedema (IM) was considered if among treatment variation. hypothyroidism was not associated with HT. Graves–Basedow disease (GBD) Material and methods was based on positive TSH receptor antibodies (TRAB). Sixteen primer hypothyroidism, 16 postoperative hypothyroidism, totally 32 female Results patients were chosen for the study and also 16 healthy, no past and familiar disease Diagnostic at onset: normal thyroid was found in 3489 cases, HT in 487 cases, and were chosen as a control group. The patients who have type 2 diabetes, who have GBD in 94 cases from whom 65% had an overlap between ATPO and TRAB. inflammatory and infectious disease and smokers were left from this group when Subacute thyroiditis occurred in 13 cases, IM in 34 cases, benign nodules in 1009 it’s diagnosed in patients and control groups and when the level of TSH is normal patients and malign nodules in 10 cases. The echographic description at onset biochemical fast parameters and level of ICAM-1 was calculated.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Results suggest that FNAC no need to be used as routine line of investigation fort he Primer hypothyroid, postoperative hypothyroid and control groups were diagnosis of thyroid nodules in cases of pulmonary tbc. approximately similar for age (38.6G7.3, 38.0G7.3, 40.6G6.3). And also body mass index was similar in patient and control groups the level of beginning ICAM-1 level in postoperative hypothyroid patients was found higher than control group (46.6G10.7, 27.1G2.3, P!0.001). When two hypothyroid group were compared the level of ICAM-1 was found really high in primer hypothyroid group (46.6G P777 10.7, 39.4G5.1, P!0.05). In both groups, the level of euthyroid ICAM-1 was Hypothyroidism due to primary hypotriiodothyronaemia: a case report found very high than the beginning datas (46.6G10.7, 51.3G10.5, P!0.001, Gerald JM Tevaarwerk 39.4G5.1, 45.3G6.8, P!0.001). University of Western Ontario, London, Ontario, Canada. Conclusion ICAM-1 level can be used for investigating hypothyroid cases. The level of ICAM- 1 is increasing in hypothyroid cases with the treatment. The level of ICAM-1 can be Objective used as a effectiveness parametria in hypothyroid cases. Report of hypothyroidism due to primary hypotriiodothyronaemia caused by a deficiency in peripheral generation. Design Case report and computer modelling. Main outcome P775 A 28-year-old woman presented with hypothyroid symptoms and delayed ankle Tuberculosis of the thyroid gland: the chameleon of thyroid pathology reflex relaxation times. She was not on any medications. The average thyroid Eusebie Zbranca, Dumitru D Branisteanu, Veronica Zbranca, Vera Pencea, stimulating hormone (TSH) concentrations was 2.5 (N: 3.8–5.5 mU/l), free Gioconda Dobrescu, Voichita Mogos, Corina Galesanu, thyroxine (T4) 12.3 (N: 10.5–20 pmol/l) and free triiodothyronine (T3) 3.15 (N: Stefania Hurmuzache & Anca Zbranca 3.50–6.50 pmol/l). Pituitary and hypothalamic hypothyroidism and secondary University of Medicine and Pharmacy, ‘Gr.T.Popa’, Iasi, Romania. causes of the low T3 syndrome were ruled out. The reverse triiodothyronine (rT3) was 180 (N: 120–540 pmol/l). Serum selenium and iodine levels were normal. Tuberculous thyroiditis is a very rare disease. Its clinical features are non-specific in The log/linear plot of the TSH versus T4 values and suppression of TSH to sub- most of the cases, mimicking other thyroid diseases. Confusions most frequently physiologic levels at mid-normal T4 concentrations, suggested a hyper-sensitive made are those with thyroid cancer and toxic nodular goiter. Therefore, diagnosis TSH-negative feedback mechanism. Computer modelling of the initial thyroid often comes as a histopathological surprise, after thyroid ablation for other reasons. hormone levels and their response to L-thyroxine replacement was most Thyroid tuberculosis was diagnosed histopathologically in six out of 1232 cases of compatible with a 30% primary decrease in peripheral type 2 deiodinase activity, thyroid surgery. Preoperatory diagnosis was of toxic nodular goiter in two cases, and and a 2% compensatory decrease in T3 inactivation, occurring in the presence of of thyroid carcinoma in the other four. We diagnosed other two cases of thyroid an extra sensitive TSH-negative feedback mechanism. tuberculosis out of 2291 nodular goiters investigated by FNAB. The two patients Conclusion were initially suspected of thyroid carcinoma and acute bacterial thyroiditis, The patient’s hypothyroidism was due to a deficiency in peripheral T3 generation respectively. Axillary lymph node biopsy in the first case showed the presence of caused by a primary deficiency in type 2 deiodinase activity, most likely as the giant epithelioid cell granulomas, with evolution toward caseous necrosis. Signs of result of a mutation in the gene coding for the enzyme. inflammation accompanied by caseation were found in thyroid aspirates in both subjects. Lo¨wenstein culture allowed the isolation of mycobacterium tuberculosis. Fine needle aspiration biopsy allows establishing the diagnosis before surgical intervention. Presence of epithelioid granulomas with necrosis and of acid-fast P778 bacilli in the aspirate is very specific. When central caseous necrosis is present, the thyroid lesion is highly suspectable of being tuberculous even in the absence of Hashimoto’s encephalopathy: a rare cause of status epilepticus 1 2 3 cellularity. Further culture of the biopsy product on special media is then mandatory. Mahamood Edavalath , Mark Cossburn & Aled Rees 1 Preoperatory diagnosis of thyroid tuberculosis may modify the therapeutic attitude. Centre for Endocrine and Diabetes Sciences, University Hospital of Wales, Cardiff, UK; 2Department of Neurology, University Hospital of Wales, Cardiff, UK; 3School of Medicine, Centre for Endocrine and Diabetes Sciences, Cardiff University, Cardiff, UK. P776 Background Is thyroid tuberculosis actually not rare? Hashimoto’s encephalopathy is a rare steroid-responsive condition associated M Fatih Yuzbasioglu1, Mesut Ozkaya2, Erman Cakal3, Harun Ciralik4, 5 2 with high antithyroid antibody titres. We report a case of autoimmune thyroiditis Nazan Okur & Kadir Gisi presenting with status epileptics. 1Department of General Surgery, Sutcu Imam University Medical Faculty, 2 Case Kahramanmaras, Turkey; Department of Endocrinology and Metabolism, A 36-year-old non-epileptic Caucasian lady presented as an emergency with Sutcu Imam University Medical Faculty, Kahramanmaras, Turkey; 3 uncontrolled generalised seizures requiring sedation, short-term ventilation and Department of Endocrinology and Metabolism, Yuksek Ihtisas Hospital, maintenance sodium valproate therapy. Further enquiry revealed a 3–4 week Ankara, Turkey; 4Department of Pathology, Sutcu Imam University 5 history of personality change, loss of memory and easy fatiguability, and a 1 week Medical Faculty, Kahramanmaras, Turkey; Department of Radiology, history of facial twitching. She had no previous history to suggest an underlying Sutcu Imam University Medical Faculty, Kahramanmaras, Turkey. tendency to seizures and her past medical history was unremarkable. There was a family history of autoimmune thyroid disease. Physical examination was normal Background and aim but higher mental functions were significantly impaired (initial Addenbrooke’s Thyroid gland is considered to be rare site of extrapulmonary tuberculosis (tbc), cognitive examination (ACE) score 74/100). even in countries with a high prevalance. The aim of this study is to ases the Investigations revealed normal full blood count, clotting, ESR, liver and renal function, correlation between thyroid nodules and pulmonary tbc with fine needle calcium and glucose. Anti-nuclear antibodies were detectable at 1:100 but anti- aspiration cytology (FNAC) and to find out the incidence of thyroid gland tbc. dsDNA, ENA and ANCA were all negative. CT scan of the head was normal as was a Material and methods subsequent MRI including a T1 coronal volume sequence. The EEG showed no focal The main purpose of this study is to find out tbc incidence in pulmonary tbc abnormalities. Cerebrospinal fluid protein was marginally raised but no organisms patients with thyroid nodules. FNAC is a rapid and minimally invasive approach were seen and culture was negative. Anti-voltage gated potassium channel antibodies to diagnose extrapulmonary tbc and has been used successfully in thyroid and anti-neuronal antibodies were negative. Thyroid function tests showed normal FT4 malignancies. Thyroid function tests and ultrasonography (USG) investigations of 15.8 pmol/l and raised TSH of 30.23 mU/l; anti-TPO antibodies were markedly were carried out an each patient. FNAC is carried out patients who had solid or elevated (O1300 kU/l; normal !60). She was treated with thyroxine replacement, dominant nodule in multinodular ones via USG. pulsed methylprednisolone and maintenance high-dose oral prednisolone. Her Results memory improved markedly with a rise in ACE score to 86/100 at discharge. The present study included 596 cases of pulmonary tbc of which 201 cases had Discussion solid or multible nodules. Majority of 201 of 596 patients were in the age group of Although seizures are a well-recognised feature of Hashimoto’s encephalopathy, it is 18–72. Mean age was 40.16 with male to female ratio of 1:1.093. Except one, rarely considered in the differential diagnosis of epilepsy. Our case illustrates the none of the patients diagnosed n tbc in thyroid nodule. importance of thyroid function assessment in patients with unexplained status Conclusion epilepticus and reinforces the value of high dose corticosteroid therapy in the The incidence of tbc increasing worldwide, the unusual presentation of treatment of Hashimoto’s encephalopathy. extrapulmonary tbc presents a diagnostic challenge. The findings of this study
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P779 P781 Thyroid function is associated with insulin sensibility Iodine status in pregnant women: do they have sufficient information Anna Volkova, Elena Grineva & Svetlana Dora about the importance of iodine nutrition during the pregnancy? St-Petersburg Medical University named I.P.Pavlov, Saint-Petersburg, Amparo Marco, Almudena Vicente, Enrique Castro, Barbara Ca´novas, Russian Federation. Julia Sastre, Eva Cruces, Esther Maqueda, Marı´aLo´pez Iglesias & Jose´ Lopez Lopez Virgen de la Salud Hospital, Toledo, Spain. Thyroid disease is associated with atherosclerosis cardiovascular disease. This is undoubted for overt hypothyroidism, but is controversy in subclinical hypothyroidism hittle is known about the relationship between insulin resistance The recommended nutrient intake (RNI) for iodine during pregnancy has been and thyroid function. It is well known that insulin resistance is the main part of re-evaluated in 2005 by an international expert committee under the auspices of metabolic syndrome. We aimed to investigate the relationship between thyroid the World Health Organization (WHO). The consensus reached was that the RNI function, body mass index (BMI) and homeostasis model assessment index for for iodine during pregnancy should range between 200 and 300 m/d with an insulin resistance (HOMA-IR) in patients with heart ischemic disease. average of 250 m/d. Methods To asses the adequacy of the iodine intake during pregnancy in a population, Seventy-three patients were included in our study. Heart ischemic disease was urinary iodine concentration (UIC) should be measured. UIC should ideally range confirmed by the results of coronarography. We studied age, gender and BMI of between 150 and 250 m/l. our patients. Fasting blood samples were taken for measuring of TSH level, Objectives glucose and insulin concentration. HOMA-IR was calculated as fasting insulin To identify the current state of iodine nutrition in pregnant women using UIC and (mU/l) times fasting glucose (mmol/l) divided by 22.5. Patients with diabetes to estimate the level of information about the importance of iodine requirements were excluded from the study. in pregnancy. Results Patients and methods Middle age of our patients was 57.23G0.48 years, BMI was 28.23G230.19 kg/m2 We studied a cohort of 185 pregnant women, average age 31.7G5.0 years, and TSH level was 2.61G0.74 IU/l. In accordance with BMI all patients were gestational age 26.9G5.6 weeks, we asked them about the use of de iodized salt divided in 3 groups: I – normal weight, II – weight abudance, III – obesity. TSH and supplements in the form of potassium iodine or multivitamin tablets level was reliable higher in patients with obesity (3.05G1.14 IU/l) and weight specifically designed for pregnancy and too about their knowledgments related to abundance (2.73G0.26 IU/l) than in group with normal weight (1.52G0.34 IU/l) the importance of iodine intake. We considered UIC adequate 150–250 m/l, mild (PZ0.02 and 0.01). Age was nearly the same in all groups. HOMA-IR was the deficiency 160–100, moderate 100–50, severe !50, more than adequate 250–500 highest in the group of obesity (4.67G1.12). In group I and II, HOMA-IR was and excessive O500 m/l. statistically lower: 1.30G0.26 and 1.52G0.74 (PZ0.002 and 0.05). Results Conclusion The median UIC was 143 m/l. In 53.2% was !150 m/l (28.5% mild, 23.1% In patients suffering from heart ischemic disease and obesity, TSH level and moderate and 1.6% severe deficiency), 25.8% had an adequate UIC, 16.1% more HOMA-IR index were statistically higher than in patients with normal weight. than adequate and 4.8% excessive. About 74.2% ingested tablets, 56.5% used We can propose that thyroid hormones may participate in mechanisms of iodized salt. Only 21.5% had received information by health personal and 11.3% peripheral insulin resistance. in published information. About 50% of pregnant women with UIC!150 m/d didn’t consume iodized salt (P!0.05), 35% didn’t ingested oral supplements (P!0.05) and 87.6% hadn’t received information (P!0.05). Conclusions (1) Pregnant women studied had mild deficient UIC. (2) The proportion of P780 pregnants that declare use oral supplements or idoized salt is elevate but in near 50% the state of iodine nutrition is insufficient. (3) The information about the Severity of coronary atherosclerosis in patients with different TSH importance of iodine nutrition during pregnancy is scarce. levels Anna Volkova, Elena Grineva & Svetlana Dora St-Petersburg Medical University named I.P.Pavlov, St-Petersburg, Russian Federation.
Subclinical hypothyroidism (SH) is very frequent condition in older population. If can occur in 12–20% of patients older than 60. It is well known today that thyroid hormones can increase gene expression of APO-B receptors in the liver and by this way improve catabolism of atherogenic lipoproteins. They also can regulate P782 processes of contractility and weakening of heart muscle. Decrease of cardiac Is Graves’ disease the most frequent immune association with output and diastolic disfunction of left ventricle can be revealed in SH patients. So Hashimoto thyroiditis? even mild thyroid failure can promote the development and progression at heart Catalina Poiana1, Dan Peretianu2, Mara Carsote1 & ischemic disease. Results of coronarography (CG) can reliable reflect the severity Larisa Ionescu Calinesti2 of coronary atherosclerosis. It seems to us very important to compare results at 1Department of Endocrinology, Carol Davila University of Medicine and CG with TSH level of heart ischemic disease patients. Pharmacy, Bucharest, Romania; 2SCM Povernei, Bucharest, Romania. Methods Four hundred and eighty-nine patients participated in our study. In all patients, CG was performed by standart methodology of Judkins et al. We studied age, Aim gender, body mass index of patients, their smoking history, genetic predisposi- To re-evaluate the prevalence of autoimmune associations in Hashimoto’s tion. Fasting blood samples were taken for measuring of TSH level by reagent of thyroiditis (HT). third generation. Subjects and methods Results The study was performed on 469 consecutive patients with HT and 536 without. There were 77.4% of men and of men and 22.6% of women. Middle age was The diagnosis of HT was based on an antithyroperoxydase antibodies (ATPO) 56.53G0.41 years. BMI was 27.23G0.17 kg/m2; TSH level was 2.53G0.30 IU/l. level above 34 IU/ml. The subjects were evaluated for other associated immune 2 In 9.5% of patients, SH was revealed (TSH level was more than 4.0 IU/l), in 5.8% diseases. The statistical analysis used the c test. of cases TSH level was !0.5 IU/l, which characterize. SH was revealed in 15.8% Results of women and 6.7% of men. There was positive correlation between TSH level Fifty-seven patients with HT (z12%) associated one or more immune diseases. and BMI in all patients (PZ0.008; rZ0.127) and TSH level and age in women The most important associations were: chronic hepatitis in 13 cases (22%), (PZ0.043; rZ0.143). Multivessel damage of coronary vessels correlated with vitiligo in 9 patients (17%), Biermer anemia in 6 cases (11%), rheumatoid arthritis man gender, age, duration of smoking, genetic predisposition, hypertension and in 5 cases (9%), diabetes mellitus type I (IDDM) in 3 patients, immune vasculitis diabetes mellitus and TSH level more than IU/l (PZ0.041, rZ0.172). The trunkal in 2 cases. In the control group 8.3% of cases had an immune disorder. These were damage of left coronary artery was also associated with elevation of TSH level. In mainly: 16 cases with rheumatoid arthritis, 7 with hepatitis, 4 vitiligo, 3 systemic patients with SH trunkal damage was revealed in 38% of cases, when in patients lupus erythematosus, IDDM, bronchic asthma, 2 cases with vasculitis and 2 with normal TSH level only in 19.3%. psoriasis. c test (one degree of freedom) Z3.09, PZ0.079. 60 patients with Conclusion increased ATPO (with HT) presented also hyperthyroidism with Graves- In heart ischemic disease patients, SH was associated with women gerder, Basedow’s disease (GBD). Prevalence was about 25%. Immune associations elevation of BMI and severity of coronary atherosclerosis. (other than GBD) did not modify the echographic and functional patient phenotype.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Discussions and lactacystin diminished the growth inhibitory effect of proEGFcyt and In our previous paper (9th ECE), we found a prevalence of immune associations reversed the down-regulation of EGF receptor proteins suggesting an in HT of 15.8% compared with 5.19% in the control group. Now, in the control involvement of the ubiquitin-proteasome system. Microarray analysis of FTC- group we found more immune diseases. If increased ATPO levels (acting through 133-proEGFcyt clones revealed a strong downregulation of the ubiquitin antibody-dependent cellular cytotoxicity) mean HT and increased thyroid C-terminal hydrolase-L1 (UCH-L1), thus, identifying proEGFcyt as a new stimulating immunoglobulins (acting at receptor level) mean GBD, then it is regulator of this de-ubiqitinating enzyme. Silencing of UCH-L1 gene activity and obvious that there could be two distinct concomitant immune thyroid diseases. the absence of UCH-L1 protein was exclusively observed in proEGFcyt and Conclusions proEGF22.23 FTC-133 transfectants but absent in proEGFdel23 and mock Contrary to those expected and already communicated, in HT immune controls implicating a possible involvement of exon23 encoded peptide of associations seem not to be higher than in controls, but the most common proEGFcyt. Westernblot analysis of total ubiquitinated protein revealed immune association in HT is GBD. significantly increased levels of cellular ubiquitinated proteins in proEGFcyt and proEGF22.23 transfectants. Specific knockdown of UCH-L1-containing proEGFdel23 and mock clones resulted in reduced EGFR protein levels similar to proEGFcyt and this decrease in EGFR was prevented in the presence of MG132. In summary, we present evidence for a novel and unique mechanism for the growth inhibitory actions of proEGFcyt in human thyroid Ca cells. We identified proEGFcyt as a new regulator of the de-ubiquitinating enzyme UCH-L1 and P783 demonstrate that proEGFcyt-mediated silencing of UCH-L1 causes the decrerase in EGFR likely as a result in post-translational hyperubiquitination of EGFR in Effects of thyroid-stimulating hormone suppression with levothyroxine human thyroid Ca cells. These findings may have important implications for the in reducing the volume and prevention the growth of solitary thyroid design of new treatments particularly of undifferentiated thyroid cancer. nodules Vesna Mijailovic, Milan Mijailovic & Dragan Micic Institute for Endocrinology and Metabolism, Belgrade, Serbia.
Suppressive therapy with thyroxine is the standard conservative treatment for solitary benign thyroid nodules. However, factors which may influence the response to treatment remains controversal, as well as the risc of thyroxine P785 administration. Isolated ACTH deficiency as a cause of impaired well-being in patients We prospectively evaluated the effects of twelve months thyroid-stimulating with primary hypothyroidism hormone suppression with Levothyroxine (L-T4) in reducing the volume of Gwendolyn Bender1, Claudia Cromme1, Stefanie Hahner1, Wiebke Arlt2, benign solitary nodules, and the effects of reduced serum TSH level on both Markus Luster1, Nicole Reisch3, Martin Reinke3 & Bruno Allolio1 cardiovascular system and bone loss in postmenopausal women. All of 52 patients 1Endocrinology and Diabetes Unit, Department of Medicine l, University of were prescribed individual Thyroxine in a dose to keep TSH levels 0.3–0.5 mU/l. Wuerzburg, Wuerzburg, Germany; 2Division of Medical Sciences, School Clinical, laboratory, ultrasographic, cytological features of the nodules, were of Medicine, University of Birmingham, Birmingham, UK; 3Medizinische assessed before treatment, in three months interval, and after 12 months. Bone Klinik - Innenstadt, Ludwig-Maximilian-University, Munich, Germany. mass density was measured before treatment and in one year interval in postmenopausal woman. Cardiovascular parameters (BP, heart rate), and ECG were monitoring during 1 year period. The therapy was effective in 25.6% Objective persons. In 5.76% persons nodules showed evolution, and in 74.4% persons there Isolated ACTH-deficiency (IAD) is considered a rare autoimmune endocrino- was no significant change during 1 year period. In group of responders, the mean pathy most frequently associated with autoimmune thyroid diseases (ATD). We reduction of volumen of nodules was 19%, homolateral lobus 6.4% and have previously diagnosed IAD in four patients with primary hypothyroidism and contralateral 3.5%. The best answer on therapy showed younger persons with negative TPO antibodies. The aim of this study was to determine the prevalence colloid nodules. There were no adverse cardiovascular manifestations during 1 of undiagnosed IAD in patients with ATD. year therapy. Subclinical hyperthyroidism in postmenopausal woman did not Methods result in accelerated bone loss. We studied 45 patients with ATD on stable L-thyroxine replacement (dose range In conclusion, we found suppressive L-T4 therapy in selected patients can be 50–350 mg) and 17 healthy subjects (Group A). Fourteen of 45 ATD patients were effective in reducing solitary thyroid nodule volume, and there is no risk of the negative for TPO antibodies; self-reported well-being was impaired in 31 (Group administration of thyroxine in 1 year period. B) and normal in 14 (Group C). All patients underwent adrenal function assessment by a low dose 1 mg short synacthen test; a peak !18 mg/dl was considered as evidence of impaired corticotrophic function and followed up by further investigations. In addition, all patients completed the SF-36 questionnaire. Results Peak serum cortisol did not differ significantly between groups (group A: 22.8G 3.2 mg/dl, group B: 25.2G4.8 mg/dl, group C 23.0G3.9 mg/dl). Subjective health status according to SF-36 correlated well with self-reported well-being (Group B P784 versus C). The analysis of individual SST responses revealed that one patient with Growth inhibitory actions of human proepidermal growth factor a peak cortisol of 14.5 mg/dl had failed the short synacthen test; she was TPO cytoplasmic domain (proEGFcyt) are mediated by the ubiquitin- positive and had complained about impaired well-being. Further work-up with a proteasome system in human thyroid carcinoma cells 250 mg short synacthen test and an ITT confirmed IAD and she was started on Aleksandra Glogowska1, Ekkehard Weber3, Marek Los2, Cuong Hoang-Vu4, hydrocortisone replacement. Intriguingly, in group C baseline ACTH and cortisol Thomas Klonisch1 & Thomas Klonisch5 levels were significantly lower than in controls (all P!0.01) albeit within the 1Department of Human Anatomy and Cell Science, Winnipeg, Manitoba, normal range, potentially indicating subtle impairment of corticoptrophic Canada; 2Manitoba Institute of Cell Biology CancerCare Manitoba, function. Winnipeg, Manitoba, Canada; 3Department of Physiological Chemistry, Conclusions Halle/Saale, Germany, Germany; 4Clinics of Surgery, Halle/Saale, Isolated ACTH deficiency may be more common than previously recognized in Germany; 5Medical Microbiology and Infectious Diseases, Winnipeg, patients with autoimmune hypothyroidism and impaired well-being, warranting Manitoba, Canada. larger studies to define the actual prevalence of IAD in ATD.
The cytoplasmic domain of the membrane-anchored human EGF proform is encoded by exons 22–24 and the function of this proEGFcyt is largely unkown. Stable transfectants of the human thyroid carcinoma (Ca) cell line FTC-133 were generated over-expressing (a) proEGFcyt, (b) truncated peptide version encoded by exons 22 and 23 (proEGF22.23), and (c) a natural splice version with a deletion of exon 23 and 24 (proEGFdel23). ProEGFcyt and proEGF22.23 P786 transfectants, but not proEGFdel23 or mock clones, demonstrated a significant From elimination to sustainable control over iodine deficiency in reduction in growth rates. This coincided with a marked post-translational Bulgaria 1997–2006 reduction in EGFR and ErbB2 protein levels in proEGFcyt and proEGF22.23 Iva Stoeva clones. Incubation of these transfectants with the proteasome inhibitors MG132 University Pediatric Hospital Sofia, Sofia, Bulgaria.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Iodine deficiency (ID) and ID disorders (IDD) are a global problem. ID P788 elimination would significantly contribute to achieving at least 6 of the 8 Hurthle cells tumors of the thyroid: personal experience at the Regina millennium developmental goals. Elena Cancer Institute, Rome (Italy) Aim Agnese Barnabei, Roberto Baldelli, Giuseppe Pasimeni & To adapt the Neonatal thyroid screening (N?S) based on TSH with a view to its Marialuisa Appetecchia applicability as a permanent indicator in monitoring the effect from the iodine Unit of Endocrinology, Regina Elena Cancer Institute, Rome, Italy. prophylaxis of IDD in Bulgaria. Hurthle cell carcinoma (HCC) represents about 5% of differentiated thyroid Tasks carcinomas. When Hurtle cell represents more than 75% of cells population, To study: 1) dependence of TSH on age after birth; 2) influence of perinatal the lesion can be considered a Hurthle cell tumor (HCT); it can be classify application of iodine-containing desinfectants on TSH concentration in newborn as malignant when capsular or vascular invasion is reported or if there is a children (NB);) TSH – distribution prospectively; 4) commercially available perithyroid infiltration or distant metastases occur. Aim of this study was to iodized salt according to the new state standard (KIO3 28–55 ppm) and its O present our own experience on the clinical and pathological features of relation to the percentage of TSH 5 mU/l. patients (pts) affected by HTC that can predict disease progression and death. Material and methods Age, disease stage, tumor size, extra glandular invasion, lymph-nodes TSH analysis (Delfia) from NTS of 619 898 NB from all over Bulgaria (1997– disease, distant metastases, extensive surgery, radioiodine therapy and 2006) by specially designed software for registering each screened NB. The TSH ! external beam radiation therapy as factors potentially associated with concentration of 5 mU/l in 3% of NB was used as a sign of iodine repletion decreased survival were evaluated for all patients. We have identified 28 (WHO proposal). pts affected by Hurthle cell tumor, 9 with HCA and 19 with HCC (22 F, 6 Statistics: SPSS 10. M) mean age of HCT pts. was 49.7 years (30–72 years) versus 49.3 years Results (15–72 years) of HCC. In all pts, a total thyroidectomy was performed. At Obvious, significant dependency of TSH on age/inversely proportional/and the hystology were found 9 adenomas, 5 ‘minimally invasive’ and 14 invasive application of iodine-containing desinfectants/directly proportional. The carcinomas. Average size of primary tumor was: 28.8 mm medium diameter percentage of NB in Bulgaria with TSH O the suspicious for congenital ! in HCT versus 25.8 mm in HCC. None patients had lymph-nodes metastases. hypothyroidism (cutoff 15 mU/l) rapidly decreased (1.8–0.09%; P 0.0001). HCC patients TNM staging showed 9 patients stage I, 5 stage II, 4 stage III The relative share of NB on L-thyroxine treatment increased from 25 to 70%. 131 O ! and 1 stage IVa (UICC 2002). All invasive carcinomas underwent I The significant reduction of NB with TSH 5 mU/l and levels 3% (first therapy (91–150 mCi). One HCC patient received external beam radio- time in 2006) was accompanied by previous stable, sustainable increase of therapy. The average follow-up period was 62 months (range 6–324). In none iodized food grade salt above 90%. of our cases, with adenoma a relapse was observed. Only one HCC patient Conclusion showed distant lung metastases at 60 months of follow up. In conclusion, Universal salt iodization is an effective strategy for ID elimination. Bulgaria has HCC was not found to have an aggressive behaviour. None of HCT showed reached the first stage of sustainable control over ID. NTS, after thorough a relapse ?daptation, might be a useful instrument in monitoring the effect of programmes for securing optimal iodine supplementation at population level among the most sensitive to ID individuals represented by the NB.
P789 Radioiodine therapy in patients with toxic nodular goitre Saeid Abdelrazek1, Franciszek Rogowski1, Anna Zonenberg2, Adam Parfienczyk1, Malgorzata Szelachowska2, Maria Gorska2, P787 Piotr Szumowsk1, Emilia Wojno1, Malgorzata Frackieli1 & Should we look for metabolic syndrome (MSy) in subclinical Urszula Karpinska1 hypothyroidism? 1Department of Nuclear Medicine, Medical University of Bialystok, Milka Drezgic, Ljiljana Marina, Miomira Ivovic, Milina Tancic-Gajic, Bialystok, Poland; 2Department of Endocrinology, Diebatology and Internal Milos Stojanovic, Marija Barac & Svetlana Vujovic Medicine, Medical University of Bialystok, Bialystok, Poland. Institute of Endocrinology, Diabetes and Metabolic Disorders, Belgrade, Serbia. The aim of our study was to assess the effectiveness of radioiodine therapy (RIT) on the achievement of euthyroidism and reduction of thyroid volume, in patients Subclinical hypothyroidism is a biochemical diagnosis defined with elevated with toxic nodular goitre (TNG). levels of TSH and normal levels of thyroid hormones. The most common Material and methods abnormality linked to this condition is hypercholesterolemia. The aim of this During the last 7 years, we treated 3800 patients with TNG, aged 30-70 years; study was to search for MSy among the persons with subclinical hypothyroidism 82% female and 18% male; 2200 patients with multinodular goitre (MNG) and which was already proven to have hypercholesterolemia when compared to 1600 with autonomous toxic nodule (ATN); thyroid volume ranged between 16 healthy control. MSy was identified in those with elevated triglycerides (Tgc), and 130 ml (30% with thyroid volume O60 ml). reduced HDL and elevated fasting glucose. We compared each of these Qualification of these patients were based on clinical features, characteristic parameters as well as the presence of MSy in patients with subclinical appearance on thyroid scans and ultrasound. Malignant changes were excluded in hypothyroidism to age and BMI matched healthy control. We evaluated 60 all nodules by fine needle aspiration biopsy. All the patients had serum TSH levels persons in two groups: 1st group: 38 patients (35 women and 3 men) with below 0.1 mU/l and effective half-life more than 3 days at the time of treatment. subclinical hypothyroidism, mean age 48.63G9.88 years, mean BMI 26.19G The activity dose was calculated by Marinelli’s formula and ranged between 200 6.17 kg/m2, with laboratory proven subclinical hypothyroidism. Second group: 22 and 800 MBq. The absorbed dose (Gy) ranged between 150 and 260 for MNG, healthy euthyroid controls, mean age 49.14G10.32 years, mean BMI 26.67G and 200-300 for ATN. Follow-up control was done every 6 weeks. Thyroid 4.57 kg/m2. None of them had a history of coronary heart disease, signs of liver ultrasound, and thyroid scan were done before and after12 months of RIT to and/or renal dysfunction or were previously treated with lipid lowering drugs. assess RAIU, volume of thyroid gland and nodules. Repeated RIT was given after Statistical analysis was performed with t-test and Mann–Whitney U-test. In the 6 months of the first dose if needed. 1st group, mean Tgc level was 2.22G1.74 mmol/l, mean HDL level was 1.23G Results 0.45 mmol/l and mean fasting glucose level was 5.21G0.92 mmol/l. In the 2nd After 4 years of follow-up, the success of treatment was: 97% of patients with group, mean Tgc level was 1.36G0.42 mmol/l, mean HDL was 1.39G ATN and 92% of patients with MNG achieved euthyroidism. Three percent of 0.35 mmol/l and mean fasting glucose was 4.63G0.41 mmol/l. There was a patient with ATN and 8% of patient with MNG develop hypothyroidism. Thirty- high statistical difference between the level of tgc between the groups (P!0.01). four patients with toxic MNG and 5 patients with ATN received more than one For the level of fasting glucose, there was a statistical difference (P!0.05). For dose of RIT. Thyroid volume reduced to 52% in MNG and 47% in ATN. the levels of HDL and the overall presence of MSy between the groups there was Conclusions no statistical difference (PO0.05). Eventhough there was no difference in HDL The achievement of euthyroidism and the remission of the symptoms and signs of levels and no difference in the overall presence of MSy between the groups we clinical hyperthyroidism, were due to well preparation of the patients; accurate think that along with hypelipidemia MSy is something to think about in measurement of administered activity, relatively high effective half-life, and well- subclinical hypothyroidism. organised follow-up.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P790 P792 A case of thyroid abscess due to piriform sinus fistula complicated by Serum ghrelin levels in thyroid dysfunction and its change with hyperthyroidism treatment Somda Frederic, Desbiez Fancoise, Mom Thierry, Thieblot Philippe & Zu¨leyha Karaca1, Ilhan Yetkin2 & Murat Yilmaz3 Tauveron Igor 1Department of Endocrinology and Metabolism, Erciyes University Medical CHU, Clermont Ferrand, France. School, Kayseri, Turkey; 2Department of Endocrinology and Metabolism, Gazi University Medical School, Ankara, Turkey; 3Department of Endocrinology and Metabolism, Bilim University Medical School, Istanbul, Acute suppurative thyroiditis is a rare disease because thyroid gland is highly Turkey. resistant to infection. The most common predisposing factor is the presence of a piriform fistula. We report an unusual case of hyperthyroidism caused by AST. Aim A 27-year-old woman was admitted to our hospital because she presented a In this study, we aimed to detect the serum Ghr levels in hypo and hyperthyroid painful swelling in the left thyroid gland with fevers. Laboratory test showed patients at the time of diagnosis and after treatment in comparison with an age-, a white leukocyte count of 14 000/ul, a CRP level of 251 mg/l, a thyrotropin and sex-matched control group. level of 0.1 mUI/l, a T4 level of 41 pmol/l. A neck computed tomography Materials and methods scan revealed an abscess in the thyroid gland and the presence of a piriform Thirty-two hypothyroid, 19 hyperthyroid and 30 control subjects were included in sinus fistula. After appropriate antibiotic therapy and propanolol adminis- the study. Basal levels of serum free T3, free T4, TSH, anti-thyroid peroxidase tration, the patient underwent fistulectomy and resection of the left upper lobe (anti-TPO), anti Tg antibodies were measured by commercially available kits in of her thyroid gland. The thyroid function became normal approximately one all patients and control group hypothyroid patients were treated with month after. levothyroxine, patients with Graves’ disease were treated with methimazole So the clinical feature of thyroid abscess includes hyperthyroidism. It can be and propranolol, patients with thyroiditis were managed with propranolol only. evocated before AST because some cases of thyrotoxicosis have been Patients were followed for three months. Serum free thyroid hormone levels and described and can complicated surgery. TSH were measured at the first and the third months of the treatment. Serum levels of Ghr were measured at the time of diagnosis, at first and the third months in patients with thyroid dysfuntion. Serum IGF-1 levels were determined at the time of diagnosis and following 3 months of treatment. Results Serum Ghr levels in hypothyroid patients were lower than the control group at the time of diagnosis and decreased more following treatment. Serum Ghr levels in hyperthyroid patients were lower than the control group at the time of diagnosis, but did not normalize after euthyroidism was achieved. No statistically significant correlation was detected between Ghr and patient age, BMI, free T3 or TSH. P791 There was not a significant correlation between Ghr and pretreatment free T4 Cognitive dysfunctions during chronic thyrotropin-suppressive therapy levels in both patient groups and the control group, but Ghr was negatively with levothyroxine in patients with differentiated thyroid carcinoma correlated with posttreatment free T4 at the first and the third month in both Katarzyna Lacka1, Aleksandra Kucharska2, Aleksandra Rajewska-Rager2 & patient groups. Jan Jaracz2 Conclusion 1Department of Endocrinology, Metabolism and Internal Medicine, Poznan, Ghr is affected in thyroid dysfunction which may be directly due to the effects of Poland; 2Department of Adult Psychiatry, Poznan, Poland. free thyroid hormones or due to the secondary weight changes or both. But further studies are warranted to determine the net effect of thyroid hormones on Ghr.
Background TSH-suppressive therapy is widely used in treatment of thyroid differentiated carcinoma. A common consequence of therapy is subclinical hyperthyroidism which may cause dysfunction of cardiovascular system, metabolism and reduction of bone mass1. Thyroid hormones are also involved in regulation of brain function2. Therefore, it is not surprising that thyroid dysfunctions are associated with frequent comorbid cognitive dysfunctions and depression. The aim of our study was to assess the cognitive functions in patients treated P793 with suppressive doses of levothyroxine due to thyroid papillary carcinoma. Hyperthyroidism associated to hyperthyrotropinemia: differential Method diagnosis between resistance to thyroid hormone and TSH secreting Twenty-eight patients with subclinical hyperthyroidism in the course of pituitary adenoma substitutive treatment with levothyroxine due to total thyroidectomy and 131I Rosa Maria Paragliola, Pietro Locantore, Francesca Ingraudo, therapy were involved in the study. The control group consisted of 17 healthy, Francesca Gallo, Francesca Ianni, Annapina De Rosa, Carlo Antonio Rota, euthyroid subjects. A battery of neuropsychological tests was administered to Alfredo Pontecorvi & Salvatore Maria Corsello assess: 1. Working memory and executive functions (the Wisconsin Card Department of Endocrinology, School of Medicine, Catholic University, Sorting Test – WCST, The Controlled Oral Word Association Test-FAS), 2. Rome, Italy. psychomotor speed (the Trial Making Test – TMT) 3. attention (the Stroop test) and 4. Short term memory (the Digit Span test). Psychometric evaluation was made using 17 items the Hamilton Depression Rating Scale and Beck Hyperthyroidism associated to hyperthyrotropinemia is a rare condition which Depression Inventory. can be due to two different causes: resistance to thyroid hormones and TSH Results secreting adenoma. The differential diagnosis is not easy. Patients compared to control group performed poorer in WCST. They made We have observed 8 patients with hyperthyroidism associated to inappropriately significantly more perseverative errors. Patients were found to perform less elevated TSH. All patients had similar basal levels of thyroid hormones and 7 out well than controls in FAS and in TMT-B. The mean score of HDRS and BI of 8 had a multinodular goiter. (3.4 and 6.6 respectively) suggest that patients were not depressed during Four out of 8 patients showed lack of TSH response to TRH stimulation. In all examination. these cases MRI showed a pituitary adenoma. Two of them also showed lack of Conclusion GH suppressibility after oral glucose load, suggestive of mixed adenoma Our results suggest that suppressive treatment with levothyroxine may affect secreting GH and TSH. Three out of 4 patients underwent successfull executive functions, working memory, psychomotor speed. transsphenoidal surgery while one patient, affected by a mixed adenoma, was References successfully treated by octreotide. 1. Biondi B, Palmieri EA, Klain M, Schlumberger M, Filetti S & Lombardi G. In the other 4 patients, TSH response to TRH stimulation was present, but 1 of Subclinical hyperthyroidism: clinical features and treatment options. Eur J them showed a pituitary adenoma. The thyrotoxicosis persisted after Endocrinol 2005 152 1–9. adenomectomy despite the decrease of TSH levels. Thyroidectomy was 2. Smith JW, Evans T, Costall B & Smythe JW. Thyroid hormones, brain function performed with histological diagnosis of Graves’ disease. and cognition: a brief review. Neurosci Biobehav Rev 2002 26 45–60. Three out of 4 patients were diagnosed as resistance to thyroid hormones. Two of them underwent thyroidectomy because of goiter. A papillary carcinoma was
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 diagnosed in 1. This patient, because of the impossibility of obtaining a proper P796 TSH suppression, represents a unique model of thyroid cancer follow-up under Iodine deficiency disorders in eastern Ukraine TSH constantly elevated. Nataliya Zelinska1,2 & Marina Mamenko1,2 These cases demonstrate that differential diagnosis of hyperthyroidism associated 1Luhansk State Medical University, Luhansk, Ukraine; 2Ukrainian Center of to hyperthyrotropinemia is hard to be done. It is necessary to evaluate clinical Endocrine Sugery and Transplantation of Endocrine Organs and Tissues, features, laboratory data and imaging. An adequate response to TRH in presence Kiev, Ukraine. of mild clinical features is suggestive of resistance to thyroid hormones, while in case of overt hyperthyroidism other etiologies should be excluded. MRI scan is essential for diagnosis of TSH secreting adenoma. Background Ukraine does not yet have a national program for control of iodine deficiency and there are no recent data on the severity of the iodine deficiency disorders (IDD) in the country. Objective P794 The aim of the present study was to assess current IDD status in eastern Ukraine. Design Decreased fibrinolytic activity due to levothyroxine suppression therapy We conducted school-based 30-cluster survey in children 6-11-year-old in urban for benign thyroid nodules and rural areas. We measured urinary iodine concentration (UI) and iodine Tevfik Demir, Baris Akinci, Abdurrahman Comlekci, Oguzhan Karaoglu, content of salt by rapid test kits. Goiter was graded by palpation and thyroid Serkan Yener, Mehmet Ali Ozcan, Faize Yuksel, Mustafa Secil & volume determined by ultrasound. We measured hemoglobin (all children), serum Sena Yesil ferritin, serum transferrin receptor, thyrotropin, thyroxine in children with goiter Dokuz Eylul University, Izmir, Turkey. and anemia. Results Thyroid dysfunction is associated with altered levels of several coagulation Children were sampled at 20 urban and 10 rural primary schools. In the 20 urban factors. The aim of this study is to investigate the effect of levothyroxine schools, the median UI was 89 mg/l, 36% of household salt samples were iodized suppression therapy for benign thyroid nodules on coagulation system. (adequate levels), the goiter prevalence was 32%. In the rural schools, the median Thirty-six patients with benign thyroid nodules, who were applicant for UI was 76 mg/l, the goiter prevalence was 18 and 12% household salt samples levothyroxine suppression therapy, were included in the study. Thirty patients were adequately iodized. Among children in the rural schools anemia prevalence completed 1 year follow-up period. Levothyroxine was given to maintain TSH was 12%, in urban schools – 36%. level between 0.1 and 0.35 mIU/l. Samples were collected before and after Conclusions therapy. In eastern Ukraine, school children in all areas are mildly iodine deficient. But the No significant decrease in diameters and volumes of 128 thyroid nodules were prevalence of IDD is higher in children in urban school. Coexisting deficiencies of observed after one year levothyroxine suppression (PO0.05). No alteration was iodine and iron and severe environmental conditions at the industrial cities can found in plasma tPA ve tfPI levels after therapy (PO0.05). However, plasma impair thyroid function. fibrinogen (P!0.001), d-dimer (P!0.001), vWF (PZ0.025), and PAI-1 antigen levels (PZ0.032) increased after levothyroxine suppression. On the other hand, plasma TAFI antigen levels decreased significantly (PZ0.005). Our results suggest a decrease in fibrinolytic activity after levothyroxine suppression therapy for benign thyroid nodules. The decrease in TAFI antigen P797 levels may be due to activation of TAFI pathway. The effect of radioiodine therapy in patient with subclinical hyperthyroidism Saeid Abdelrazek1, Franciszek Rogowski1, Malgorzata Szelachowska2, Adam Parfienczyk1, Anna Zonenberg2, Emilia Wojno1, Piotr Szumowski1, Urszula Karpinska1 & Marta Marciniak1 P795 1Department of Nuclear Medicine, Medical University of Bialystok, Graves’ disease and myasthenia gravis: who comes first? Bialystok, Poland; 2Department of Endocrinology, Diebatology and Internal Carmen Vulpoi1, Lidia Andriescu1, Delia Gabriela Ciobanu1, Maria Medicine, Medical University of Bialystok, Bialystok, Poland. Christina Ungureanu1, Dan Cuciureanu1, Mihai Grigoras2 & 1 Eusebie Zbranca 131 1University of Medicine and Pharmacy, Gr.T.Popa, Iasi, Romania; The aim of our study was to assess the influence of radioiodine ( I) therapy on 2University Hospital St Spiridon, Iasi, Romania. the achievement of euthyroidism, prevention of adverse effects on the cardiovascular and skeletal systems and prevent evolvement to overt hyper- thyroidism. Graves’ disease (GD) and myasthenia gravis (MG) may be associated and Material and methods influence one another clinical expression. We report the cases of 3 female patients We treated 630 patients, aged 30–70 years; 85% of them were female and 15% who presented this particular association. First patient (RL, 55 years), was male; 220 patient with multinodular goitre (MNG), and 310 patient with diagnosed with MG and, 5 years after, developed GD, remitted after 2 years of autonomous nodule (ATN). Some of the patients were treated with antithyroid anti-thyroid drugs (ATD). She is still euthyroid after more than 10 years, and MG drugs for 6 to 24 months before I131 therapy (110 patient). Malignant changes is compensated with moderate doses of anticholinesterase drugs (ACD). Thoracic were excluded in all nodules by fine needle aspiration biopsy. All the patients had CT showed stable thymus hyperplasia. Second patient (AI, 42 years) have been serum TSH levels !0.1 mU/l and effective T-half was more than 3 days at the diagnosed with both diseases practically in the same time: suspicion of MG, time of treatment. The activity dose was calculated by the use of Marinelli’s positive electromyography, clinical symptoms suggesting GD with biological formula and ranged between 200 and 600 MBq. The absorbed dose (Gy) ranged confirmation. She had normal thoracic CT. She had a more difficult evolution, between 150 and 300, and was proportional to thyroid volume. Follow up control with cardiac failure, rapid installation of hypothyroidism on medium doses of was done every 6 weeks. ATD and persistence of important neuro-muscular symptoms, which made Results necessary near-total thyroidectomy. Post-surgical she presented higher LT4 Euthyroidism achieved in 99% of patient with ATN and 95% of MNG; 1% of necessary (200 mcg/d) but MG was spectacularly improved. Third patient (MM, patient with ATN and 5% of patient with MNG develop hypothyroidism. In all of 56 years) had a first episode of GD and, 5 years later, relapse of GD and onset of the patients, the symptoms and signs of subclinical hyperthyroidism disappeared MG. Near-total thyroidectomy was performed, with post-surgical hypothyroidism (palpitation, tachycardia, atrial fibrillation, exercise tolerance improved, the blood compensate with 75 mcg LT4. However, MG symptoms persisted, and needed pressure normalised and the quality of life improved). One percent of the patients higher doses of ACD. Thoracic CT showed thymus tumour which was resected. received 2nd dose of radioiodine. The histology showed thymolipoma and the necessary ACD doses remained Conclusions unchanged. The association of GD and MG is challenging because the evolution Our result is good and is in the range of the existing literature. The achievement of of one disease may be influenced by the other. Two of our patients had an euthyroidism and the remission of the symptoms and signs of subclinical improvement of the MG evolution after remission of GD but neither hyperthyroidism, were due to good diagnosis, well preparation of the patients; thyroidectomy nor thymectomy could diminish the ACD needs for the third. accurate measurement of administered activity, effective half-life, and well- The diagnosis of MG had preceded, followed or been contemporary to the GD organised follow up. We recommend early treatment of subclinical hyperthyroid- diagnosis. No matter who comes first, one should have in mind this association ism, and long period of follow up visits in our department (up to 10 years) to and adjust the management to the specific evolution. evaluate the long term effect of RIT.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P798 Subjects and methods We studied patients with OH (nZ15), with surgically induced OH (SOH) (nZ15) and SUH (nZ15), mean age 43G10 years (TSH: 40G10, 79G21, 7.7G 3.4 mIU/ml, respectively). Fifty healthy subjects (C) matched for age and BMI, were also studied. Thyroid hormone levels, biochemical parameters, creatinine clearance and microalbuminuria were measured by standard laboratory Abstract unavailable techniques. CML and 8-isoprostanes levels were determined by ELISA. Dietary AGE intake (dAGE) was estimated by 3-day dietary records and specific questionnaires. The IR was estimated by HOMA index (GfastingcI fasting)/22.5). Results HOMA was higher in OH, SOH and SUH groups compared to C (2.4G1, 2G1, P799 2.2G0.7, 1.4G0.6, respectively, P!0.05). Levels of 8-isoprostanes were higher only in OH and SUH compared to C (230G44, 214G86, 133G69 pg/ml, Thyroid hormone abnormalities in chronic renal failure ! 1 1 1 respectively, P 0.05). Higher CML levels were observed in OH, SOH and SUH Jiri Horacek , Sylvie Dusilova Sulkova , Eva Malirova , groups compared to C (15G5, 13G4, 11G4 U/ml, respectively, P!0.005) with Vladimira Bednarova2, Martin Simkovic1, Stepan Sulek2, Jaroslav Vizda1 & 1 positive correlation to HOMA index and 8-isoprostanes levels in all groups except Jaroslav Maly the SOH (rZ0.6, P!0.03, respectively). All the subjects had normal renal 1Faculty of Medicine and University Hospital Hradec Kralove, Charles 2 function and did not exhibit statistically different dAGE values. University Prague, Hradec Kralove, Czech Republic; 1st Medical Faculty Conclusion and General University Hospital Prague, Charles University Prague, Prague, Increased OS and IR possibly induce increased AGE formation in OH and SUH, Czech Republic. which might contribute to the enhanced risk of cardiovascular disease. However, other mechanisms such as disrupted function of the AGE receptors cannot be In 162 patients with end-stage renal disease (ESRD), 112 on maintenance excluded and warrant further investigation. haemodialysis (HD) and 50 on continuous ambulatory peritoneal dialysis (CAPD), thyroid status was evaluated: thyrotropin (TSH, IRMA, normal range 0.15–5 mU/l), total thyroxine (TT4, RIA, 70–140 nmol/l), free thyroxine (FT4, RIA, 11–25 pmol/l), total triiodothyronine (TT3, RIA, 1–3 nmol/l), free thyroxine (FT3, RIA, 2.5–5.8 pmol/l); in 113 patients (63C50) also reverse T3 (RT3, RIA, 0.14–0.54 nmol/l) was assayed. None of the patients had previously been treated for or suspected of a thyroid dysfunction. P801 Among HD patients, 11.6% had higher TSH, 38.4% lower TT4, 56.3% lower FT4, 21.4% lower TT3, 19.6% lower FT3, and 17.5% higher RT3 TSH levels and thyroid nodules correlation in autoimmune thyroiditis than the respective normal range. In CAPD patients, the corresponding Luigi Vianale, Alessandra De Remigis, Paola Ranieti & Pierluigi values were 20, 8, 62, 16, 10, and 4%. There was a significant difference De Remigis between HD and CAPD groups in TSH (medians 2.07 and 3.12, Endocrine Unit of General Hospital, Chieti, Italy. respectively, P!0.001, Mann–Whitney), in TT4 (77.5 and 107.3, P!0.001), in FT3 (3.17 and 3.82, PZ0.019), and in RT3 (0.34 and 0.28, The role of TSH in the pathogenesis of thyroid nodule (TN) is controversial. PZ0.004). Both in HD and CAPD patients there were highly significant We have evaluated the prevalence of TN in a group of 800 subjects with and correlations (all P!0.001) between TT4 and FT4 (Spearman rho 0.658 and without autoimmune thyroiditis (AT). The prevalence of TN, the number and 0.674, in HD and CAPD respectively), and between TT4 and TT3 (0.355 volume of nodules was evaluated in relation with TSH and antithyroid antibodies and 0.526). Less expectedly, there were also strong correlations between titles. TT4 and RT3 (0.605 and 0.695), and FT4 and RT3 (0.700 and 0.674). The subjects were of both sex, aged between 20 and 80 years and were recruited in Our data confirm the frequent deviations from normal values in ESRD a random manner, in the context of an epidemiological study (FATA); nobody patients, reflecting the complex alterations in thyroid hormone metabolism were under farmacologic treatment. as well as assay-dependent variations. The pattern of non-thyroidal illness All the subjects were submitted to an echographic study of the neck region and to was more expressed in HD than in CAPD patients, including an increase in determination of TSH and antithyroid antibodies (TAb). RT3, rarely observed in renal disorders. The close correlation between T4 We found in the total population a prevalence of TN of 26.8%; TN prevalence and RT3 may theoretically reflect variations in deiodinase I activity among was significantly higher (P!0.01) in the subjects with TSH levels less to patients with kidney failure. 4.5 mUI/ml (29.1%) than those with above 4.5 mUI/ml (25.9%); the difference in the prevalence of TN between thyroid antibodies (AbC) respect to (AbK) subjects, is not significative. A negative correlation was found between TSH levels and number of thyroid nodules (rZK0.245 P!0.001); while there was no correlation with the levels of P800 antithyroid antibodies. Related to volumes of TN the subjects with TSH levels above 4.5 mUI/ml showed Insulin resistance and oxidative stress induce advanced glycation end a mean TNV of 17.7 cc., significantly reduced (PZ0.000) respect to the subjects products formation in patients with clinical and subclinical with TSH below 4.5 mUI/ml (mean TNV of 20.95 cc). A statistically difference hypothyroidism (PZ0.05) was also observed in the mean TNV between subjects AbC (20.01 cc) Melpomeni Peppa1, Dimitrios Hadjidakis1, Maria Alevizaki2, 1 1 1 related to those AbK (20.96 cc). George Dimitriadis , Georgia Isari , Theofanis Economopoulos , Results show TSH seems to play no role in the TN growth, because higher levels Jaime Uribarri3, Helen Vlassara3 & Sotirios A Raptis1,4 1 are not associated to bigger TN, while TAb presence determines a lesser TN Endocrine Unit, Second Department of Internal Medicine-Propaedeutic, growth. Athens University Medical School, Research Institute and Diabetes Center, ‘Attikon’ University Hospital, Athens, Greece; 2Endocrine Unit, Depart- ment of Clinical Therapeutics, Athens University Medical School, ‘Alexandra’ Hospital, Athens, Greece; 3Division of Experimental Diabetes and Aging, Mount Sinai School of Medicine, New York, New York, USA; 4Hellenic National Diabetes Center, ‘Attikon’ University Hospital, Athens, Greece. P802 Introduction Serum thyrotropin concentration as a biochemical predictor of thyroid Advanced glycation end products (AGEs) formation is accelerated in various malignancy in patients presenting with thyroid nodules pathological conditions characterized by insulin resistance (IR) and/or increased Stergios Polyzos1, Marina Kita1, Zoe Efstathiadou1, Pavlos Poulakos1, oxidative stress (OS). Hypothyroidism – overt (OH) or subclinical (SUH) – is Aristidis Slavakis2, Danae Sofianou2, Nikolaos Flaris3, Maria Leontsini3, associated with a variety of metabolic disorders leading to IR and increased OS. Anargyros Kourtis1 & Avraam Avramidis1 Aim 1Department of Endocrinology, Hippokratio General Hospital, Thessalo- To estimate the 3N-carboxymethyl-lysine (CML) levels, in subjects with OH and niki, Greece; 2Department of Microbiology, Hippokratio General Hospital, SUH and seek for possible correlations with various metabolic parameters Thessaloniki, Greece; 3Department of Pathology, Hippokratio General including IR and OS. Hospital, Thessaloniki, Greece.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Background P804 Fine-needle aspiration biopsy is the ‘gold standard’ in the preoperative The effect of radioiodine therapy in patient with non-toxic goitre after management of thyroid nodules. pre-treatment with a single dose of recombinant human thyroid Aim stimulating hormone (rhTSH) The aim of this study was to investigate whether serum TSH is a predictor of Saeid Abdelrazek, Adam Parfienczyk, Franciszek Rogowski, thyroid malignancy in patients presenting with thyroid nodules. Piotr Szumowski, Agnieszka Kociura-Sawicka & Emilia Wojno Subjects and methods Department of Nuclear Medicine, Medical University of Bialystok, About 565 patients without overt thyroid dysfunction, who presented with Bialystok, Poland. palpable thyroid nodule(s) between 1988 and 2004 and underwent at least one FNAB, were retrospectively evaluated. Results The aim of our study was to assess the effectiveness of radioiodine therapy (RIT) The final diagnostic outcome was established after surgery (nZ122) or after a on the reduction of thyroid volume after pre-treatment adjunct of rhTSH in minimum of one-year clinical follow-up period. Higher rates of malignancy were patients with non-toxic goitre with low RAIU. observed in patients with serum TSH in the upper tertile of the normal range Material and methods (PZ0.026). Binary logistic regression analysis revealed significantly increased We treated 36 patients; (28 female, 8 male) aged 35–77 years. Initial 24 h adjusted odds ratios for the diagnosis of malignancy in patients with serum TSH RAIU was ranged between 5 and 17%, and thyroid volume ranged between 1.5–4.0 mIU/l compared to those with either TSH 0.4–0.8 mIU/l (PZ0.005) or 42 and 128 ml. Twelve patients had compressive symptoms. Malignant TSH 0.9–1.4 mIU/l (PZ0.007). changes were excluded in all nodules by FNAB. All the patients received a Conclusions single dose of 0.05 mg rhTSH given intramuscular. About 24 h later The risk of malignancy in thyroid nodules increases in parallel with TSH diagnostic dose of 131I was administered and RAIU after 24, 48 and 72 h concentrations within the normal range. TSH concentration at presentation is an was estimated. Therapeutic dose of 131I was given on the third day of rhTSH independent predictor of thyroid malignancy. administration. Serum TSH, fT4 and fT3 were determined, 24 h, 72 h after rhTSH administration and on the 3rd day after RIT. The activity dose calculated by Marinelli’s formula and ranged between 400 and 800 MBq. The absorbed dose ranged between 160 and 300 Gy. Follow up control was done every 6 weeks. Thyroid ultrasound, and thyroid scan were done again after12 P803 months of RIT. Thyroid peroxidase antibodies and levels of thyroid stimulating Results A significant 4-fold increase in 24 h RAIU from 12.2 to 54% was observed. The hormone as predictors of development of hypothyroidism in euthyroid G G subjects significant increase in serum TSH from 1.4 0.5 to a peak level 12.21 4.62 was Annemieke Roos1, Thera Links1, Lolkje de Jong-van den Berg3, Rijk Gans2, seen after 24h . After 12 months 91% of patient were in euthyroidism, 9% (3 Bruce Wolffenbuttel1 & Stephan Bakker2 patients) develop hypothyroidism. Thyroid volume reduced to about 45% 1Department of Endocrinology, University Medical Center Groningen and average. In all of the patients the compressive symptoms relieved and exercise University of Groningen, Groningen, The Netherlands; 2Department of tolerance improved. Conclusions Internal Medicine, University Medical Center Groningen and University of 131 Groningen, Groningen, The Netherlands; 3Department of Social Pharmacy, Pre-treatment with rhTSH allows the therapeutic dose of I to be reduced by 50– Pharmacoepidemiology and Pharmacotherapy, University Medical Center 58% without compromising the result of thyroid volume reduction. This mode of Groningen and University of Groningen, Groningen, The Netherlands. therapy can be recommended, especially when RAIU is low and the dose of radioiodine to be administered is high.
Introduction Presence of thyroid peroxidase antibodies (TPOAbs) may be a marker of future thyroid failure. However, prospective studies in a euthyroid population have not been performed. Aim of the study To prospectively investigate the relationship between presence and levels of TPOAbs and incident hypothyroidism in euthyroid subjects in the general population. Study population The database used for this study consisted of a random sample of 2703 P805 participants of the PREVEND (prevention of renal and vascular end stage High prevalence of pathologic TSH values in patients admitted to a disease) study, inhabitants aged 28–75 years of the city of Groningen, The clinic of general internal medicine Netherlands. We excluded subjects with a TSH level outside the laboratory’s Walter Reinhardt1, Oliver Gross2 & Friedrich Jockenhoevel2 reference range (0.35–4.94 mIU/l; nZ115) at baseline and subjects taking thyroid 1 Z Z Endocrine Outpatient Clinic and Evk Hospital, Herne, Germany; medication (n 37) and/or medications that may affect thyroid function (n 56). 2Evangelisches Krankenhaus, Herne, Germany. Incident hypothyroidism was defined as initiation of L-thyroxine therapy in the absence of thyreostatic medication by the participants during follow-up. Results Currently there are only rare data on the prevalence of thyroid dysfunction in Prevalence of positive TPOAbs at baseline was 8.5%, with levels between 12 and hospitalized patients. Therefore, we prospectively measured TSH values in 3767 IU/ml. Prevalence significantly increased with increasing TSH concen- patients admitted to a clinic of general internal medicine in an area of moderate trations (P!0.001). Median age at baseline was 46 years. Median follow up was iodine deficiency. 6.7 years. Incidence of hypothyroidism was 0.5% (3.0% in TPOAbs positive versus In 1011 patients (mean age 66.2 years; median 72 years) TSH was consecutively 0.2% in TPOAbs negative subjects; P!0.001). Sex (HR 8.6 (1.10–67.17), evaluated. PZ0.04), TSH level (HR 3.4 (2.07–5.60), P!0.001) and TPOAbs level (log The mean TSH was 1.74 uU/ml (range 0.00–93.3); median 1.1 uU/ml. transformed; HR 3.93 (2.26–6.82), P!0.001) were significant predictors of In 732 patients (74.4%) TSH was within the normal range (0.35–2.8 uU/ml) 120 incident hypothyroidism in univariate analysis. Age was not related. When tested patients (11.9%) had TSH levels above 2.8 uU/ml. multivariately, the product term of TSH level and TPOAbs level was significantly About 139 patients (13.7%) had TSH levels below 0.35 uU/ml. Among those 139 related to incident hypothyroid cases (PZ0.01), reflecting highest risk in subjects patients 51 patients had TSH values below 0.1 uU/ml. with both high levels of TPOAbs and high levels of TSH within the reference range. There was a negative correlation of age and TSH (P!0.05). Conclusion We found pathologic TSH values in 25% of patients admitted to a clinic of We have demonstrated that TPOAbs level and TSH level are interdependent general internal medicine. Whether these alterations are related to true predictors for future hypothyroidism, even when TSH is still within the thyroid dysfunction or are influenced by the underlying illness needs further laboratory’s reference range. evaluation.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
P806 Conclusion A rare clinical picture: thyroid cystic nodule as a localization of Recognition of variables at diagnosis of Graves’ disease or at the end of long-term Aspergillus pulmonary infection (pulmonary-thyroid form) ATD course could be used to select pacients for surgery or radioiodine because of Pierluigi De Remigis1, Lorenzo Di Liberato2, Eligio Pizzigallo3, Alessandra lower remission rate with medical treatment. De Remigis1, Walter Bisello2, Francesco Emma4, Marina Vivarelli4 & Luigi Vianale1 1Endocrine Unit of General Hospital, Chieti, Italy; 2Nefrologic Clinic of University, Chieti, Italy; 3Infective Clinic of University, Chieti, Italy; 4Children Hospital ‘Bambino Gesu`’, Rome, Italy. P808 Is pre-ablative thyroglobulin useful as a predictor of cure in Aspergillus infection (A)is often recognized in severely immunocompromised differentiated thyroid carcinoma? patients. Miguel Paja, Amelia Oleaga, Josu Perez, Aitzol Lizarraga, Cristina Moreno, Although involvement of the thyroid gland is reported for 9–15% of patients with Ana Izuzquiza & Fernando Gon˜i disseminated disease, a localized clinical picture it’s not reported. Hospital Basurto, Bilbao, Vizcaya, Spain. Here, we present a case of Aspergillus in a LES young patient (15-year-old girl), who underwent to a strong immunosuppressive regimen (high doses of Surgery followed by 131I ablative therapy (IAT) is the usual treatment for patients corticosteroids, endoxan and plasmaferesis). After about one month she with differentiated thyroid carcinoma (DTC). Thyroglobulin levels obtained 9–12 developed pulmonary A. Chest CAT revealed signs of A infection (interstitial months after IAT under TSH stimulation (Tg2) is a very reliable marker for the and cavernous form). Routine respiratory cultures repeatedly grew A. flavus. presence of thyroid tissue. The value of stimulated thyroglobulin previous to The galactomannan enzyme-linked immunosorbent assay, one of the most ablation (Tg1) is more controversial. The aim of this study was to examine the sensitive test available for aspergillosis diagnosis, had a positive result. relationship between Tg1 and Tg2. Laboratory tests performed before A development, in order to test autoimmune Material and methods associated diseases, showed TSH mild elevated (8.5 mUi/ml), normal FT3 Seventy-five patients treated for a DTC between 2001 and 2006 were studied. All (2.38 pg/ml) and FT4 (1.07 ng/dl) AbTg (3.7 UI/ml) AbTPO (33 UI/ml), patients had undergone total o near-total thyroidectomy followed by IAT after suggesting a form of autoimmune thyroiditis. thyroid hormone withdrawl or stimulation with Thyrogen. Serum TSH, Tg and Tg She was treated with L-T4. When A has arisen, at physical examination of the antibodies (Tg Ab) were measured postoperatively just before IAT or three days neck a small nodule was appreciated. after the second dose of Thyrogen and 9-12 months after ablation with stimulation An anecoic imagine was shown by ultrasound, no colour signs at ecocolor- of TSH. Serum Tg was measured by inmunoradiometric assay with functional doppler A FNA was made and septate hyphae, consistent with Aspergillus sensitivity of 0.5 ng/ml. species, were identified in Periodic acid-Schiff stain cytology. Results The patient was put in antifungeal therapy and the thyroid nodule was monitored. Twenty-four patients were excluded: 1 with evidence of macroscopic disease, 5 The A. pulmonary picture remitted, while the thyroid cyst is still evident at with TgAb positive, 8 patients in which TgAb were not measured and 10 who had ecography, presenting the same size and ecostructure, and at FNA positive not Tg2 done. The remaining 51 were divided in three groups as follows: Group 1 Periodic acid-Schiff stain cytology for hyphae. (nZ11) Tg1 between 0 and 1 ng/ml: all of them had Tg2 !1 ng/ml; Group 2 The involvement of thyroid by A is frequent, mostly in the context of a A diffusive (nZ21) Tg1 between 1 and 5 ng/ml: 2 presented Tg2 O1 ng/ml; Group 3 (nZ19) form. This is characterized by a destructive form of thyroiditis. Tg1 O5 ng/ml: 6 with Tg2 O1 ng/ml. 131I uptake outside the thyroid bed was A localized form as a thyroid cystic nodule, like we described here, associated to demonstrated in 3 patients in group 1, 5 in group 2 and 10 in group 3. pulmonary A (pulmonary-thyroid form) is unusual. It’s interesting it seems to Discussion show a some resistance to antifungeal therapy. The prognostic value of the Tg levels measured just before IAT is often debated because of the presence of thyroid remnants that contribute to the Tg synthesis. In our series, patients with Tg levels !2 ng/ml before IAT did not show Tg O1 ng/ml 9–12 months post ablation.
P807 Clinical variables associated with recurrence of hyperthyroidism in Graves’ disease Familiar Cristina1, Moraga Inmaculada1, Cruces Eva2, Vicente Almudena2, P809 Sastre Julia2 & Lopez Jose2 Simultaneous papillary (PTC) and medullary (MTC) thyroid cancer: 1Mostoles Hospital, Mostoles, Madrid, Spain; 2Virgen de la Salud Hospital, more than a coincidence? Report of two cases Toledo, Spain. Amelia Oleaga, Miguel Paja, Egan˜a Nerea, Ugarte Estibaliz, Espiga Javier & Elorza Jose Ramon Hospital Basurto, Bilbao, Vizcaya, Spain. Introduction In Graves’ hyperthyroidism with long-term antithyroid drugs (ATD) treatment, remission is often umpredictable. However variables at diagnosis or at the end of The simultaneous occurrence of MTC and PTC in the same thyroid can be the ATD regimen are associated with a highest likelihood of recurrence and could observed as a mixed tumour folliculo-medullar (OMS 1988) or as a collision be used to decide an ablative treatment. tumour separated by normal thyroid parenchyma, which has only been described Objective in less than thirty patients. We report two cases. To identify variables before and at the end of a long-term treatment with ATD Case 1 (O6 months) associated with higher rates of relapse during a follow-up of at A 72 years old woman who underwent total thyroidectomy for a multinodular less 1 year after discontinuing ATD. goiter. Histology showed a 2.5 cm CPT in the left lobe and a 4.5 cm CMT in the Subjects right lobe. She received 100 mCi 131I. After 2 years serum thyroglobulin (Tg) About 250 subjects with a first episode of Graves’ disease between January 1999 levels remain undetectable, calcitoninZ11 (normal !12 pg/ml) and has a and December 2004 seen in the same institution. negative neck ultrasound. The RET proto-oncogen study did not show any Results mutation. At baseline mean age was 41G14 years, 21% were male and 33% smokers, Case 2 49% used iodinated salt and 40% were classified as having a goiter O grade A 43 years old man harbouring a RET mutation at codon 611 who underwent total 2. Mean TSI decreased from 11G18 to 2.5G4(P!0.05) at the end of ATD thyroidectomy and central neck dissection. Histology showed a 0.3 cm CPT in the regimen. About 29% were excluded of a further analysis because of an left lobe and a multifocal bilateral CMT (0.3 cm and !0.1 cm). Four out of five ablative treatment as soon as ATD were stopped. Relapse ocurred in 60% of cervical lymph nodes contained MTC. He received 100 mCi 131I. Tg pre-ablation the resting 177 subjects submitted to a long-term treatment (mean 18G8 levels were 0.9 ng/ml and he showed cervical lymph nodes 131I uptake. After 4 months) during the follow-up period (mean: 3.1G1.7 years). Of analyzed months serum calcitonin levels remain below 4 pg/ml. variables at diagnosis,only male gender, smoking history and iodinated salt Discussion use were significantly associated with failure of medical treatment. In a We report two cases of collision tumour with special features. As far as case 1 is logistic regression analysis only male gender and smoking cigarettes were concerned the size of the CPT is the biggest one to our knowledge and the independent predictive factors for recurrence. TSI 3 times above the normal outcome is good despite the tumour size and the patient’s age. In case 2 the RET value at the end of the treatment yield a 98% positive predictive value for mutation at codon 611 has not been previously described since all tumour relapse. collision had been associated with mutations at codon 790, 791 and 804. We want
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 to emphasize the good response to treatment despite the aggressive presentation. was 50.7G13.1 years (25–78). Only one case was diagnosed before The simultaneous occurrence of MTC and PTC may be due to a common genetic thyroidectomy. The PTM prevalence was higher in thyroid solitary nodule drive although a coincidence cannot be ruled out. (40%), followed by euthyroid multinodular goitre –MNG- (28%), hypofunction- ing MNG (20%), thyrogloss cyst (20%), Graves-Bassedow disease (7.7%) and toxic MNG (7.3%). The mean tumor size was 0.3G0.2 mm (0.1–10). Multi- focality was observed in 29.6%. One case (2.6%) has extrathyroid extension (adenopathy). Euthyroidism, hypothyroidism and hyperthyroidism were presents P810 in 81.6%, 13.2% and 5.3%, respectively. Thyroid autoimmunity in 7.9%. The prevalence was 20.3 without sex differences (22.7 M, 20 F). The annual incidence Effects of rituximab (RTX) treatment on IL-6 and soluble IL-6 receptor oscilated among 2.6 and 34.2, showing a striking and progressive increase at the secretion in patients with thyroid-associated ophthalmopathy (TAO) 1 1 2 1 last years. Irene Campi , Guia Vannucchi , Davide Dazzi , Danila Covelli , Conclusions Paola Bonara3, Nicola Curro`4, Paolo Beck-Peccoz1 & Mario Salvi1 1 PTM is more frequent in nodular thyroid disease. Its prevalence is high, as well as Endocrine Unit, Fondazione Ospedale Maggiore Policlinico, Mangiagalli e its multifocality (almost 1/3), increasing at the last years. It depends on the Regina Elena, IRCCS, Department of Medical Sciences, University of 2 3 extended indications for total thyroidectomy for benign diseases, on progress in Milan, Milan, Italy; Ospedale di Fidenza, Fidenza, Italy; Department of the field of diagnostic procedures, and on the pathology examination. Internal Medicine, Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, IRCCS, Milan, Italy; 4Ophthalmology, Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, IRCCS, Milan, Italy. P812 We described a significant clinical response to RTX treatment in patients with active TAO. In order to understand the possible mechanisms of action of RTX, we Thyroid cancer in a patient with ankylosing spondylitis on infliximab 1 2 measured serum concentrations of IL-6 and its soluble receptor (sIL-6R). We Panagiotis Athanassiou , Ifigenia Kostoglou-Athanassiou , 1 1 1 treated 10 patients with RTX: 8 women, 2 men aged 31-51 yr with Graves’ Charalampos Gerodimos , Nikolaos Dadiras , Eirini Batsila & 2 disease. We also treated 14 patients with i.v. steroids (IVGC). All had active Philippos Kaldrymidis 1 TAO. In all patients we studied thyroid function, serum autoantibodies and Department of Rheumatology, St Paul’s Hospital, Thessaloniki, Greece; 2 peripheral blood lymphocytes and by ophthalmologic evaluation the clinical Department of Endocrinology, Metaxa Hospital, Pireaus, Greece. activity score (CAS). Patients were treated with RTX (1000 mg i.v. twice at 2-week interval) or with IVGC (500 mg i.v. for 16 weeks). Serum cytokines were Biological agents have been successfully introduced in the therapeutics of measured by highly sensitive assays (Quantikine, R&D Systems, USA) at autoimmune diseases, in particular rheumatoid arthritis and ankylosing baseline and at the time of CD20C depletion, 30 and 50 weeks from therapy. spondylitis. However, their use has been found to increase the risk of serious Basal serum IL-6 concentrations were 30.6G83.6 and 9.4G17.4. in patients infections and neoplasms. Infliximab, a neutralizing antibody to tumor necrosis treated with RTX and IVGC respectively, and did not change after therapy factor-alpha, appears to be effective therapy in ankylosing spondylitis. Tumor (ANOVA; PZNS). Serum IL-6 did not change in relation to CD20C depletion necrosis factor (TNF) plays an important role in host defense and tumor growth (ANOVA; PZ0.17). There was no correlation between serum IL-6 and either control. Therefore, anti-TNF antibody therapies may increase the risk of serious thyroid autoantibodies or the CAS. Mean basal serum sIL-6R concentrations were infections and malignancies. 478.2G132.3 and 578.6G172.7 pg/ml in patients treated with RTX and IVGC The aim was to describe the case of a patient with ankylosing spondylitis who respectively, and did not change after therapy (Anova). Serum sIL-6R did not developed a papillary thyroid carcinoma while being on therapy with infliximab. change in relation to CD20C depletion (ANOVA; PZ0.30). There was no A female patient, aged 39 years, with ankylosing spondylitis diagnosed at the age correlation between serum sIL-6R and either thyroid autoantibodies or the CAS of 19 years, was given infliximab. Four years after the initiation of therapy (PZNS) We did not observe any significant change of either serum IL-6 or sIL- nodular disease of the thyroid was diagnosed, as an incidental finding in computer 6R with respect to the modality of treatment (ANOVA). These findings suggest tomography scanning of the spine. A fine needle aspiration biopsy was performed that: a) the RTX effect on TAO does not seem to involve the IL-6/sIL-6R system; showing a papillary thyroid carcinoma. Near total thyroidectomy was performed. b) the therapeutic action of IVGC is also not modifying the secretion of these On histolory a papillary thyroid carcinoma of the follicular type was diagnosed. cytokines; and c) the beneficial effects of RTX may be solely related to the She was given radioiodine therapy. Infliximab therapy was stopped and consequences of B cell depletion. ankylosing spondylitis flared. Conclusion Treatment with anti-TNF-a biological agents in rheumatoid arthritis has been reported to increase the risk of malignancies, namely skin cancers and malignant lymphoma. Treatment with infliximab in ankylosing spondylitis has been found to P811 increase the risk of serious infections. In the case described treatment with infliximab may have been related to the occurrence of a papillary thyroid Papillary thyroid microcarcinoma in 188 consecutive thyroidectomies 1 2 carcinoma of the follicular type. This is the first report of thyroid cancer, which Juan Angel Herna´ndez Bayo ,Mo´nica Belincho´n Sz.-Somoza , may be linked to anti-TNF-a biological agent therapy in ankylosing spondylitis. Pablo Monsalve3 & Manuel Garcı´a Viera4 1Endocrinology, General Hospital of La Palma, Bren˜a Alta, Canary Islands, Spain; 2Primare Care, San Andre´s y Sauces, Canary Islands, Spain; 3Otorrhinolaringology, General Hospital of La Palma, Bren˜a Alta, Canary Islands, Spain; 4Pathology, General Hospital of La Palma, Bren˜a Alta, Canary Islands, Spain. P813 Changes in cystatin C during the treatment of subclinical hypothyroidism Objective Zelija Velija-Asimi & Becir Heljic Papillary thyroid microcarcinoma (PTM) is a malignant thyroid tumor with University Clinical Centre of Sarajevo, Sarajevo, Bosnia and Herzegovina. potential multifocality and diameter %1 cm. This carcinoma has been discovered more frequently like incidentaloma, and the epidemiology is not clearly established. We have analysed epidemiologic and clinical characteristics in La Background Palma Island. Serum cystatin C is a novel marker for kidney function that has been claimed to be Patients and methods superior to serum creatinine. Cystatin C concentrations increased in the We collected all cases of PTM diagnosed in 188 consecutive thyroidectomies hyperthyroid patients and decreased in the hypothyroid patients. The cystatin C performed for whichever cause, admitted from 2000 to 2007. We reported the pre- test detects kidney disease at earlier stages, before symptoms appear and surgical diagnosis, sex, age at thyroidectomy, thyroid function, thyroid creatinine levels rise. Another advantage is that, unlike creatinine, blood levels of autoimmunity, tumor size, multifocality, tumor extension, and cytology and cystatin C are less influenced by age, gender, race, or lean muscle mass, which pathology results. The prevalence and incidence were expressed as percentage makes it a better indicator of kidney function. This study was performed to and percentage per year, respectively. The mean values were expressed as evaluate changes in cystatin C and creatinine during the treatment of subclinical mediaGS.D. hypothyroidism (SH). Results Methods Thyroidectomy was performed in 166 females and 22 males. The mean age was Cystatin C, creatinine, CRP and lipids were determined at the time of diagnosis of 50.6G14.8 years (13–85). We found 38 cases of PTM (5 M, 33 F). The mean age SH (TSHO4.2 mIU/ml with normal level of fT3 and fT4), and when TSH
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 returned into the normal range after treatment with levothyroxine in 35 SH undergoing levothyroxine (LT4) replacement therapy. TSH values between 0.35 women ages 35.3G9.5 years. and 4.94 ng/dl were consider euthyroidism. Results A sample of 257 women having a mean age of 40.9G11.2 years old and a mean TSH was 9.4G4.3 mU/l (reference 0.3–4.2) at diagnosis and decreased to 2.9G BMI of 44.6G7.1 kg/m2 was evaluated. We found a primary hypothyroidism 1.2 mU/l following treatment with levothyroxine. Cystatin C increased from prevalence of 13.2%. The prevalence of diagnosed hypothyroidism undergoing 0.68G0.19 mg/l (reference 0.5–0.96) in the hypothyroid state to 0.89G0.16 mg/l levothyroxine replacement therapy was 5.8% (i.e. 15 patients). From these 5.8%, when TSH normalized (P!0.01). Creatinine decreased from 98G11 umol/l 86.7% were well-controlled, while 13.3% maintained high levels of TSH under (reference 45–115) in the hypothyroid state to 67G14 umol/l when TSH therapy. In the remaining 94.2% (i.e. 242 patients), a prevalence of 7% normalized (P!0.05). CRP levels also decreased when TSH normalized (5.2G hypothyroidism, 92.6% euthyroidism and 0.4% hyperthyroidism was found. 1.1 vs 2.5G0.9 mg/l). Mean total and LDL-cholesterol levels decreased too, but From the above-mentioned 7% of patients with hypothyroidism, a prevalence of not significantly. subclinical hypothyroidism was found to be 68.4%. Conclusion In the same sample, the mean age of patients with hypothyroidism was 39.3G Subclinical hypothyroidism has a substantial impact on cystatin C levels. In 11.6 years old with a mean BMI of 47.9G11.6 kg/m2, and a mean waist contrast to creatinine concentrations, Cystatin C levels are lower in the circumference of 128.4G18 cm, while those having euthyroidism revealed a hypothyroid state as compared with the euthyroid state. Therefore, thyroid mean age of 41.1G11.1 years old, a mean BMI of 44.3G6.8 kg/m2 and a mean function has to be considered when cystatin C is used as a marker of kidney waist circumference of 120.6G13.4 cm. The only patient with hyperthyroidism function at many diseases like diabetes, hypertension, and cardiovascular was 20 years old and revealed a BMI of 60.2 kg/m2. diseases. From this study, the occurrence of a low hypothyroidism prevalence in the analysed sample could be observed. Furthermore, the analysed female patients with hypothyroidism revealed higher BMI and waist circumference and a lower age average than those having normothyroidism.
P814 Mixed papillary, poorly differentiated and anaplastic thyroid carcinoma Ifigenia Kostoglou-Athanassiou1, Anastasios Goudouvas1, P816 Dimitrios Thomas1, Theodosia Bakola1, Eirini Veniou1, Pelagia Batika1, 2 1 Thyroid autoimmunity and assisted reproductive technology (ART) Panagiotis Athanassiou & Philippos Kaldrymidis Ines Bucci1, Marianna Guglielmi1, Maria Grazia De Vita2, Barbara Di 1Department of Endocrinology, Metaxa Hospital, Pireaus, Greece; 1 1 1 1 2 Nenno , Dominique Errone , Cesidio Giuliani , Giorgio Napolitano , Department of Rheumatology, St Paul’s Hospital, Thessaloniki, Greece. Giammario Tiboni2 & Fabrizio Monaco1 1Chair of Endocrinology, University ‘G D’Annunzio’, Chieti, Italy; 2Chair Well differentiated thyroid carcinoma is associated with prolonged survival in of Obstetrics and gynaecology, University ‘G D’Annunzio’, Chieti, Italy. terms of decades and anaplastic carcinoma is associated with survival in months. Intermediate malignancy with a more guarded prognosis is also known to exist. About 5–10% of fertile women have anti-thyroid antibodies (AAT); however this The aim was to describe the case of a patient with a mixed papillary, poorly prevalence is higher in infertile women. Few studies have been focused so far on differentiated and anaplastic thyroid carcinoma. the role of thyroid autoimmunity in the outcome of ART. Aims of our studies have A female patient, aged 73 years presented with a multinodular goiter and therefore been: a) evaluate prevalence of thyroid antibodies in infertile women associated lymphadenopathy. A near total thyroidectomy was performed with before ART; b) investigate whether AAT are more prevalent in a specific subset lymph node dissection. On histology a diffuse thyroid carcinoma was observed. It of infertile women; c) investigate the possible influence of AAT or thyroid was found to have areas of papillary differentiation, areas of insular architecture dysfunction on the outcome of ART. and areas of anaplastica carcinoma, multiple psammoma bodies and foci of About 105 women (mean age 35.7C4.7) have been investigated; 11 subjects have fibrosis and calcification. Multiple neoplasmatic emboli were noted within the been excluded from the study because of known thyroid diseases. The remaining blood vessels and massive metastatic disease in the lymph nodes. The carcinoma 95 women have been divided according to the cause of infertility; 34% were was found to invade the surgical limits of dissection. A whole body scan was idiopathic, 26.6% had a male factor, 6.4% had ovulatory disorders, 10% had 131 131 performed with I which was negative. She was given 100 mCi I. On follow endometriosis and 17.6% had tubal factor. TSH, FT4, Tg-Ab, TPO-Ab, TSHr-Ab up she developed metastatic disease in the area of the neck. (both stimulating and blocking) have been assayed before ovarian stimulation. Multinodular goiter is known to be a risk factor for the development of thyroid AAT have been detected in 23 (24.4%) women, all of them being euthyroid cancer and in some cases the development of anaplastic carcinoma. except 1 subclinical hyperthyroid and 1 subclinical hypothyroid. The highest Carcinogenesis in the thyroid is known to be a multi-step procedure. Papillary prevalence of AAT (27%) have been found in women with tubal factor infertility. thyroid carcinoma is sometimes dedifferentiated to forms of carcinoma with less Out of the 94 women, 85 have undergone ART (9 being non-responders to ovarian favorable prognosis. In the case described areas of papillary carcinoma were stimulation) and pregnancy was obtained in 23 cases; in 3 cases, however, found along with areas of insular carcinoma and areas of anaplastic carcinoma. As precocious abortion has been observed. 6 out of these 23 were AAT positive predicted by the histology and the massive metastatic disease the clinical course (26%, 5 deliveries, 1 abortion). Amongst the 62 non-pregnant women, 15 were of the patient was not favorable. In this extremely rare case of thyroid carcinoma AAT positive (24.2%). TSH was not significantly different (1.6C0.95 mUI/l vs the multi-step procedure of carcinogenesis is characteristically depicted in the 1.8C1.04 mUI/l for pregnant and non-pregnant women respectively). histological findings. Nine women were positive for TSHr-Ab (in 7 cases without contemporary TPO- or Tg-Ab) 2 of them becoming pregnant. According to TSH value 70 (82.3%) women had a value below 2.5 mUI/l; 21 (30%) of them became pregnant but 2 had precocious abortion. Fifteen (17.7%) women had TSH value above 2.5 mUI/l (but still within the normal range); 3 (20%) became pregnant but 1 had precocious P815 abortion. Our data suggest; a) higher prevalence of AAT in infertile women; b) AAT were Prevalence of primary hypothyroidism in an obese population more frequently associated to tubal factor infertility; c) more cases are needed in Selma Souto1, Joana Mesquita1, Ana Oliveira2, Paula Freitas2, 3 1 2 1 order to draw final conclusion about the possible interference of within-the- Flora Correia , Ana Varela , Davide Carvalho , Jose Luis Medina & normal-range TSH value above 2.5 mUI/l with the positive outcome of ART. D Braga1 1Hospital S Joao, Porto, Portugal; 2Faculty of Medicine, University of Porto, Porto, Portugal; 3Faculty of Food and Nutritional Sciences, Univeristy of Porto, Porto, Portugal.
A positive association between thyrotropin (TSH) secretion and body-mass index P817 (BMI) was previously reported. There are many studies concerning thyroid Five new mutations leading to partial deficiency of thyroxine-binding function in obesity, and some of them describe higher TSH levels in obese globulin subjects. Lars C Moeller1, Philip Vinzelberg1, Joachim Pohlenz2, Andrea Jaeger1, Evaluation of the hypothyroidism prevalence in a sample of obese women in their Klaus Mann1 & Onno E Janssen1 first obesity appointment at Hospital Sa˜o Joa˜o. 1Department of Endocrinology, Universityhospital of Essen Medical Anthropometric variables and serum levels of TSH, free triiodothyronine (FT3) School, Essen, Germany; 2Children’s Hospital of the Johannes Gutenberg and free thyroxine (FT4) were evaluated. They were asked if they were University, Mainz, Germany.
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008
Introduction TSHR. Such TSH bin- ding inhibition immunoglobulin (TBII) assays determine Thyroxine-binding globulin (TBG) is the main thyroid hormone transport protein the ability of TRAb to inhi- bit the binding of labelled TSH to immobilized in blood. So far, 26 TBG deficiency mutations have been reported, 7 of them TSHR. TRAb are present in low con- centrations and mostly recognize leading to partial TBG deficiency. We examined T4 binding capacity and the conformational epitopes. The conformational structure of the TSHR is sensitive TBG gene in patients with normal free T4 (fT4) and reduced total T4 (TT4). We to thermal stress. Incubation times of current as- says must be for a minimum of present and characterize five new partial TBG deficiency mutations. 2 h to obtain good sensitivity. Due to these tech- nical difficulties no rapid Methods automated TRAb assay could be developed so far. Automated chemiluminescence immunoassays were used for the determination of We report on the 1st automated TRAb assay on the Elecsys/ cobas e immuno- TSH, fT4, TT4 and TBG. In case of TBG deficiency, the extent of deficiency was assay platform. TRAb inhibit the binding of a human monoclonal thyroid stimula- determined by a TBG-specific T4-binding assay. Direct DNA sequencing of the ting autoantibody (M22; labelled with a ruthenium complex) to preformed TBG gene (exons 1-4 and the non-coding exon 0) was used to identify mutations immuno- complexes based on aggregates of solubilised multiple porcine TSHR in the propositi. To characterize the mutations, they were introduced into a TBG (pTSHR) and a mouse monoclonal capture antibody (4E31 IgG; labelled with expression vector, which was then transfected into HepG2 cells. After 48 h, T4- biotin). 4E31 does not interfere with the binding of TRAb and M22 to the pTSHR. binding capacity, representing TBG concentration, was measured in the media. The lyophili- zed immunocomplexes are stabilized after reconstitution by Results chemical chaperones. The assay uses a delayed competitive test principle. Total T4 binding capacity in media of cells transfected with a normal TBG-vector was assay time is 3!9 min only. Firstly, sample TRAb – if present – bind to the set as 100%. T4 binding capacity in media of cells transfected with an empty multiple TSHR binding sites. Secondly, TRAb are allowed to interact with the vector as a negative control was 2.6%. Five TBG mutations lead to a severe TSHR further. Thirdly, labelled M22 and streptavidin-coated microparticles reduction of T4 binding capacity, representing partial TBG deficiency: R35Q: are added. M22 binds to still free bin- ding sites. Immunocomplexes are bound 11.4%; S52R: 12.4%; N112L: 12.0%; R381G: 4.8%; S382R: 10.5%. to the solid phase via interaction of biotin and streptavidin. Assay calibration Conclusion is against the NIBSC 90/672. Its measuring range extends from 0.3–40 IU/l. Mutations in the TBG gene can lead to TBG deficiency. We report 5 new partial The functional sensitivity is w0.9 IU/l. TBG deficiency mutations and experimentally characterized their T4 binding The automated Elecsys Anti-TSHR correlates well with current TBII assays and capacity. provides clinical performance and total precision which will meet customer needs.
P818 Clinical evaluation of 3rd generation assay for thyrotropin receptor P820 autoantibodies in autoimmune thyroid diseases Visual evoked potentials in children with hypothyroidism Matthias Schott1, Claudia Graeber1, Julia Domberg1, Roswitha Charko1, Teresa Zˇ ak, Anna Noczyn´ska, Joanna Klempous, Witold Pilecki & Derik Hermsen2, Sven Schinner1, Werner A Scherbaum1 & Holger Teresa Szawronowicz S Willenberg1 Department of Endocrinology and Diabetology for Children and Adoles- 1Department of Endocrinology, Diabetes and Rheumatology, University cents, Wroclaw, Poland. Hospital Duesseldorf, Duesseldorf, Germany; 2Institute of Laboratory Medicine, University Hospital Duesseldorf, Duesseldorf, Germany. The clinical picture of hypothyroidism is well described. It is well known that thyroid hormones are very important to development and maturation of the Recently a new procedure for measuring serum TSH receptor (TSHR) central nervous system. They have influence on the synthesis of proteins and autoantibody (TRAb) was reported in which the autoantibodies inhibit binding production of enzymes and myelin. of a human monoclonal thyroid stimulating antibody M22 (labeled with biotin) to Myelin synthesis is an important factor in determining the speed of impulse TSHR-coated ELISA plate wells. This assay was termed 3rd generation TRAb transmission along complex polysynaptic pathways, such as those mediating the assay. The aim of the present study was to clinically evaluate the TRAb 3rd evoked potentials. generation assay in comparison with the 2nd generation TRAb assay (TRAb-2nd) Visual evoked potentials are reliable and objective method for measuring the based on the recombinant human TSH-receptor. function of visual pathway conduction. Visual Evoked Potentials (VEP) were Altogether, 158 patients were analyzed, of whom 84 patients suffered from performed in 40 children. We studied 26 girls and 14 boys. The flash stimulation Graves’ disease (GD), 34 patients had Hashimoto’s thyroiditis (HT) and 40 with frequency of 1 Hz was used. patients had euthyroid nodular thyroid disease (NTD) without signs of At the time of the present study patients were euthyroid with no clinical signs of autoimmunity. TRAb measurements were performed according to the disease. manufacturer’s instructions. The TRAb-2nd assay revealed a high sensitivity The latencies to the peak P100 were measured. We compared the results with and specificity as 81 of 84 (96.4%) GD patients were positive. One GD patient had normal control group of 35 children (21 girls and 14 boys). The recording of VEP TRAb values within the grey zone (1.0–1.5 IU/l). All patients with HT and NTD is a sensitive technique for detection of subclinical lesions of the visual system. were negative except 6 (17.6%) and 3 (7.5%) cases with TRAb values within the grey zone. On the basis of the TRAb-3rd assay, 77/84 (91.6%) GD patients were TRAb positive. One patient (2.9%) with HT and three cases (7.5%) with NTD were also TRAb positive. The sensitivity of the second and third generation assays were 93% and 84%, while the specificity were 100% and 96.2%, respectively. There was a close correlation (rZ0.821, P!0.0001) between P821 TRAb-3rd and TRAb-2nd assays in 84 patients with GD. Problematically, the Iodothyronine antibodies are not correlated with prevalence or interassay coefficient of variation was 28.2% using the recommended cut-off limit prognosis of non-thyroidal illness syndrome of 1 IU/l. Johannes W Dietrich1, Antje Ackermann1, Abira Jeyabalan1, Our results indicate that the 3rd generations TRAb assay has a lower sensitivity Yarlini Kunanayagam1, Tabotnini Tharmalingam1, Aline Urban1, and specificity compared to the second generation human TSH receptor based Axel Stachon2, Harald H Klein1 & Steffen Hering1 TRAb assay. 1Medical Hospital I, Bergmannsheil University Hospitals, Ruhr-University of Bochum, Bochum, NRW, Germany; 2Transfusion and Laboratory Medicine, Institute for Clinical Chemistry, Bergmannsheil University Hospitals, Ruhr-University of Bochum, Bochum, NRW, Germany.
P819 Patients suffering from critical illness usually exhibit a characteristic functional First rapid and automated immunoassay for TSH receptor antibodies state of thyrotropic feedback control that is referred to as non-thyroidal illness Dieter Gassner1, Ruth Golla1, Werner Stock1, Jane Sanders2 & Bernard syndrome (NTIS). Today, there are still important questions unsolved, e.g. Rees Smith2 regarding the interdependence of immunological and endocrine functions in 1Roche Diagnostics GmbH, Penzberg, Germany; 2RSR Ltd, Cardiff, UK. critical illness. Therefore, in the context of the prospective AQUA FONTIS study we investigated 164 patients that were treated in medical, surgical and heart surgical Hyperthyroidism in Graves’ disease is due to TSH receptor (TSHR) intensive care units (ICUs) of the Bergmannsheil university hospitals in Bochum, autoantibodies (TRAb) directed against the TSH binding pocket. Detection of Germany. Here, we examined the titres of antibodies reacting with thyroxine TRAb in clinical rou-tine is performed by 2nd gen assays using human or porcine (T4-ab) and triiodothyronine (T3-ab) that were determined 24 h after admission to
Endocrine Abstracts (2008) Vol 16 10th European Congress of Endocrinology, Berlin, Germany, 2008 the ICU, and investigated their correlation with parameters of thyroid P823 homeostasis, length of stay in hospital (LOSIH) or ICU (LOSICU) and survival Analysis of selected adipocytokines in children with autoimmune of patients. thyroid diseases All patients exhibited Gaussian distributed antibody titres that were in the normal Artur Bossowski1, Beata Sawicka1, Miroslawa Urban1, Marcin Skrzydlo1 & range for healthy volunteers. Moreover, the titres didn’t correlate with functional Mieczyslaw Szalecki2 characteristics like thyrotroph thyroid hormone sensitivity index (TTSI) as a 1 2 0 2 nd Department of Children’s Disease, Bialystok, Poland; The Children’s parameter for the central component of NTIS, or sum activity of 5 -deiodinase as Memorial Health Institute, Warsaw, Poland. a marker for impaired deiodination. Again, antibody titres didn’t exhibit correlation with survival, LOSIH or LOSICU, in the latter two cases even if only the subgroup of surviving patients was considered. Leptin, adiponectin and resistin play an essential role in regulation of body mass, In conclusion, despite of immunological activation, e.g. in case of sepsis, which is controlled by thyroid hormones levels. antibodies directed against T3 or T4 are not elevated among critically ill patients The aim of the study was to evaluate leptin, adiponectin and resistin levels in nor do they play a role in the prognosis of the disease. young patients with Graves’ disease and in children with Hashimoto’s thyroiditis. The study group formed 78 patients suffering from Graves’ disease (30 girls and 2 boys; aged from 6 to 21- mean 15.2 years) and Hashimoto’s thyroiditis (30 girls and 3 boys; aged from 9 to 18- mean 14.5 years). The control group consisted of children with struma nodosa- 11 girls and 2 boys; aged from 9 to 18 -mean 14.6 years. In all patients were performed leptin, adiponectin and resistin levels – ELISA’ method (R&D System, USA). P822 In children with Graves’ disease we found significantly higher levels of leptin compared to group with Hashimoto’s thyroiditis (12.64 ng/ml vs 7.67 ng/ml, No association between BRAFV600E and metalloproteinase activity in P!0.001). Adiponectin level was higher in children suffering from Graves’ anaplastic thyroid cell lines disease compared to group with control and Hashimoto’s thyroiditis (12.33 mg/ml Elvira Carissimi, Alessandra Bommarito, Giuseppe Pizzolanti, vs 11.7 mg/ml, P!0.05; vs 11.21 mg/ml, P!0.05). Resistin level was higher in Giovanni Zito, Pierina Richiusa, Leonardo Russo, Antonina Coppola, group of hypothyroid than hyperthyroid (14.199 ng/ml vs 12.42 ng/ml, P!0.01). Lucia Smeraldi, Aldo Galluzzo & Carla Giordano We conclude that thyroid dysfunction plays significant affect on adipocytokine Laboratory of Molecular Endocrinology, DOSAC, University of Palermo, concentrations. Palermo, Italy.
A strong evidence suggests the role of BRAFV600E mutation in determining the aggressiveness of thyroid cancer. To detect how the association of BRAF P824 mutation could influence the aggressiveness of particular subtypes of thyroid Moderate hyperhomocysteinemia in hypothyroidism tumors, we analysed a possible correlation between BRAFV600E and metallopro- Horea Ursu, M Purice & F Alexiu teinase (MMPs) activity, as its enhanced production could be an important Institute of Endocrinology, Bucharest, Romania. determinant of tumor invasion. For this purpose, we investigated the activity and the expression of different MMPs in anaplastic thyroid cell lines, such as FRO, ARO and KAT-18, by means of zymography and real time-polymerase chain Moderately elevated plasma homocysteine levels (O12 mmol/l) are highly reaction (RT-PCR). FRO and ARO cell lines are homozygote and heterozygote prevalent in the general population and are associated with an increased risk for V600E respectively for BRAF , while KAT-18 cells are negative for BRAF cardiovascular disease. Homocysteine is an amino acid produced during mutation. catabolism of the essential amino acid methionine. Metabolism of homocysteine Analysis of the enzymatic activity in the different cell supernatants showed that requires an adequate supply of folic acid, vitamin B12 and vitamin B6. the activity of MMP-2 and MMP-9 was absent in ARO cell line and low in FRO Moderate hyperhomocysteinemia may be caused by a variety of factors: chronic cell lines. In KAT-18 we have found a higher MMP-2 activity, instead MMP-9 disorders (hypothyroidism, diabetes mellitus, systemic lupus erythematosus, resulted absent. chronic renal failure), nutritional deficiencies (folic acid, vitamin B12, vitamin Real-time PCR revealed that MMP3 and MMP-2 were higher in KAT-18 than B6), drugs (methotrexate, anticonvulsant agents, cyclosporine), postmenopausal FRO, while it was absent in ARO cells. The MMP-9 was absent in ARO and status, smokers, enzyme deficiencies. KAT-18 and low expressed in FRO. In summary, BRAFWT/MUT ARO cell line Measurement of plasma homocysteine was performed by ELISA method, during MUT/MUT was negative for all MMPs, while BRAF FRO was faintly positive. the fasting state. WT/WT BRAF KAT-18 cell line was strongly positive for MMP2 and MMP3 and Hypothyroidism is associated with increased cardiovascular morbidity, which might negative for MMP9. be explained by the atherogenic lipid profile and/or hyperhomocysteinemia. V600E Our results show that no complete association between BRAF and MMPs We studied plasma homocysteine and folate levels in a group of 25 patients with activity seems to exist. Our findings could be explained by the fact that not all the primary hypothyroidism, before and duringlevothyroxine treatment. Afterachieving MMPs genes have an AP-1 site in promoter region regulated by BRAF-dependent euthyroidism, plasma homocysteine and folate were also measured before and after ERK pathway. Several other transcription factors, such as ETS, NF-kB, and three months of daily folate supplimentation. In some of our patients with plasma STAT, may modulate differently the expression of each MMP gene. In homocysteine lower than 10 mmol/l during levothyroxine therapy, a significant conclusion, BRAF could be involved in tumor progression through other decrease of plasma homocisteine levels was achieved after the folate mechanisms independently from MMPs pathway. supplementation.
Endocrine Abstracts (2008) Vol 16 jY gpA!d gdQ A gJ d:g2 \dg_gQ8 A _\d8 A b!d8 B
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