Meet-the-Professor (MTP) S197

Meet-the-Professor

the UKPD and from three other trials, ACCORD (Action to Control MTP1 Management of diabetes and cardiovascular protection Cardiovascular Risk in Diabetes), ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release March 27 (Sat.) 11:10-12:00 Room 2 Controlled Evaluation) and VADT (Veterans Affairs Diabetes Trial), has been conducted. All of these trials were designed primarily to MTP1-1 determine whether targeting lower versus higher glucose levels Management of diabetic nephropathy could reduce the risk of cardiovascular events in patients with type 2 diabetes. The meta-analysis showed that targeting more intensive Ryuichi Kikkawa (1) glucose lowering modestly reduced major macrovascular events but (1)Shiga University of Medical Science, Otsu, Japan increased major hypoglycaemia over 4.4 years in persons with type Although the clinical management of diabetic nephropathy has been 2 diabetes. improved considerably in recent years, the number of patients intro- duced into dialysis therapy or kidney transplantation have been still increasing worldwide. Furthermore, the presence of nephropathy MTP2 Primary aldosteronism is known to seriously affect the prognosis of diabetic patients by increasing the cardiovascular death in western countries.We have March 27 (Sat.) 11:10-12:00 Room 3 been following type 2 Japanese diabetic patients in our diabetes clinic examining their various diabetic complications annually for MTP2-1 more than ten years. During the observation period about 30% of Current issues on the diagnosis and treatment of primary microalbuminuric diabetics progressed to macroalbuminuric stage aldosteronism though more than half of them ameliorated either returning to nor- Sadayoshi Ito (1) Meet-the- moalubuminuric stage or showing the reduction of urinary albumin Professor by more than 50%. The amelioration of urinary albumin was sig- (1)Division of Nephrology, Endocrinology, and Vascular Medicine, Department of Medicine, Tohoku nificantly related to glycemic control, blood pressure level and use University School of Medicine, Sendai, Japan of ARB. On the other hand, the progression of micro- to macro-al- Primary aldosteronism (PA) is the most common cause of second- buminuria was significantly related to higher incidence of not only ary hypertension, accounting for 5-10% of all forms of hypertension. renal but also cardiovascular outcomes. It is important to acknowl- Far from being a benign form of hypertension, PA is associated with edge, therefore, that the target of treating diabetic nephropathy is high cardiovascular mortality and morbidity. However, PA is still not only to halt the disease from progressing end-stage renal failure underdiagnosed in general practice. The two most common subtypes but also to defend the patients from various cardiovascular diseases. of PA are aldosterone-producing adenoma (APA) and bilateral idio- We are now facing with new paradigm of the treatment for diabetic pathic hyperaldosteronism (IHA). Life-long medical therapy is the nephropathy. treatment of choice in patients with IHA, while unilateral adrenalec- tomy results in improvement of blood pressure and regression of car- MTP1-2 diovascular complications. Thus, the key diagnostic step in patients Management of diabetes and cardiovascular protection who want to pursue a surgical cure for PA is to distinguish between unilateral and bilateral aldosterone-hypersecretion. Despite recent Rury R. Holman (1) advances in imaging technology, however, the adenoma may not be (1)Diabetes Trials Unit, OCDEM, University of Oxford, UK detectable on adrenal-directed CT or MRI. Indeed clinical decisions The number of people worldwide with diabetes is predicted to based solely on imaging could lead to serious and irreversible treat- exceed 370 million by the year 2030. Over 90% of these will have ment errors. Although adrenal vein sampling (AVS) is the golden type 2 diabetes, which confers a two to four times greater risk of standard to for localization of aldosterone-hypersecretion, its indica- heart disease and stroke than in the general population and a con- tion, the lack of standardized protocol and the successful cannulation comitant reduction in life expectancy of five to ten years. Despite continue to be challenging issues. Because of the large number of PA risk-reduction strategies that include lowering of cholesterol and BP, patients, comprehensive programs of screening of PA and referral to and smoking cessation, the majority of those with diabetes continue special centers would be needed to be developed by an interested to die from cardiovascular causes, but the degree to which improved group of endocrinologists, hypertension specialists, internists, radi- glucose control could help address this residual cardiovascular risk ologists and surgeons within each local community. remains uncertain. The UK Prospective Diabetes Study (UKPDS) showed that gly- MTP2-2 cosylated haemoglobin was a statistically independent and poten- Primary aldosteronism tially modifiable risk factor for cardiovascular disease, in addition to Franco Mantero (1), Maria-Verena Cicala (1) LDL cholesterol, HDL-cholesterol, BP and smoking. Findings from other large observational studies have confirmed the continuous and (1)Endocrinology Unit, Department of Medical and Surgical Sciences, University of Padova, Italy positive association between various measures of glycaemia (includ- PA is a group of disorders in which aldosterone production is inap- ing fasting and post-load glucose levels and HbA1c) and the risk of propriately high, relatively autonomous from the renin-angiotensin cardiovascular disease. The UKPDS did not demonstrate a statisti- system, and nonsuppressible by sodium loading. Such inappropriate cally significant risk reduction for myocardial infarction during the production of aldosterone causes cardiovascular damage, suppres- trial but significant differences in the risks for myocardial infarction sion of plasma renin, hypertension, sodium retention, and potassium and all-cause mortality emerged during the ten-year post-trial moni- excretion that if prolonged and severe may lead to hypokalemia. PA toring period. A meta-analysis of the data from the first five years of is commonly caused by an adrenal adenoma, by unilateral or bilat- S198 14th International Congress of Endocrinology eral adrenal hyperplasia, or in rare cases by the inherited condi- tent with a diagnosis of primary IGF deficiency (IGFD) and, possi- tion of GRA. Cross-sectional and prospective studies report PA in bly, some degree of growth (GH) insensitivity. Established more than 10% of hypertensive patients. The aldosterone/renin ratio etiologies of primary IGFD include molecular defects of the GH (ARR) is currently the most reliable available means of screening (extracellular, transmembrane or intracellular), defects for PA. Patients with a positive ARR measurement should undergo of the post-receptor signaling cascade, specifically signal trans- confirmatory tests, like oral sodium loading test, SIT, FST, Captopril ducer and activator of transcription (STAT)5b, defects of the IGF-I challenge test, and should perform an imaging study (adrenal CT or gene, and defects of the acid-labile subunit (ALS). To this can be MRI), to make subtype classification and to definitively confirm or added defects of the IGF-I receptor, where relative IGF resistance exclude the diagnosis. Lateralization of the source of the excessive manifests itself as growth failure, despite normal-increased serum aldosterone secretion is critical to guide the management of PA, and IGF-I concentrations. These conditions are characterized by various AVS is the most accurate means of differentiating unilateral from degrees of GH insensitivity and often prove refractory to GH ther- bilateral forms of PA. Recommended treatment in unilateral PA apy, even with high GH dosages. The recent availability of recombi- (APA or UHA) is laparoscopic adrenalectomy, while medical treat- nant DNA-derived IGF-I has provided a new therapeutic option for ment with mineralocorticoid receptor antagonists (MRA) is indicated such patients. IGF-I is administered, customarily, as a BID dosage, in patients with bilateral adrenal disease (idiopathic adrenal hyper- although clinical trials have demonstrated efficacy of qd therapy, as plasia, bilateral APA, GRA) or those unable or unwilling to undergo well. Additional studies, now in progress, are testing the feasibility surgery. MRA appear to be effective at controlling blood pressure and value of combination GH and IGF-I administration. It is antici- and to provide blood pressure-independent target organ protection. pated that as our understanding of the molecular basis of growth The most used drugs are Spironolactone, Potassium Canreonate or failure increases, appropriate targeted therapy may be administered, Canrenone, Eplerenone or less frequently Amiloride. reflecting the etiology of the short stature.

MTP3 GH and IGF-1 deficiency MTP4 action and disease

March 27 (Sat.) 11:10-12:00 Room 4 March 27 (Sat.) 11:10-12:00 Room 5 MTP3-1 MTP4-1 Novel syndrome of growth hormone deficiency: Adult Genetic Mutations of CYP19A1 in humans combined GH, PRL and TSH deficiency associated with Makio Shozu(1) circulating anti-PIT-1 antibody (1)Department of Reproductive Medicine, Graduate School of Medicine, Chiba University, Japan Yutaka Takahashi(1) Aromatase is an essential enzyme for estrogen formation. CYP19A1 (1)Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Kobe University is the only gene that encodes aromatase in the human genome. There Graduate School of Medicine, Kobe, Japan are two conditions caused by the genetic mutations of CYP19A1: In children, GH deficiency typically results from isolated GH defi- namely, a loss-of-function mutation and a gain-of-function mutation. ciency, rare genetic causes including GH, PIT-1 and PROP-1 gene A loss-of-function mutation leads to estrogen deficit, thus resulting mutations, or other central structural abnormalities. In contrast, adult in a complete loss of secondary sexual characteristics in females. growth hormone deficiency is caused by various damages in the One of the most striking phenotypes, which had not been anticipated hypothalamic-pituitary region including tumor, inflammatory, auto- until our discovery of the first case, is excess, including immune, vascular, radiation, and invasive insults and manifests neg- female pseudohermaphroditism at birth and progressive masculin- ative effects on body composition, cardiovascular risk factors, and ization after puberty. Another hitherto unexpected phenotype is the quality of life, those are related with reduced life expectancy. We bone phenotype in males, namely severe osteoporosis and a failure report three cases of adult-onset combined pituitary hormone defi- to achieve epiphyseal closure. The discovery of a male patient with ciency, characterized by complete deficiency of GH and PRL with aromatase deficiency revealed an aspect of estrogen as a metabolic severe decrease of TSH secretion, whose endocrinological findings hormone. Fifteen loss-of-function mutations have been reported so were compatible with those of short stature attributed to the abnor- far, including sense mutation, frame shift mutation and null mutation. mality of the POU1F1 (PIT-1) gene, but whose body heights and A gain-of-function mutation leads to symptoms of estrogen excess: development were all normal, thereby considered the etiology to be namely, gynecomastia in males and macromastia in females. An acquired. We found a presence of anti-PIT-1 antibody in the serum over-expression of aromatase in whole body cells causes estrogen of all three patients whereas we failed to detect any mutations in excess in prepubertal boys, thereby causing progressive and recur- the PIT-1 and PROP-1 gene. ELISA-based screening for anti-PIT-1 rent gynecomastia. Estrogen excess also causes premature growth antibody demonstrated that this antibody is highly specific for these spurts, early epiphyseal fusion, thus resulting in shorter adults. This patients. The immunohistochemical analysis of the pituitary gland phenotype suggests the importance of estrogen in the bone physiol- of case 2 revealed that neither PIT-1-, GH-, PRL- nor TSH-positive ogy, as previously demonstrated by aromatase deficiency. We iden- cells were detected despite the presence of ACTH and tified the first three families with micro-inversions around exon 1 of containing cells. In addition, the patient accompanied a broad spec- CYP19A1 as a causative recombination of this disease. The other trum of autoimmune endocrinopathy. Various autoantibodies were types of recombination so far identified include: micro-deletions and detected in these patients. Therefore, the combined GH, PRL and micro-duplications upstream of CYP19A1. TSH deficiency with anti-PIT-1 antibody might be a novel subtype of autoimmune polyendocrine syndrome type II. MTP4-2 MTP3-2 The link between the LKB1/AMPK pathway and aromatase in the breast provides a link between obesity and breast cancer Diagnosis and management of IGF deficiency Evan R. Simpson (1), Kristy A. Brown (1) Ron G. Rosenfeld (1) (1)Prince Henry’s Institute of Medical Research, Australia (1)Department of Pediatrics, Oregon Health & Science University, Portland, Oregon, USA It is now well established that obesity is linked to an increased risk of The combination of animal knockout studies and human mutational cancers such as colon and breast. Given the obesity problem world- analysis has confirmed the primary role of the IGF system in both wide, tens of millions more women may contract breast cancer in prenatal and postnatal growth. It has been estimated that 25-35% of their senior years than was previously thought. After menopause, it children currently labeled as idiopathic short stature have low serum is the local production of oestrogens within the breast adipose that concentrations of IGF-I, despite normal GH concentrations, consis- is believed responsible for the increased proliferation of breast can- Meet-the-Professor (MTP) S199 cer cells. We have demonstrated that the LKB1/AMPK pathway is alterations are related with obesity in experimental animals and in inhibitory of aromatase expression in primary human breast adi- humans, however mechanistical explanations for such alterations is pose stromal (hAS)cells by inhibiting the nuclear entry of CRTC2, still lacking. a CREB co-activator. Factors produced in obesity, such as , were shown to inhibit AMPK activity and cause the nuclear trans- location of CRTC2, resulting in increased expression of aromatase. Conversely, a factor produced in lean individuals, , inhib- MTP6 Graves’ disease ited the PGE2-mediated expression of aromatase. Metformin, an oral anti-diabetic drug, is believed to act primarily by stimulating AMPK. March 27 (Sat.) 11:10-12:00 Room 7 We examined the effect of metformin on aromatase expression and on AMPK activity within the breast. HAS cells obtained from breast MTP6-1 reduction surgeries were treated with metformin and aromatase tran- Antithyroid drug therapy of Graves’ disease: Methimazole or script expression was quantified. Treatment resulted in the inhibition propylthiouracil and how much of the dosage? of aromatase expression. AMPK activity was measured by examin- ing its phosphorylation, and metformin caused a significant increase Hirotoshi Nakamura (1) in AMPK phosphorylation. In summary, this study identifies the (1)Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Japan LKB1/AMPK/CRTC2 pathway as a regulator of aromatase expres- Antithyroid drug (ATD) therapy is the main management of sion within the breast and suggests a mechanism whereby an anti- Graves’ disease (GD). Although methimazole (MMI) and propylth- diabetic drug that targets this pathway could be used to treat obesity- iouracil (PTU) are used widely, the superiority of the drug, which related postmenopausal oestrogen-dependent breast cancer. depends on the efficacy of decreasing thyroid , inducing remission and incidence of adverse effects, has not been decided. Only limited studies that compared the effectiveness of MMI and PTU were available. Regarding adverse effects, PTU is known to MTP5 Obesity and hypothalamo-pituitary axis have serious side effects such as severe hepatotoxicity and MPO- ANCA positive vasculitis, although the frequency of minor side March 27 (Sat.) 11:10-12:00 Room 6 effects was reported not to differ between the two drugs. In order to decide the suitable regimen, we undertook a prospective randomized MTP5-1 study on treatments for GD by comparing MMI 30mg/day, MMI Obesity and central regulation of appetite 15mg/day and PTU 300mg/day. For the whole group (240 patients) MMI 30mg/day normalized FT4 in more patients than PTU 300mg/ Masamitsu Nakazato (1) day and MMI 15mg/day at 12 weeks. When patients were divided (1)Neurology, Respirology, Endocrinology and Metabolism, Division of Internal Medicine, University of into two groups by initial FT4, in the patients with severe hyper- Miyazaki, Miyazaki, Japan thyroidism (FT4 >7ng/dl) MMI 30mg/day normalized FT4 more Meet-the- Energy balance is controlled by the complicated and minute interac- effectively than PTU 300mg/day at 8 and 12 weeks and MMI 15mg/ Professor tions of substances to stimulate or suppress food intake and energy day at 8 week, respectively. No remarkable difference among the expenditure. The molecular mechanisms of energy balance are com- treatments was observed in patients with initial FT4 <7ng/dl. Minor ing to light by the recent robust progresses in the molecular biology adverse effects were much higher with PTU and lower with MMI and neuroscience. , the center of energy homeostasis, 15mg/day. Our study showed the superiority of MMI than PTU from receives information related to satiety and fast from the body and the points of short-term efficacy and side effects. MMI 15mg/day is other brain regions, integrate them, and mediate interactions with suitable for most GD, while MMI 30mg/day is advisable for very efferent pathways. The hypothalamus produces a large array of sub- severe cases. PTU is not recommended for initial use. stances to regulate feeding. We have clarified that the vagal afferent is the major pathway conveying feeding-regulatory signals of gut MTP6-2 hormones to the hypothalamus. Recent findings will provide a clue The etiology of Graves’ disease: Is it all in the thyroiditis? to our better understanding of the molecular etiology of body weight control and the pathogenesis of obesity and anorexia in humans. Terry F. Davies (1) (1)Mount Sinai School of Medicine, New York, USA MTP5-2 The autoimmune diseases represent a collection of heterogeneous Obesity and hypothalamo-pituitary axis disorders often controlled by complex genetic and environmental Felipe F. Casanueva (1) factors and stochastic contributions. A common view of Graves’ Disease is that TSH Receptor-Abs promote the disease by enhanc- (1)Department of Medicine, Santiago de Compostela University, Complejo Hospitalario Universitario de Santiago, Spain ing thyroid antigen expression. However, T cell activation and sub- sequent thyroid infiltration in Graves’Disease patients are difficult Obesity has been associated with relevant alterations at hypothala- to explain entirely via a direct autoantibody-induced mechanism. mo-pituitary level, however no clear-cut or mechanistical explana- The pathogenesis of Graves’ Disease is more likely the result of a tions has been provided. The paradigmatic effect of obesity on the breakdown in the mechanisms controlling tolerance at different lev- somatotrop axis lead some authors to postulate that excess of adi- els (central and peripheral) and involving different cellular subsets posity generate growth hormone (GH) deficiency. In fact, the spon- (mainly B and T cells). The likely scenario for T cell activation and taneous GH secretion evaluated over 24h is severely reduced in recruitment of inflammatory cells in the gland may be due to the pro- both experimental animals and humans. Moreover, GH discharge duction of certain cytokines and chemokines released via by-stander is blocked when obese subjects are challenged by all the dynamic T cells along with antibody-mediated activation of thyrocytes and/or stimuli known so far. The GH hyposecretory state fades when damaged thyrocytes. The released TSHR from thyrocytes then stim- obesity is reduced or eliminated by either diet or gastric surgery. ulates T, B and antigen-presenting (dendritic) cells further activat- However, there are several reasons to negate that obese subjects ing cellular subsets to perpetuate the disease process. This view of are GH deficient: IGF-1 total and free levels in plasma are normal; Graves’ Disease suggests that a background degree of autoimmune potent GH stimuli such as a GHRS plus GHRP-6 and are able to thyroiditis is an essential component of the disease and is compatible induce a significant GH release. Furthermore, obese children grow with the the intrathyroidal lymphocytic infiltrate seen in patients. normally.Another relevant action of obesity resides in the reproduc- tive function. It is evident that obese women suffer fertility prob- lems, although no clear explanation of the cause is available. On the other hand, obesity is a leading cause of the age-related reduction in testosterone levels in males.In summary, several neuroendocrine S200 14th International Congress of Endocrinology

MTP7 Andropause MTP8 Cardiac natriuretic

March 27 (Sat.) 11:10-12:00 Room 8 March 27 (Sat.) 11:10-12:00 Room 9 MTP7-1 MTP8-1 Effects of testosterone replacement therapy for late-onset Positioning of rapid BNP assay in the emergency room and hypogonadism patients mainly suffering from psychological intensive care unit symptoms Michihiro Yoshimura(1) Tadashi Matsuda (1) (1)The Jikei University School of Medicine, Japan (1)Department of Urology and Andrology, Kansai Medical University, Hirakata, Japan Brain natriuretic (BNP) is an extremely valuable tool for Late-onset hypogonadism (LOH) is defined as a clinical and bio- diagnosing cardiac failure in various clinical settings. BNP values chemical syndrome associated with advancing age and character- are useful for the following: ized by typical symptoms and deficiency in serum testosterone lev- the early diagnosis of heart failure in health screening, as well as els. Testosterone replacement therapy (TRT) is performed to treat for determining the differential diagnosis, severity, therapeutic LOH, however the effects and duration of TRT have not been elu- effects and prognosis of patients with heart failure. A rapid assay cidated. I demonstrate characteristics of the patients visiting LOH has recently become available that has further expanded the appli- clinics in Japan and effects of TRT, according to the experiences cability of BNP, particularly in the emergency room (ER) and inten- of 511 patients in our institute. Half of the patients suffered from sive care unit (ICU). Rapid BNP assays are useful when patients severe symptoms of all three categories when evaluated using Aging transported to the ER have suspected heart failure. Combining chest Male Symptom (AMS) score, including physical, mental and sexual X-ray images with standard blood test findings and BNP values ren- symptoms. Self-rating Depression Scale (SDS) indicated that 50% ders a differential diagnosis of heart failure a relatively simple mat- of the patients were depression. 40% of the patients showed low ter. The severity of heart failure when complicated by pneumonia total testosterone (TT) and/or free testosterone measured by a radio- was previously difficult to determine when BNP could not be mea- immuno assay (FT-RIA). Testosterone enanthate 250mg im every 3 sured. However the introduction of the rapid BNP assay allows eas- weeks was performed on 220 patients and was effective in 45% of ier diagnosis of heart failure. Therefore, BNP can play a major role the patients once received TRT. Symptoms or QOL scores includ- in the differential diagnosis and severity assessment of heart failure ing AMS, SDS, IIEF5 and SF-36 improved significantly after TRT. in the ER. Measuring BNP values is also strongly recommended When TRT was effective, it continued for 6 months and stopped. for patients in the ICU, particularly for understanding the course of 60 months after discontinuation of TRT, SF-36 maintained bet- heart failure. Chronological changes in BNP values after admission ter than the pre-TRT status according to the follow-up study. Even are important to know. Several clinical studies have clarified that though LOH syndrome shows a variety of symptoms, the majority persistently high BNP values are associated with a poor prognosis, of Japanese patients visiting LOH clinics suffer from 3 categories of and this can be improved by planning therapy based on BNP values. symptoms; physical, mental and sexual. Short-term TRT is effective Overall, BNP values are useful for assessing therapeutic effects and in less than half of these patients and the effects continue after dis- the prognosis of patients with heart failure in the ICU. continuation of TRT in some of the patients. MTP8-2 MTP7-2 Cardiac natriuretic peptides: Looking to the future Andropause - Fact or fiction? M. Gary Nicholls (1) Ilpo T. Huhtaniemi (1) (1)Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand (1)Department of Surgery & Cancer, Division of Cancer, Reproductive Biology & Clinical Obstetrics & Of the cardiac natriuretic peptides, plasma B-type natriuretic peptide Gynaecology, Imperial College London, London, UK (BNP) and NTproBNP have found widespread use in the diagnosis The decline of testosterone (T) secretion of ageing men, associ- of heart failure in emergency departments. Benefits result also from ated with a variety of sexual, physical and psychological symp- their use in guiding the complex pharmacotherapy of chronic heart toms, has received lots of attention recently. This novel syndrome failure, and there is potential in tailoring drug therapy and body fluid has many names including male menopause, andropause, and the balance for patients with end-stage renal failure on chronic dialysis. recommended term late-onset hypogonadism (LOH). In this presen- In the future, BNP and NTproBNP may find a place in the diagno- tation we will review the current information about the diagnostic sis of heart failure in primary care, provide prognostic information criteria, including the discriminatory value of the different clinical following acute myocardial infarction and for patients with cardiac and laboratory findings in LOH, as well as the various therapeutic valve disease, in predicting adverse cardiovascular events in patients options for LOH. The information is largely based on the recently at risk (hypertensives and diabetics in particular, and prior to major conducted European Male Ageing Study (EMAS) (Wu et al. JCEM surgery) and perhaps even in the general population. Interpretation 2008; 93:2737). Some of the key findings of this study are: Serum of BNP and NTproBNP levels should take account of age, gender, T decreases in men on average by 0.5-1%/yr, but most older men BMI, race, medications, and concomitant disorders including renal remain eugonadal. Purely ageing-related hypogonadism is relatively impairment and thyroid dysfunction. The place of BNP in therapeu- rare, it is more often due to obesity and/or systemic diseases. The tics is unclear. diagnosis of LOH entails a combination of hypogonadal symptoms We have discovered recently the presence in human plasma of a (sexual and physical) and consistently decreased serum total (<8-10 fragment of BNP signal peptide (BNPsp), the venous levels of which nmol/L) and/or free T (<225 pmol/L). Scientific evidence for ben- are 14.1±0.4 pmol/L (mean±SEM, range 7-25 pmol/L) in healthy efits of androgen replacement therapy (ART) in LOH remains weak volunteers (n=125) with similar values in chronic renal or heart fail- in the absence of large well-controlled studies. The main conclu- ure. In patients with ST-elevation myocardial infarction (STEMI), sions are: 1. LOH can be defined as consistent decrease of circulat- peripheral venous levels of BNPsp were increased 6-fold above the ing T and sexual (and physical) symptoms of hypogonadism. 2. The normal range 4-5 hours after the onset of symptoms and significantly commonest causes of LOH are obesity and/or systemic diseases. 3. earlier than myoglobin, troponin I or NTproBNP responses. Future Weight reduction, life-style modification and treatment of systemic studies will determine the diagnostic specificity and clinical utility of diseases should be attempted before embarking on life-long ART. venous BNPsp in acute cardiac ischaemia. 4. Scientifically convincing results on benefits of androgen replace- ment therapy in LOH are still missing. Meet-the-Professor (MTP) S201

MTP9 FGF family and disease MTP10 Diabetes insipidus

March 27 (Sat.) 11:10-12:00 Room 10 March 27 (Sat.) 11:10-12:00 Room 15 MTP9-1 MTP10-1 Evolution and functional diversity of the Fgf gene family Subclinical diabetes insipidus Nobuyuki Itoh (1) Yasumasa Iwasaki (1) (1)Kyoto University Graduate School of Pharmaceutical Sciences, Kyoto, Japan (1)Health Care Center, Kochi University, Kochi, Japan Fgfs (Fibroblast growth factors) are polypeptides with diverse bio- Diabetes insipidus (DI) is characterized by polyuria and polydip- logical activities in multiple developmental and metabolic pro- sia. Differential diagnosis (central DI, nephrogenic DI, psychogenic cesses. The human/mouse Fgf gene family comprises twenty-two polydipsia) in patients with overt polyuria (> 5L/day) is easily made members. During the evolution of early vertebrates, the Fgf gene by hypertonic saline infusion test, DDAVP loading test, and pituitary family greatly expanded via two large-scale genome duplications MRI. However, that in patients with mild polyuria (2.5-5 L/day) or and acquired this functional diversity (Itoh and Ornitz, Dev. Dyn. even without polyuria (only nocturia) is sometimes difficult. In this (2008) 237, 179-186). Fgfs can be divided into intracellular Fgfs, session, we present the heterogeneity of the subclinical forms of DI, canonical Fgfs, and hormone-like Fgfs. Canonical and hormone-like and the pathophysiological background will be discussed. Fgfs as extracellular proteins mediate their biological responses by binding to cell surface Fgf receptors. Canonical Fgfs function in a MTP10-2 paracrine manner, while hormone-like Fgfs function in an endocrine Diabetes insipidus - Translational aspects manner. Most members of the Fgf gene family have been targeted in mice. Phenotypes range from early embryonic lethality to sub- Soren Rittig (1) tle changes in adult physiology. Canonical Fgfs have essential roles (1)Pediatric Research Center Skejby, Dept. of Pediatrics, Aarhus University Hospital, Denmark as proliferation or differentiation factors in development. In con- This review will focus on translational aspects of the neurohypo- trast, hormone-like Fgfs, Fgf15/19, Fgf21, and Fgf23, have impor- physeal hormone arginine vasopressin (AVP) and the impact on cur- tant roles as hormones in metabolism. Fgf signaling disorders also rent clinical management. In particular, the molecular background result in human diseases. Fgf21 produced in the liver functions as behind different hereditary clinical diabetes insipidus phenotypes a hormone-like Fgf. Hepatic Fgf21 expression is greatly increased will be addressed. Autosomal dominant familial neurohypophyseal by fasting. The phenotypes of hepatic Fgf21 transgenic mice sug- diabetes insipidus (adFNDI) is characterized by development of a gest that Fgf21 is required for lipolysis in adopocytes, ketogenesis severely deficient neurosecretion of AVP that appears after a postna- and triglyceride clearance in the liver, and growth hormone signal- tal period with completely normal AVP function. The genetic basis ing. In contrast, the phenotypes of Fgf21 knockout mice indicate is now well characterized as the rate of new mutation reports has

that Fgf21 is not required for ketogenesis, triglyceride clearance, and declined markedly. The mutation pattern, together with evidence Meet-the- Professor growth hormone signaling. Fgf21 regulates lipolysis in adipocytes in from clinical, cellular, and animal studies, points toward a patho- response to the metabolic state (Hotta et al., Endocrinology (2009) genic cascade of events, initiated by protein misfolding, involving 150, 4625-4633). intracellular protein accumulation, and ending with degeneration of the AVP producing magnocellular neurons. Molecular research has MTP9-2 also provided an important diagnostic tool in the occasionally diffi- Fibroblast growth factor-23 (FGF23) cult differential diagnosis of DI and examples of kindreds suspected of adFNDI but proving to have partial congenital nephrogenic DI Kenneth E. White (1) (CNDI) will be presented. Molecular evidence from such examples (1)Indiana University School of Medicine, USA suggests that different CNDI mutations can create the same clini- The phosphaturic hormone Fibroblast growth factor-23 (FGF23) is cal phenotype through different intracellular mechanisms, e.g. defect produced in bone and circulates to the kidney to control phosphate V2 receptor translocation and defect receptor affinity. In conclusion, metabolism. This hormone has provided key insight into disorders molecular research in adFNDI has provided an important tool in dif- of phosphate handling, and to physiological phosphate homeostasis. ferential diagnosis of different DI forms and in the understanding of Autosomal dominant hypophosphatemic rickets (ADHR), X-linked underlying pathogenic mechanisms as well as an opportunity to per- hypophosphatemic rickets, autosomal recessive hypophosphatemic form pre-symptomatic diagnosis. The improved molecular under- rickets (ARHR), and tumor induced osteomalacia (TIO) are all char- standing of antidiuresis has furthermore created an opportunity to acterized by hypophosphatemia with inappropriately normal 1,25 develop new treatment strategies. (OH)2 vitamin D concentrations and osteomalacia. These disor- ders are associated with elevated FGF23. ADHR is caused by gain of function mutations in FGF23, and XLH is due to mutations in PHEX. Patients with the novel disorder ARHR, due to mutations in MTP11 Translational research in RAS Dentin matrix protein-1 (DMP1), have very similar manifestations to patients with XLH. Hyperphosphatemic tumoral calcinosis (TC) March 28 (Sun.) 11:10-12:00 Room 2 is caused by FGF23, GALNT3, and Klotho loss of function muta- tions. The mutations in FGF23 and GALNT3 likely result in mis- MTP11-1 processing of FGF23, and the secretion of inactive FGF23 peptide A mouse model for pregnancy-associated hypertension fragments. An H193R substitution in KL leads to increased renal induced by the "human" renin-angiotensin system reabsorption of phosphate, likely through an end-organ resistance to FGF23. New aspects of FGF23 function, including discovery of Akiyoshi Fukamizu (1) endocrine feedback with PTH, and a potential intra-renal signaling (1)Center for Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Japan axis, has led to new hypotheses underlying phosphate handling. The Preeclampsia is a life-threatening complication of pregnancy for recent genetic, clinical, and basic discoveries involving FGF23 and both mother and fetus during gestation. Although it is character- its receptor complex may provide novel targets for the treatment of ized by blood pressure (BP) elevation and proteinuria after 20 weeks disorders involving impaired phosphate handling. of gestation in human, the etiology and pathology of preeclampsia remain unclear. We had generated mice associated with hyperten- sion during pregnancy (pregnancy-associated hypertension: PAH) by mating females expressing human angiotensinogen (hANG) with males expressing human renin (hRN). In PAH mice, maternal blood S202 14th International Congress of Endocrinology pressure is elevated from 13 days of gestation (E13) until delivery thesis inhibitors and/or surgical treatment (total adrenalectomy) to (E19–20) due to the generation of excessive angiotensin I, the pre- control hypercortisolism is recommended with favorable prognosis, cursor of angiotensin II, by hRN secretion from the fetal side to the but regular follow-up with repeated localization studies is required maternal circulation. Systolic BP at E19 in PAH mother reaches 160 until covert tumor becomes overt (wait & watch) . mmHg, whereas that in normal pregnant mouse remains around 100 mmHg. In addition to hypertension, PAH mothers show proteinuria, MTP12-2 cardiac hypertrophy and often convulsions. The fetus at term in PAH Adrenal Cushing’s syndrome pregnancy shows severe intrauterine growth retardation (IUGR), and the mean body weight of PAH fetus at E19 is about 65% of that André Lacroix (1) of wild-type (WT) fetus. Recently, it is now widely recognized as (1)Department of Medicine, Centre hospitalier de l’Université de Montréal (CHUM), Canada the aberrantly activated AT1 signaling in PIH patients. To clarify the ACTH-independent adrenal etiologies are responsible for 15-20% significance of AT1 signaling in PAH, we investigated the effects of of endogenous Cushing’s Syndrome (CS). Unilateral functional AT1 blockade in this model by means of the genetic and pharmaco- adenomas and, less frequently, carcinomas are responsible for the logical approaches. I will summarize the recent progress upon our majority of adrenal CS. In 10-15% of cases, adrenal CS is due to molecular studies on PAH. bilateral adrenal lesions including primary pigmented nodular adre- nocortical disease (PPNAD), primary non-pigmented micronodular MTP11-2 hyperplasia, ACTH-independent macronodular adrenal hyperpla- Translational research and the renin angiotensin system sia (AIMAH) and rarely bilateral adenomas or carcinomas. PPNAD or bilateral non pigmented micronodular hyperplasia can be found Detlev Ganten (1) either alone or in the context of Carney complex, a multiple endo- (1)Stiftung Charite, Berlin, Germany crine neoplasia syndrome, and be secondary to mutations of type The Renin Angiotensin System (RAS) and its role in blood pressure 1 alpha-regulatory subunit of cAMP-dependent protein kinase A regulation has a long history of translational research since its dis- (PRKARIA) or of phosphodiesterases (PDE11A or PDE8B).AIMAH covery by Tigerstedt and Bergman in 1898. By 1956 the biochemisty can also present as incidental radiological finding or with sub-clini- of the RAS was pretty well worked out and in 1958 Gross made the cal or overt CS, occasionally with secretion of mineralocorticoids or startling claim that renin stimulated aldosterone. It was then discov- sex steroids. The aberrant adrenal expression and function of one or ered that the RAS, in addition to being a circulating hormonal sys- several G-protein coupled receptors can lead to cell proliferation and tem involved in cardiovascular homeostasis and hypertension also abnormal regulation of steroidogenesis in AIMAH and in unilateral had important paracrine functions in various tissues, including the adrenal tumors. In familial cases of AIMAH, specific aberrant hor- arterial wall, the heart and the brain, indicating its pathophysiolog- mone receptors may be functional in the adrenals of affected mem- ical relevance even if plasma renin and angiotensin were not ele- bers. Other mechanisms such as Gsp or ACTH receptor mutations vated. Inhibitors of the RAS were subsequently developed to reduce and paracrine adrenal hormonal secretion have been rarely identified the production and action of angiotensin at all levels of the enzy- in other cases of AIMAH. The identification of aberrant receptors matic cascade and at the receptor level. Today these drugs count can offer specific pharmacological approach to prevent disease pro- among the most efficient and best tolerated drugs in the treatment gression and control abnormal steroidogenesis particularly for bilat- of high blood pressure. The pharmacology, translational research eral AIMAH. For unilateral etiologies of for PPNAD, unilateral or and the exemplary multicenter clinical outcome trials have become bilateral laparoscopic adrenalectomy is the treatment of choice. a success story in the treatment of hypertension and cardiovascular diseases and milestones of modern medicine.

MTP13 Mineralocorticoid hypertension

MTP12 Cushing’s syndrome March 28 (Sun.) 11:10-12:00 Room 4

March 28 (Sun.) 11:10-12:00 Room 3 MTP13-1 Mineralocorticoid receptor, salt-sensitive hypertension and MTP12-1 metabolic syndrome ACTH-dependent Cushing’s syndrome Toshiro Fujita (1) Yukio Hirata (1) (1)Department of Nephrology and Endocrinology, University of Tokyo, Tokyo, Japan (1)Department of Endocrinology & Metabolism, Tokyo Medical & Dental University , Tokyo, Japan Obese persons with metabolic syndrome often have associated with ACTH-dependent Cushing’s syndrome (CS) consists of Cushing’s salt-sensitive hypertension, microalbuminuria, and cardiac dys- disease (CD) and ectopic ACTH syndrome (EAS), which account function, and the plasma aldosterone level in one third of metabolic for 35-40% and 4-10% of endogenous CS respectively, in Japan. syndrome patients is clearly elevated. Hyperaldosteronism, which EAS caused mostly by pulmonary tumors typically presents with may be caused at least partially by certain adipocyte-derived fac- profound hypokalemia and skin pigmentation due to ACTH hyper- tors, contributes to the development of proteinuria in obese hyper- secretion. However, differential diagnosis of EAS from CD is chal- tensive rats, and salt loading aggravates the proteinuria and induces lenging. Recent advances in dynamic endocrine test (DST, CRH) as cardiac diastolic dysfunction because of inadequate suppression well as imaging tests (CT, MRI, PET) enable us to distinguish less of plasma aldosterone level. However, mineralocorticoid recep- frequent EAS from more common CD. However, diagnostic accura- tor (MR) antagonists prevent salt-induced renal and cardiac dam- cies of DST and CRH test are relatively limited. Pituitary microad- age, suggesting that aldosterone excess and a high-salt diet exert an enoma can be detected by brain MRI in 40-60% of CD. Therefore, unfavorable synergistic action on the kidney and heart. In Dahl salt- inferior petrosus sinus (IPS) sampling for assessment of central to sensitive rats, however, despite appropriate suppression of plasma peripheral plasma ACTH ratio before and after CRH stimulation is aldosterone with a high-salt diet, salt loading paradoxically activated gold standard test to differentiate EAS from CD, it is difficult to renal MR signaling, and the renal injury was markedly prevented localize ectopic ACTH source with occult tumor by the conventional by MR antagonists. Accordingly, we discovered an alternative path- imaging tests and scintigraphy. Although way of MR activation in which Rac1, a small GTP-binding protein, selective venous samplings other than IPS do not add to information activates MRs. Salt loading activates renal Rac1 in Dahl salt-sensi- with imaging studies, we recommend selective pulmonary arterial tive rats, and Rac1 in turn induces MR activation, which results in sampling in an occult small pulmonary tumor because occult EAS renal injury, and the renal injury has been found to be prevented by is more frequent in pulmonary carcinoid. Even if occult tumor could Rac1 inhibitors. Moreover, several metabolic-syndrome-related fac- not be detected by any means, medical treatment using steroid syn- tors induce Rac1 activation, and one of them, hyperglycemia, acti- Meet-the-Professor (MTP) S203 vates MRs via Rac1 activation. Consistent with this, Rac1 inhibitors MTP14-2 attenuated the proteinuria and renal injury in obese hypertensive ani- -like growth factors, diabetes and metabolism mals. Thus, both salt and obesity activate Rac1 and cause MR acti- vation. Abnormal activation of the aldosterone/MR pathway plays a Leon A. Bach (1,2) key role in the development of salt-sensitive hypertension and renal (1)Department of Endocrinology and Diabetes, The Alfred Hospital, Melbourne, Australia, (2)Department injury in metabolic syndrome. of Medicine (Alfred), Monash University, Melbourne, Australia Insulin-like growth factors (IGFs) share significant structural homol- MTP13-2 ogy with proinsulin. Although IGFs have physiologically important Mineralocorticoid hypertension proliferative actions, they also have insulin-like metabolic actions. IGFs increase glucose uptake into skeletal muscle and may also sup- Paul M. Stewart (1) press hepatic glucose uptake. IGF-I also increases insulin sensitivity (1)Endocrinology, Clinical & Experimental Medicine, University of Birmingham, Birmingham UK. in vivo, at least in part by suppressing secretion of growth hormone Mineralocorticoid Excess refers to inappropriate sodium retention, (GH), which has counter-regulatory actions, via a negative feedback characterized by suppression of plasma renin activity and is the com- loop. In short-term studies, IGF-I has been shown to decrease blood monest form of secondary hypertension. Primary aldosteronism was glucose levels in patients with type 1 and type 2 diabetes and syn- described by Jerome Conn over 50 years ago and was thought to dromes of extreme insulin resistance. IGF-I levels are decreased in be rare, but now newer methods of diagnosis through the use of the poorly-controlled type 1 diabetes but free IGF-I levels appear to be plasma aldosterone/renin ratio indicate that this may represent up to increased in type 2 diabetes. However, interpretation of these find- 10% of all cases of essential hypertension. Establishing the cause of ings is difficult because the IGF system is affected by diabetes as primary aldosteronism is also crucial since autonomous adenomas well as possibly contributing to its development. Prospective stud- can be cured with surgery, but the commoner cause, bilateral adre- ies suggest that high circulating IGF-I levels are inversely associated nal hyperplasia is resistant to surgery and must be treated medically. with the risk of developing type 2 diabetes. This protective effect New mineralocorticoid antagonists and the realization that min- may be due to direct trophic effects on beta-cells as well as improved eralocorticoids may have important actions on the heart and vas- insulin sensitivity. The use of IGF-based therapeutics in diabetes is culature have raised the profile of mineralocorticoid excess states. limited by theoretical long-term concerns that they may accelerate Rarely, “mineralocorticoid excess” can be inherited as “monogenic” microvascular complications of diabetes and/or increase cancer risk. forms of hypertension - glucocorticoid-suppressible hyperaldos- Nevertheless, increased understanding of the IGF system may pro- teronism due to a chimaeric 11β-hydroxylase/aldo synthase gene, vide insights into the aetiology of diabetes and lead to the develop- Liddle’s syndrome due to mutations in epithelial sodium channel ment of targeted safe therapies for this disease. subunits (ENaC’s), activating mutations within the mineralocorti- coid receptor (MR) itself, and Apparent Mineralocorticoid Excess (AME), secondary to failure of inactivation of cortisol in the kid- ney by 11β-hydroxysteroid dehydrogenase type 2. Who to screen MTP15 TSH-secreting pituitary adenoma Meet-the-

for mineralocorticoid excess and how to establish the diagnosis and Professor differential diagnosis are important considerations for the Clinical March 28 (Sun.) 11:10-12:00 Room 6 endocrinologist that will be explored through this Meet the Professor session. MTP15-1 TSH-secreting pituitary adenoma: Pathology Robert Y. Osamura (1) MTP14 Novel therapies for diabetes: Insulin and beyond (1)Tokai University School of Medicine, Japan The majority of TSH-secreting pituitary adenomas(TSHomas) are March 28 (Sun.) 11:10-12:00 Room 5 macroadenomas and invasive. And neurosurgeons have pointed out that the tumors are frequently firm most likely correlating with MTP14-1 fibrosis. Somatostatin analogue(SA), such as octreotide, has been Incretins and diabetes used in this group of pituitary adenomas(TSHomas and GHomas) which demonstrate high proportion of SSTR2a immune-positiv- Nobuya Inagaki (1) ity on the cell membrane. Immunohistochemical positivity cor- (1)Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, relates well with the response to pre-operative SA administration. Japan Dopamine 2 receptor(D2R) is localized on the cell membrane and Incretin hormones, GIP and GLP-1, have numerous actions includ- suggest the response to the dopamine agonist. From our experience, ing the insulinotropic effect and inhibition of glucagon secretion. Among various pituitary adenomas, from our experience, TSHomas It is known that insulin secretion rather than insulin sensitivity is are the most frequent tumors expressing both SSTR2a and D2R the more important factor in progression from normal glucose tol- which are eligible for the therapy by chimeric compound binding erance (NGT) to type 2 diabetes mellitus (T2DM) in Japanese sub- with both receptors. In the cases studied by immunohistochemistry, jects. While the potentiation of insulin secretion by incretin after O6-methylguanine–DNA methyltransferase(MGMT) is negative in meals (incretin effect) is reduced in T2DM, it is not known whether TSHomas which may predict the response to temozolomide. Thus, this defect contributes to the development of T2DM in Japanese. We pathologists are expected to play multiple roles in TSHomas for the measured GIP and GLP-1 levels during OGTT in Japanese NGT diagnosis and treatment. subjects and evaluated factors associated with GIP and GLP-1 secre- tion. MTP15-2 On the other hand, recently, a decrease in β-cell mass is thought to TSH-secreting pituitary adenomas be involved in the development and progression of T2DM. We have examined the effect of GLP-1 on the β-cells of Akita mice, a model Paolo Beck-Peccoz (1) of diabetes due to the ER stress-induced β-cell failure, and clearly (1)University of Milan, Fondazione Ca Granda IRCCS, Milan, Italy showed that GLP-1 ameliorates diabetes through its cytoprotective Thyrotropin-secreting pituitary adenomas (TSH-omas) are a rare effect on pancreatic β-cells. cause of hyperthyroidism. The number of reported cases tripled In this talk, the effects of incretin hormones will be discussed in the last years as a consequence of the routine use of ultrasensi- focusing on their role in the development and treatment of type 2 tive immunometric assays for measuring TSH levels. Contrary to diabetes. previous RIAs, ultrasensitive TSH assays allow a clear distinction between patients with suppressed and those with non-suppressed circulating TSH concentrations, i.e. between patients with primary S204 14th International Congress of Endocrinology hyperthyroidism (Graves’ disease or toxic nodular goiter) and those secondary prevention trials have confirmed benefit in those with dia- with central hyperthyroidism (TSH-oma or pituitary resistance betes but the residual risk remains high. Trials of more intensive sta- to thyroid hormone action). Failure to recognize the presence of a tin therapy have demonstrated improved benefit and in meta-anal- TSH-oma may result in dramatic consequences, such as improper ysis show a further 16% reduction in coronary events and an 18% thyroid ablation that may cause the pituitary tumor volume to fur- further reduction in stroke.Given the benefits of statin therapy all ther expand. The diagnosis mainly rests on dynamic testing, such as patients with diabetes over the age of 40 years should be considered TRH and T3 suppression tests. The medical treatment of TSH-omas for statin therapy regardless of baseline LDL. It is clear that it is the mainly rests on the administration of somatostatin analogs, such absolute reduction in LDL that is the major determinant of benefit. as octreotide and lanreotide. These drugs were effective in reduc- ing TSH and α-subunit secretion in more than 90% of cases with consequent normalization of FT4 and FT3 levels and restoration of the euthyroid state in the majority of them. In about one third of MTP17 Osteoporosis patients, a clear shrinkage of tumor mass and vision improvement could be demonstrated. Tachyphylaxis, cholelithiasis and carbohy- March 28 (Sun.) 11:10-12:00 Room 8 drate intolerance occurred in a minority of treated patients. Whether somatostatin analog treatment may be an alternative to surgery and/ MTP17-1 or irradiation in patients with TSH-oma remains to be established. Management of osteoporosis: The Japanese guidelines and topics of secondary osteoporosis Ryoichi Takayanagi (1) MTP16 Statins and diabetes (1)Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan Guidelines on the prevention and treatment of primary osteoporo- March 28 (Sun.) 11:10-12:00 Room 7 sis were updated in 2006 and those on glucocorticoid (GC)-induced osteoporosis (GIO) were developed in 2004 in Japan. In Japan, there MTP16-1 is evidence that bone mineral density (BMD) lowering, prevalent Lipid metabolism in type 2 diabetes mellitus and statin fracture, and age are risk factors for fracture. WHO shows that alco- therapy hol consumption, current smoking and family history of hip fracture are also risk factors. Based on those risk factors, criteria for initia- Nobuhiro Yamada (1) tion of drug therapy is proposed as follows: persons above 50 years (1)University of Tsukuba, Tsukuba, Japan old with a prevalent fragility fracture(s) (PFF), persons without PFF The clinical and epidemiological importance of cardiovascular but with BMD less than 70% of young adult mean (YAM), persons diseases, has increased rapidly in recent years. Diabetes mellitus above 50 years old without PFF but with BMD ranging from 70 to which serves as a basis for the development of atherosclerosis, are 80% YAM and one of the risk factors. Criteria for initiation of drug induced by a genetic predisposition coupled with environmental fac- therapy for GIO is as follows: patients using or planning to use oral tors. Hypernutrition and insufficient exercise lead to diabetes melli- GC for 3 months or longer with prior fragility fracture or new frac- tus, hyperlipidemia, hypertension, obesity, and insulin resistance in ture during treatment, with BMD less than 80% YAM, or with a individuals genetically predisposed to these disorders, which even- dose of 5mg/day or higher as prednisolone equivalent, since those tually produce ischemic heart disease and cerebrovascular disease. were found to be thresholds for increased fracture risk. Fragility The Japan Diabetes Complication Study (JDCS) has reported that fracture (FF) is sometimes observed in the patients who under- the prevalence of atherosclerosis in patients with diabetes mellitus is went liver transplantation. There are two major causes of FF. One is approximately three times that in individuals without diabetes, and a osteoporosis induced by GC or liver damage, which is usually devel- Finnish study has reported that the risk of ischemic heart disease is oped within 1 year after transplant, and the other is osteomalacia by extremely high in patients with type 2 diabetes mellitus. We found hypophosphatemia, which is developed 2 or 3 years after transplant. that a major risk factor for ischemic heart disease in JDCS was high Etiology of hypophosphatemia will be discussed. plasma LDL cholesterol level and that for cerebrovascular disease was high blood pressure. In order to prevent the development of ath- MTP17-2 erosclerosis, in particular, ischemic heart disease in patients with Advances in the treatment of osteoporosis type 2 diabetes mellitus, the risk of development of hyperlipidemia John P. Bilezikian (1) should be carefully controlled. (1)College of Physicians and Surgeons, Columbia University, USA MTP16-2 Newer concepts in the treatment of osteoporosis are emerging due to Diabetes: The need for intensive statin therapy greater understanding of the pathways by which bone cells are reg- ulated. They are providing greater therapeutic breadth to the tradi- D. John Betteridge (1) tional classes of antiresorptive and osteoanabolic agents that are cur- (1)University College London, UK rently available. An example is the regulatory system comprised of Diabetes is associated with increased morbidity and mortality from RANKL, its receptor (RANK), and osteoprotegerin. RANKL stimu- cardiovascular disease (CVD).Prevention of CVD is an important lates osteoclastogenesis and osteoclast action. Denosumab, a human part of the overall management of the patient with attention to all antibody against RANKL, inhibits the actions of RANK and, thus, modifiable risk factors. Dyslipidaemia is common in type 2 diabetes reduces the development and actions of osteoclasts. A recent phase consisting of increased concentrations of triglycerides, low concen- 3 study has shown that vertebral, non-vertebral and hip fractures trations of HDL and the accumulation of cholesterol-rich remnant are significantly reduced by denosumab in postmenopausal women particles. LDL concentrations tend to mirror the background popu- with osteoporosis. Another agent in development is targeted at the lation but there are important qualitative changes which make LDL cysteine protease, Cathepsin K, an osteoclast enzyme that degrades more atherogenic.There is robust evidence from well-conducted, the organic bone matrix. Odanacatib, a Cathepsin K inhibitor, ren- controlled, clinical trials to support the primary and secondary pre- ders the osteoclast dysfunctional. Odanacatib is currently in phase 3 vention of CVD in diabetes with statins. In the CARDS study, the clinical trials. Other recent advances relate to newer approaches to first statin trial to be conducted specifically in a population of patients the use of . A transdermal system shows prom- with type 2 diabetes with no pre-existing CVD and relatively low ise. Calcilytics that stimulate the endogenous production of PTH LDL levels (baseline LDL 3mmol/l) there was a 37% reduction in have also received attention. Pathways that lead to stimulation of CVD events after approximately 4 years of follow-up with atorvas- bone formation are also being targeted for drug development. The tatin 10mg/day. Stroke was reduced by 50%. Sub-group analysis of Wnt pathway, for example, is an essential means by which the osteo- blast is regulated. Sclerostin, a regulatory product of the SOST gene, Meet-the-Professor (MTP) S205 inhibits the Wnt pathway and thus controls osteoblast function. An antibody raised against sclerostin is showing therapeutic promise. MTP19 Gonadotropin regulation These new approaches to osteoporosis are likely to have profound effects on how we treat this disease March 28 (Sun.) 11:10-12:00 Room 10 MTP19-1 Regulation of gonadotropin receptor MTP18 Polycystic ovary syndrome Takashi Minegishi (1), Kazuto Nakamura (1), Soichi Yamashita (1), Sadatomo Ikeda (1), Kayoko Kogure (1) March 28 (Sun.) 11:10-12:00 Room 9 (1)Department of Obstetrics and Gynecology, Gunma University Graduate School of Medicine, Japan MTP18-1 The luteinizing (LHR) is essential for elevated levels of progesterone to maintain pregnancy during the first trimes- New Creiteria of polcystic ovary syndrome in Japan ter; the maintenance of the expression of LHR is a key factor to con- Minoru Irahara (1) trol the duration of luteal function. Therefore, since the expression (1)The University of Tokushima, Tokushima, Japan of LHR might be mainly regulated by the stability of the receptor Chronic anovulation, menstrual irregularity and polycystic mor- mRNA at the luteal phase of human menstrual cycle, we focused phology of the ovaries are essential factors of PCOS and have on the studies of stability of the mRNA in stead of production of been adopted for the diagnostic criteria of PCOS. Hormonal fac- mRNA. In addition, LHR (exon 9), one of the splice variants among tors has been considered important in diagnosis because incidences hLHR, was cloned in the corpus luteum of a patient with a regular of symptoms(obese or hyperadrogenism ) are deferent from the menstrual cycle. The results of Western blots using Percoll gradi- Caucasian. Especially, elevated serum LH level which is highly ent fractionation indicated that hLHR formed complexes with hLHR prevalent in Japanese PCOS patients has been also adopted in the (exon 9), which are transferred to the lysosome, where they are former diagnostic criteria of PCOS established by Japan Society of eventually degraded, instead of being translocated from the endo- Obstetrics and Gynecology in 1993(JSOG 1993: all of following 3 plasmic reticulum to the transducing organelle. This work reveals factors; menstrual irregularity, elevated serum LH level, PCO find- the essential function of regulatory and structural elements involved ing by USG). in human LH receptor splicing, and hLHR (exon 9) can negatively Elevated LH level was seen in majority of PCOS patients in control the function of wild-type receptors. Moreover, this finding Japan. But, it is well-known its reproducibility was poor, especially presented a novel mechanism of regulation of LHR in the human in the serum collected within 10 days from withdrawal bleeding and corpus luteum. in obese patients. Additionally, more sensitive kits for examination of are abailable. So, we establish the revised criteria of MTP19-2 PCOS in Japan (JSOG 2007: all of following 3 factors; menstrual Gonadotropin regulation by GnRH pulses and steroids Meet-the- irregularity, PCO finding by USG, elevated serum LH level and/or Margaret A. Shupnik (1), Heather Ferris (1), Heidi E. Walsh (1), Takanori Kowase (1), Professor hyperandrogenemia). In new criteria, it is recommended to assess Aurora Rodriguez (1), Josefa Andrade (1) LH level after more than 10 days from withdrawal bleeding, and to (1)Department of Medicine, University of Virginia, Charlottesville, VA, USA use LH/FSH ratio in obese PCOS for the diagnosis and hyperandro- genemia seemed useful also in Japan as a complementary factor. Appropriate gonadotropin production is critical for fertility. GnRH pulse frequency determines which pituitary gonadotropin (LH, MTP18-2 FSH) is secreted, and defines transcription rates of the subunit genes: LHβ, FSHβ and the common α-subunit. FSH secretion and FSHβ Polycystic ovary syndrome transcription occur preferentially with slower GnRH pulses (1/120 Stephen Franks (1) min), and LH secretion and LHβ transcription at more rapid pulses (1)Institute of Reproductive & Developmental Biology, Imperial College London, UK (1/30 min). Although there is no single explanation for differential Polycystic ovary syndrome (PCOS) is the commonest cause of ano- transcription by GnRH pulses, GnRH-stimulated signaling path- vulatory infertility, menstrual disturbances and hirsutism. The clas- ways play a role, and androgens and modify both GnRH sic presentation is amenorrhoea or oligomenorrhoea associated pulses and pituitary responses to GnRH. Increased ERK1/2 activ- with clinical and/or biochemical evidence of hyperandrogenism. ity is required for GnRH stimulation of alpha-subunit and FSHβ, However, it is clear that the spectrum of presenting symptoms of but not LHβ mRNA. Androgens and slow GnRH pulses increase women with polycystic ovaries is wide, including anovulation with- basal ERK1/2 activity and prolong the GnRH response, in part by out hirsutism (androgen levels are usually raised) and hirsutism with decreasing ERK1/2 phosphatase actvity. For LHβ, JNK is essen- regular cycles. This has been recognised in the form of a revised tial in mediating responses to pulsatile GnRH, whereas JNK main- definition of PCOS resulting from the joint ESHRE/ASRM consen- tains FSHβ basal expression but plays no role in GnRH stimulation. sus conference (Rotterdam criteria). The typical gonadotrophin pro- GnRH-driven expression and dynamic chromatin binding of tran- file is elevated serum levels of LH with normal or slightly low FSH. scription factors also contribute to differential transcription. Rapid PCOS is also associated with a metabolic disturbance in which the GnRH pulses preferentially stimulate expression of Egr-1, required central abnormality is insulin resistance. Women with PCOS are rel- for LHβ transcription, whereas slower GnRH pulses increase c-Jun atively hyperinsulinaemic and insulin resistant when compared with and c-Fos, which stimulate FSHβ. Estradiol enhances GnRH- weight-matched controls; 30-45% of obese PCOS subjects have stimulated Egr-1 levels, and suppresses the transcriptional suppres- impaired glucose tolerance. Women with PCOS are at increased sor Zfhx1a, thus augmenting LHβ expression during the ovulatory long-term risk of developing type2 diabetes (T2D) and, possibly, surge. Transcription factors bind the LHβ promoter with 30min peri- cardiovascular disease. The diagnosis of PCOS is made principally odicity, mimicking required physiological GnRH pulses, and with a on clinical grounds, supported by a small number of biochemical slower period to FSHβ. Thus, GnRH-regulated cell signaling, tran- investigations. The choice of investigations in women with PCOS scription factor expression, and chromatin binding all contribute to depends primarily on the mode of presentation. Because of the high differential gonadotropin expression. risk of impaired glucose tolerance or frank diabetes, obese, anovula- tory women with PCOS should have an oral glucose tolerance test. It is not necessary to measure circulating insulin levels. Treatment should be tailored to the presenting complaint but, for all indications, diet and lifestyle modification in overweight or obese subjects is the most important first step. S206 14th International Congress of Endocrinology

MTP20 Thyroid carcinoma / MEN2A MTP21 Disorders of sex development

March 28 (Sun.) 11:10-12:00 Room 14 March 28 (Sun.) 11:10-12:00 Room 15 MTP20-1 MTP21-1 Treatment of medullary thyroid carcinoma based on germline Genetics of DSD (disorders of sex development) RET mutation analysis Tsutomu Ogata (1) Akira Miyauchi (1) (1)National Research Institute for Child Health and Development, Japan (1)Department of Surgery, Kuma Hospital, Kobe, Japan DSD is usually noticed because of ambiguous genitalia at birth, Medullary thyroid carcinoma (MTC) derives from calcitonin pro- while it is also recognized at a later age or at the pubertal period. ducing C cells of the thyroid. It can arise as a component of multiple Recent progress in molecular genetic has successfully identified endocrine neoplasia (MEN) type 2A or 2B, familial MTC or as spo- multiple genes involved in DSD with ambiguous genitalia. Here, I radic MTC. MEN 2A, 2B and familial MTC are hereditary diseases will review the genetics of 46,XY DSD and 46,XX DSD, and show with autosomal dominant inheritance and the patients carry germline several representative cases. 46,XY DSD with ambiguous genitalia mutations in RET proto-oncogene. The mutations activate constitu- is primarily ascribed to incomplete androgen effects during the criti- tively RET gene product leading C cells to hyperplasia and carci- cal period for sex development. Thus, this condition can be caused noma. Thus, these hereditary MTCs arise multicentrically and are by mutations of genes involved in testis formation, testosterone pro- usually bilateral and multiple. On the other hand patients with spo- duction, conversion of testosterone into DHT, androgen receptor sig- radic MTC do not carry germline RET mutations and the tumors are naling, and formation of genital anlagen. In addition, insulin like 3 usually solitary. We have routinely performed germline RET muta- signaling plays a critical role in the determination of gonadal posi- tion analysis in all patients with MTC since December 1995. About tion. I will show patients with SF1 mutations, ARX mutations, and 16% of the patients with apparently sporadic disease were found to 9p deletions. These disorders are associated with a wide range of carry germline RET mutations. Total thyroidectomy is necessary phenotypes, probably depending on other genetic and environmen- for patients with the mutations. We also perform systematic mod- tal factors. Furthermore, environmental estrogen signaling is also ified neck dissection (MND) on the sides of macroscopic tumors relevant to 46,XY DSD, especially hypospadias and cryptorchid- irrespective of clinical sign of node metastases. If bilateral, we do ism. 46,XX DSD with ambiguous genitalia primarily results from bilateral MND. Based on the presence of germline RET mutation in excessive androgen effects during fetal life. This condition is usually young family members, so-called prophylactic total thyroidectomy caused by excessive androgen production from the gonad (ovotes- was performed in seven patients. The recently published manage- ticular DSD), the adrenal, and the placenta. Here, I will introduce ment guidelines for MTC by the American Thyroid Association rec- POR deficiency, and refer to the backdoor pathway to DHT. POR is ommend total thyroidectomy even for sporadic MTC. However, we a unique disorder that often causes 46,XY DSD and almost invari- think total thyroidectomy is not always necessary for sporadic MTC ably leads to 46,XX DSD. if the host patient is negative for germline RET mutation analysis and the tumor is solitary and confined to one thyroid lobe. We will MTP21-2 demonstrate our results. Disorders of sex development MTP20-2 Elaine M.F. Costa (1) (1)The Developmental Endocrinology Unit of Clinicas Hospital, University of Sao Paulo, Sao Paulo, Brazil Recent advances in diagnosis and treatment The birth of a child with disorders of sex development (DSD) Jeffrey F. Moley (1) prompts a long-term management strategy that involves an experi- (1)Washington University School of Medicine, USA enced multidisciplinary team working with the family. Optimal care Medullary thyroid carcinoma (MTC) is a neuroendocrine malig- of DSD patients begins in the newborn period when most of DSD nancy of the thyroid C-cells. Metastatic spread commonly occurs patients may be recognized and precocious diagnosis allows a better to cervical and mediastinal lymph nodes, and sometimes distant therapeutic approach. The diagnostic evaluation of DSD includes a metastatic spread occurs to lungs, bone and liver. MTC cells do not careful clinical evaluation, hormone measurements, imaging, cito- concentrate radioactive iodine, and are not sensitive to hormonal genetic and molecular studies and in some cases endoscopic, laparo- manipulation. Surgery is the only therapy at present that can reli- scopic and gonadal biopsy. A specialized psychologist must be act ably lead to cure, reduction in tumor burden or effective palliation. as soon as the diagnosis is suspected, and follow the family before MTC occurs in sporadic and hereditary forms. The hereditary forms and after genitoplasty. The social sex determination must consider are the multiple endocrine neoplasia type 2 syndromes. Genetic test- the etiological diagnosis, phallus size, ethnic traditions, sexual iden- ing of at-risk MEN 2 family members identifies RET gene mutation tity and the acceptance of the assigned social sex by the parents. The carriers who undergo preventative thyroidectomy. Central lymph affected child and his/her family must be followed throughout life to node dissection is considered in preventative operations if the cal- ascertain adjustment of patient to his/her social sex. The purpose of citonin level is elevated. Systematic surgical removal of at-risk or hormonal therapy is the development of sexual characteristics sim- involved lymph node basins (compartmental dissection) is recom- ulating normal puberty. In female social sex patients, a low dose of mended in all patients with palpable primary tumors and recurrent estrogen is started at 9-11 years and in boys, a low dose of testosterone disease. Although data is limited, standard chemotherapy and radi- is started at 10-11 yrs. The surgical treatment aims to allow develop- ation therapy have not been shown to be effective in treatment of ment of adequate external genitalia and removal internal structures MTC. Newer targeted drug therapies, including Vendatinib (Astra that are inappropriate for the social sex. Patients must undergo sur- Zeneca) are promising, and are being examined in therapeutic clini- gical treatment preferably before 2 years of age. Currently, in vitro cal trials. fertilization techniques has enabled 46,XY DSD patients to produce offspring. We will discuss the management of DSD patients based on two decades of experience with these patients. Meet-the-Professor (MTP) S207

MTP22 Ghrelin: Physiology and disease MTP23 Adult GH deficiency

March 29 (Mon.) 11:10-12:00 Room 2 March 29 (Mon.) 11:10-12:00 Room 3 MTP22-1 MTP23-1 Clinical applications of ghrelin Clinical practice for treating adult patients with severe growth Takashi Akamizu (1) hormone deficiency in Japan (1)Ghrelin Research Project, Translational Research Center, Faculty of Medicine, Kyoto University, Kyoto, Akira Shimatsu (1) Japan (1)National Hospital Organization Kyoto Medical Center, Kyoto, Japan Ghrelin is a 28-amino-acid that was discovered Adult growth hormone deficiency (GHD) and its long-term con- in 1999 as an endogenous ligand for the growth hormone (GH)- sequences have thoroughly been described in Caucasian sub- secretagogue receptor (GHS-R). This peptide possesses a unique jects. However, the clinical phenotypes of GHD in Japanese adult fatty acid modification, an n-octanoylation, at Ser 3. There are two patients still remain to be fully demonstrated, considering the dif- circulating forms of ghrelin, acylated and unacylated (desacyl). Of ferent genetic and environmental background from Caucasian. GH these, the acylated form is essential for biological activities of ghre- replacement therapy commenced into clinical practice in 2006 after lin through the GHS-R. Ghrelin is mainly produced in the stomach approval of GH therapy for severe adult GHD in Japan. We have col- and circulates in the blood at a considerable plasma concentration. lected and analyzed data on clinical characteristic of adult patients Expression of ghrelin is also detectable in the hypothalamus, intes- with severe GHD from the post-marketing surveillance study of GH tine, pituitary, placenta and other tissues. Ghrelin plays a role in a products in Japan. variety of physiological processes. For example, ghrelin strongly Mean age was 46 years, and the percentage of adult-onset (AO) stimulates growth hormone (GH) secretion, functions in energy patients was about 70 %. The common underlying causes of GHD homeostasis by stimulating food intake, and promotes adiposity were pituitary adenomas, craniopharyngiomas and germ cell tumors. via a GH-independent mechanism. These actions of ghrelin should In Japanese AO patients, mean body mass index, waist circumfer- be invaluable for the development of novel treatments and disease ences and serum triglyceride levelswere abnormally high. The prev- diagnostic techniques. Indeed, ghrelin administration to humans has alence of hypertension, dyslipidemia, cerebro- or cardio-vascular been performed to assess the therapeutic utilities, including cachexia diseases, liver dysfunction and osteoporosis were higher when com- (congestive heart failure, chronic obstructive pulmonary disease and pared with normal Japanese population. We have evaluated the qual- cancer-derived), functional anorexia and aging-related disorders. In ity of life (QoL) status using Japanese version of SF-36v2 and newly this symposium, these recent researches/trials on clinical applica- developped Adult Hypopituitarism tions of ghrelin including ours will be introduced and discussed. Questionnaire (AHQ). GHD patients scored lower than national norms in SF-36. These low scores were seen not only in AO patients MTP22-2

but also in CO patients, which showed in contrast to the results from Meet-the- Professor Ghrelin and its analogues: Which clinical perspectives ? previous clinical trials in Japanese subjects. These findings suggest that the major reason for prescribing GH is to improve QoL of adult Ezio Ghigo (1) GHD patients in clinical practice. (1)Div Endocrinology, Diabetology and Metabolism, Dept Internal Medicine, University of Turin, Italy Ghrelin (GRLN), a peptide mostly produced by the stomach, was MTP23-2 discovered in 1999 as GH-releasing peptide, endogenous ligand of Growth hormone deficieny in adults the GHS-R1a provided its acylation in Ser3 by the enzyme GOAT. More recent concepts in the GRLN field were the following: a) Ken K. Y. Ho (1) GRLN action is not specific for GH; b) not just acylated but also non- (1)Pituitary Research Unit, Garvan Institute of Medical Research and Department of Endocrinology, St. acylated GRLN is a biologically active peptide; c) GRLN forms act Vincent’s Hospital, Sydney, Australia via more than one specific receptor. GRLN actions pointed toward GH is produced throughout adult life. It regulates the metabolic pro- potential clinical perspectives for this peptide and its analogues. The cess and the integrity of many tissues. Adults who lack GH develop most considerable clinical perspectives seem: 1) acylated GRLN and a characteristic clinical picture of metabolic, body composition and its analogues would represent a reliable provocative test for the diag- functional abnormalities. These patients exhibit insulin resistance, nosis of GHD but these molecules would unlikely replace rhGH for hyperlipidaemia and increased levels of pro-inflammatory cytok- treatment of GHD; 2) the ability of acylated GRLN and its analogues ines, collectively increasing the risk of cardiovascular mortality. to stimulate GH and IGF-I secretion represents the rational basis to Body fat is increased while muscle and bone mineral are reduced. test these molecules as potential anabolic intervention in cachexia Cardiac function, muscle strength and physical fitness are impaired. and in various clinical catabolic conditions; 3) the strong orexigenic Psychological function and quality of life are adversely affected. action of GRLN pointed toward the hypothesis that antagonists of GH stimulation tests are required for accurate diagnosis. Testing for acylated GRLN would represent an option for treatment of obesity; GH deficiency are to include patients with hypothalamic-pituitary 4) GRLN agonists have potential to treat hypomotility disorders and disease, those who have received pituitary irradiation or sustained would represent a new class of gastroprokinetics; 5) acylated GRLN traumatic brain injury. Testing may indicate isolated GH deficiency negatively while non acylated GRLN positively affect glucose however idiopathic isolated GH deficiency occurring de novo is not metabolism. As non acylated GRLN, its fragments and analogues a recognised entity. The insulin tolerance test, combined adminis- improve glucose and lipid metabolism, insulin secretion and sen- tration of GHRH with arginine or with growth-hormone releasing sitivity as well as beta cell survival, they (or alternatively a GOAT peptide, growth-hormone releasing peptide alone, and glucagon are inhibitor) have potential as therapeutic intervention for the treatment validated tests of GH stimulation tests for adult GH deficiency. A of diabetes mellitus. low IGF-I in the presence of hypopituitarism is a reliable indica- tor of GH deficiency, however a normal IGF-I does not rule out GH deficiency. GH replacement reverses metabolic and body composition abnor- malities resulting in improved physical and psychological function. GH status should be re-evaluated in the transition age for contin- ued treatment to complete somatic development. It is not yet known whether cardiovascular mortality is returned to normal. Ten-year experience reveals that the benefits of GH replacement are sustained, S208 14th International Congress of Endocrinology that GH is safe with no evidence of increased risk of tumour recur- this issue, a pathophysiological approach will be taken, and the focus rence or of de novo malignancy. will be on why the specific components used in all versions form a Adults with GH deficiency have impaired health, which improve cluster of related CVD risk factors. More specifically, evidence will with GH treatment. Adults with GH deficiency should be replaced be presented that insulin resistance, and how the organism responds with GH. to this defect, provides the only coherent explanation as to why the Supported by the NHMRC of Austrlia abnormalities that comprise the current versions of the MetS clus- ter together.

MTP24 Insulin resistance and metabolic syndrome MTP25 Thyroid dysfunction and cardiovascular diseases March 29 (Mon.) 11:10-12:00 Room 4 March 29 (Mon.) 11:10-12:00 Room 5 MTP24-1 Visceral fat and metabolic syndrome MTP25-1 Yuji Matsuzawa (1) Cardiovascular problems in Hashimoto thyroiditis and hypothyroidism (1)Sumitomo Hospital, Japan Nobuyuki Amino (1) Clustering of multiple risk factors such as impaired glucose metabo- lism, lipid disorders and hypertension has been shown to be major (1)Department of Internal Medicine, Kuma Hospital, Japan background of atherosclerotic diseases and disease entities such as Hashimoto thyroiditis was discovered by Dr. Hakaru Hashimoto in metabolic syndrome become popular as highly atherogenic state. 1912. This is one of typical organ specific autoimmune diseases and Although each common risk may generally co-exist by accident the concept of disease was widened after introduction of autoim- in one individual, multiple risk factors clustering in metabolic syn- mune nature. Disease was classified into four stages. The final stage drome does not occur by accident and there should be a key player is the hypothyroidism induced by atrophic thyroiditis. In patients for the syndrome. Visceral fat accumulation has been shown to with hypothyroidism, peripheral vascular resistance is increased and cause impaired glucose metabolism, lipid disorders and hyperten- resting cardiac output is decreased. The rate of ventricular relax- sion, therefore visceral fat accumulation is considered to be a key ation during diastole is lower, and diastolic filling and compliance player in metabolic syndrome. In order to clarify the mechanism of are impaired. Diastolic hypertension, left ventricular diastolic dys- metabolic syndrome, we studied on the molecular characteristic of function, impaired endothelium-mediated vasodilatation, hyperco- adipose tissue and adipocytes by investigating expressed genes in agulable state, hypercholesteremia and high serum homocysteine visceral and subcutaneous adipocytes and revealed that adipocytes, are all improved after thyroid hormone therapy. These factors are especially visceral adipocytes are secreting a variety of bioactive risk for coronary artery disease and accelerated atherosclerosis. In substances such as which we called adipocytokines. We demon- patients with subclinical hypothyroidism, changes in cardiovascu- strated that visceral fat accumulation causes abnormalities of adipo- lar function and risk factors for cardiovascular disease are similar to cytokine secretion such as hypersecretion of PAI-1 which is related but smaller in magnitude to those in patients with overt hypothyroid- to thrombogenic vascular diseases. More importantly, we also dis- ism. Patients with destructive thyrotoxicosis (painless thyroiditis) covered an important benign adipocytokine named adiponectin induced by subacute aggravation of Hashimoto thyroiditis, some- which protects against the development of diabetes mellitus, hyper- times associate with atrial fibrillation. After delivery, autoimmune tension, inflammation and atherosclerotic vascular diseases. Plasma thyroiditis aggravates and postpartum thyroiditis develops. During levels of adiponectin decreased in the subjects with visceral fat accu- postpartum period, acute heart failure may also occur due to postpar- mulation and hypoadiponectinemia caused by visceral fat accumu- tum autoimmune myocarditis through immune rebound mechanism. lation might be one of major causes of metabolic syndrome. In this Therefore clinician should be careful for association of postpartum lecture, I would like to show the molecular mechanism of metabolic thyroiditis and postpartum autoimmune myocarditis when patients syndrome with respect to visceral fat accumulation focusing on adi- show sign and symptoms of heart dysfunction. ponectin and I would like to discuss about therapeutic strategy which may improve adipocytokine secretion especially about foods and MTP25-2 drugs which may increase plasma levels of adiponectin. Cardiovascular consequences of subclinical hyperthyroidism MTP24-2 E. Chester Ridgway (1) (1)Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA Why a cluster is truly a cluster: Insulin resistance and the metabolic syndrome The prevalence of subclinical hyperthyroidism varies with gender, age, ethnicity, and geography. It is more prevalent in women, older Gerald M. Reaven (1) subjects, black Africans, and in areas of iodine sufficiency. In the (1)Stanford University School of Medicine, USA Colorado cross-sectional study of 25,862 subjects, it was found in Three sets of diagnostic criteria have been proposed to identify indi- 0.9% of 24,337 individuals. In the NHANES III study, it was 0.7% in viduals with what has been termed the metabolic syndrome (MetS): people over 12 yr of age. In the Cardiovascular Health Study of 3233 WHO, ATP III, and the IDF. The goalis to identify individuals at U.S. community-dwelling individuals over 65 years, the prevalence increased cardiovascular disease (CVD) risk, and the same compo- of subclinical hyperthyroidism was 1.5%. The natural evolution of nents are used to make the diagnosis. However, the three organi- subclinical hyperthyroidism also varies according to the initial TSH zations differ in their approach to diagnosing the MetS. The WHO level, those with TSH levels below 0.1 mIU/Liter progress to overt requires that evidence of insulin resistance be present in order to hyperthyroidism more frequently than those whose TSH is between make a diagnosis, whereas the American Heart Association and the 0.1 and 0.4 mIU/L. The cardiovascular risk in patients with subclini- National Heart, Lung, and Blood Institute, focused on the ATP III cal hyperthyroidism is related to increases in the systolic depolariza- criteria, state that the MetS “is truly a syndrome, i.e., a grouping tion and diastolic repolarization rate. Atrial arrhythmias (sinus tachy- of ASCVD risk factors, but one that probably has more than one cardia, atrial premature beats, and AF) are the most frequent rhythm cause.” In contrast, the IDF states that “central obesity, as assessed disturbances and are similar to those of overt hyperthyroidism. The by waist circumference was agreed as essential” to the diagno- risk of AF appears to increase with age. A significant increase in the sis, based on “the likelihood that central obesity is an early step in left ventricular mass index (LVMI) has been documented in almost the etiological cascade leading to the full metabolic syndrome.” all studies of patients with subclinical hyperthyroidism. The conse- Questions have been raised as to the clinical utility of diagnosing the quences of increased left ventricular mass is the increase in diastolic MetS, regardless of the version used. However, rather than address dysfunction. The combination of atrial arrythmias and decreased left Meet-the-Professor (MTP) S209 ventricular compliance may account for subslinical hyperthyroidism being a negative prognostic factor for cardiovascular mortality and MTP27 Cushing’s disease morbidity in the general population. March 29 (Mon.) 11:10-12:00 Room 7 MTP27-1 MTP26 Adrenal carcinoma Management of Cushing's disease Akira Teramoto (1) March 29 (Mon.) 11:10-12:00 Room 6 (1)Department of Neurosurgery, Nippon Medical School, Japan MTP26-1 I have experienced transsphenoidal surgery (TSS) in 230 patients with Cushing’s disease which occupies 8% of my TSS series (2,300 Discerning malignancy in adrenocortical tumors cases). Hironobu Sasano (1) (1)Department of Pathology, Tohoku University School of Medicine, Sendai, Japan MTP27-2 The most important clinical aspect in the management of patients Diagnostic challenges and medical treatment of Cushing’s with adrenocortical tumors is how to differentiate carcinoma from disease adenoma. In this presentation, I will cover pro and limitations of Lynnette K. Nieman (1) preoperative image analyses, endocrinological evaluations includ- (1)National Institutes of Health, USA ing measurement of steroid metabolites and other relevant diag- nostic work-ups. Especially, I will emphasize the following points Having made the diagnosis of Cushing’s syndrome, clinicians must in which practicing endocrinologists should know ; 1. characteris- discover the etiology, which will dictate the appropriate treatment. tic steroid profiles of adrenocortical carcinoma cases, 2. features of Usually the primary adrenal ACTH-independent causes can be dis- radiological evaluations suggestive of adrenocortical malignancy tinguished from the ACTH-dependent causes by measurement of and 3. limitations of fine needle aspiration or core needle biopsy and plasma ACTH, which will be low or suppressed (< 10 pg/ml) in the intraoperative consultation including frozen tissue sections diag- former, and normal or occasionally high in the latter conditions. The nosis in discerning malignancy. The final diagnosis of adrenocor- distinction between the causes of ACTH-dependent Cushing’s syn- tical carcinoma is usually done by histopathological evaluation of drome, an ectopic vs pituitary source, is more difficult. Pituitary resected specimens but macroscopic evaluation of the specimens is MRI should be obtained at the outset to exclude a large tumor, which very important, which I will emphasize in this presentation. I will may change the diagnostic strategy. The best test is inferior petrosal also cover the areas of histological diagnosis of which practicing sinus sampling. If performed at an experienced center, its diagnostic endocrinologists should be aware, including an employment of the accuracy is about 95%. It should be done only after sustained hyper- criteria of Weiss, which evaluated eight different histopathlogical cortisolism, however, since lack of corticotrope suppression may

give a false result in patients with ectopic ACTH secretion. In addi- Meet-the- parameters and is in general considered a gold standard of the diag- Professor nosis. In particular, the limitations or difficulties in predicting the tion, a lack of central to peripheral gradient should be interpreted clinical outcome of the adrenocortical carcinoma patients or classi- with knowledge of the venous drainage, as anomalies can give a fying them into low and high risk groups and possible response to false negative result in patients with Cushing’s disease. Another op’-DDD will be also mentoined. Potential contributions of biologi- approach is to perform the 8 mg dexamethasone suppression test cal or molecular analyses will be covered as well as their limitations. and, separately, the CRH stimulation test, again during prolonged Finally, the differentiation between adrenal primary and metastatic hypercortisolism. If both are positive, the patient almost certainly carcinoma will be also presented. has Cushing’s disease. Any other combination of results is non- diagnostic. There is no long-term medical treatment that reduces MTP26-2 ACTH. Cabergoline is effective in some patients, but many escape treatment and larger long-term trials are awaited of this and other Clinical management of adrenal cortical carcinoma investigational drugs. Steroidogenesis inhibitors are helpful until Xavier Bertagna (1), Rossella Libé (1), Guillaume Assié (1), Lionel Groussin (1), radiotherapy is effective. Florence Tenenbaum (1), Frédérique Tissier (1), Paul Legmann (1), Bertrand Dousset (1), Jérôme Bertherat (1) (1)Hôpital Cochin, Faculté de Médecine Paris Descartes, Paris, France Adrenal cortical carcinoma (ACC) is a rare tumor with an estimated MTP28 Regulation of endometrial function incidence between 1 to 2/million /year. ACC can be observed in hereditary cancer syndromes as the the Li-Fraumeni and Beckwith- March 29 (Mon.) 11:10-12:00 Room 8 Wiedemann syndromes. Similar somatic genetic alterations have been observed in sporadic ACC. Loss of heterozygosity at 17p13 MTP28-1 (the p53 locus) are common in ACC and can be used as a molec- Apoptosis of human endometrium and endometriosis ular diagnostic tool. ACC is most often responsible for endocrine Naoki Terakawa (1,2), Tasuku Harada (2) symptoms but can also be diagnosed after local symptoms or as an adrenal « incidentaloma ». Imaging relies primarily on CT-scan, but (1)Nissay Hospital, Osaka, (2)Ob & Gyn Tottori University Faculty of Medicine, Yonago, Japan recent data show the diagnostic usefulness of 18FDG Pet-scan and Apoptosis play a critical role in maintaining tissue homeostasis and Iodometomidate scintigraphy. Independent prognostic factors of represents a normal function to eliminate excess or dysfunctional poor outcome as determined by the study of a cohort of 202 con- cells. Apoptosis is directly involved in the regulation of menstrual secutive patients from a single Center are : age, extra-adrenal tumor cycle, by eliminating senescent cells from the functional layer of staging, and cortisol oversecretion. Transcriptome analysis, provides uterine endometrium. Endometriosis is defined as the presence of new molecular markers both for the diagnosis and prognosis of adre- endometrial tissues outside the uterus. Despite decades of clinical nal cortical tumors. Op’DDD remains the first choice treatment in experiences and experimental researches, endometriosis remains an patients that cannot be totally cured by surgery, and may also prove enigma and its pathogenesis is still controversial. Altered apopto- beneficial in an adjuvant setting by increasing disease free survival sis in endometriotic tissues is a notion that illuminates some aspect after complete resection. Trials are on the way with new regimen in of the pathogenesis of endometriosis. We recently reported that the metastatic disease. ectopic endometriotic stromal cells (EMSCs) have the distinct bio- logical characteristics of the resistance to drug-induced apopto- sis compared to the endometrial stromal cells from women with- out endometriosis. Impaired sensitivity of the endometrial tissue to S210 14th International Congress of Endocrinology spontaneous apoptosis may cause the abnormal implantation and these patients is an ectopic adrenal residual tumor, with a prevalence growth of endometrium at ectopic sites, suggesting that decreased of almost 10%. Long-term excessive androgen production in male susceptibility of endometrial tissue to apoptosis may contribute to patients with 21-OHD also causes hypogonadism, which leads to the pathogenesis of endometriosis.We further investigated the role of severe and irreversible aspermatogenesis. Another important issue inhibitor of apoptosis proteins (IAPs) in resistance to drug-induced is how to administer GC to patients with 21-OHD. What kind and apoptosis in the EMSCs. We focused on enhanced survivin expres- what doses of GC are optimal for effective treatment, and at what sion in EMSCs, being representative of the IAP family. Because time of the day should GC be administered? To fully suppress the survivin expression has a prominent cancer bias, in contrast, it is early morning rise of ACTH, strong GCs such as dexamethasone undetectable in most adult tissue. Our data suggested that aberrant should be administered in the evening or before sleep. However, it survivin expression in EMSCs may sustain their abnormal survival is also important to consider the risk of side effects associated with in unfavorable environment. Therefore survivin may play a signifi- long-term GC therapy, including diabetes mellitus and osteoporo- cant role in the pathophysiology of endometriosis. A survivin inhibi- sis. In this lecture, I will discuss these problems by introducing our tor may be effective as a novel treatment for endometriosis. clinical cases. MTP28-2 MTP29-2 Impact of endometriosis on endometrial function Management of congenital adrenal hyperplasia in adults Asgerally Fazleabas (1) Wiebke Arlt (1) (1)Department of Ob/Gyn & Reprod Biol., Michigan State University College of Human Medicine, Grand (1)Centre for Endocrinology, Diabetes and Metabolism, School of Clinical & Experimental Medicine, Rapids, Michigan, USA University of Birmingham, Birmingham, UK Although endometriosis is a major cause of infertility, the caus- Congenital Adrenal Hyperplasia (CAH) is the commonest inborn ative factors associated with reduced fecundity have not been clearly endocrine disorder. Treatment requires both corticosteroid replace- elucidated. Due to the limitations associated with controlled stud- ment and control of ACTH-driven androgen excess. No consensus ies in women with endometriosis, we have developed an induced exists for management of adults with CAH due to a paucity of data endometriosis model in the baboon by inoculating the peritoneal from cohorts of meaningful size. This session will discuss issues cavity with menstrual endometrium on two consecutive menstrual relating to current therapeutic options in CAH, treatment monitoring cycles. This model, which persistently results in clinically docu- by hormonal parameters, transitional management aspects, monitor- mented endometriosis in the peritoneum, permits repeated sampling ing for complications (fertility, metabolic syndrome, bone density, of both the eutopic and ectopic endometrium during the progression psychosexual well-being), and suggested approaches for specialist of the disease. To determine if the presence of endometriotic lesions multi-disciplinary team management of this often overlooked dis- influenced the gene expression in the eutopic endometrium, endo- order, which however is the origin of disease in about 20% of all metrial tissues were harvested repeatedly for 15 months from the adult patients with adrenal insufficiency. The session will also dis- same cohort of animals during the window of uterine receptivity. cuss potential improvements of therapeutic approaches in CAH and Microarray expression profiling for elucidation of molecular players their implications as well as the significance of genetic testing and was done on an Affymetrix platform. Gene expression patterns and counselling in affected patients. validations by both Taqman analysis and protein assays revealed a complex series of changes that occur at different time points during disease progression. The initial phase of the disease was associated with an increase in genes associated with transcription, angiogene- MTP30 MEN1 sis and cell adhesion. The latter stages were characterized with the acquisition of progesterone resistance which resulted in a decrease March 29 (Mon.) 11:10-12:00 Room 10 in the expression of markers of uterine receptivity as well as a resis- tance to embryonic signaling. We propose that this progressive MTP30-1 change in gene expression in the eutopic endometrium of baboons Tumor suppressor menin regulates Wnt/β-catenin signaling with endometriosis is a result of epigenetic modifications and results in an altered uterine environment that is detrimental to the establish- Guang Ning (1) ment of pregnancy. (1)Shanghai Institute of Endocrine and Metabolic Diseases. Shanghai, China Our study reveals that Wnt/β-catenin signaling participates in β-cell proliferation in MEN1, loss of menin induced β-catenin nuclear translocation and activation. We demonstrate that menin physically MTP29 Congenital adrenal hyperplasia interacts with β-catenin and exports β-catenin out of the nucleus via two functional nuclear export signals (NES). Absence of menin March 29 (Mon.) 11:10-12:00 Room 9 leads to nuclear β-catenin accumulation and transcriptional activa- tion in cells. We speculate that β-catenin is a key partner of menin MTP29-1 and nuclear β-catenin accumulation caused by loss of menin results Management of congenital adrenal hyperplasia in adults in pancreatic β-cell proliferation.We further revealed that CRM1- specific nuclear export inhibitor leptomycin B not only blocked Toshihiko Yanase (1) menin mediated β-catenin nuclear export, but also reduced β-catenin (1)Dept. of Endocrinology and Diabetes Mellitus, School of Medicine, Fukuoka University, Japan degradation, indicated that menin mediates β-catenin degradation The care for sexual dysfunction of young adult patients and the dependent on its nuclear export function. Nevertheless, menin with tendency for infertility after marriage are the major problems that NES mutations was rapidly degraded as reported previously and its tax the brain of the internist in the management of congenital adre- nuclear export function was impaired as well. It is consistent with nal hyperplasia (CAH), particularly 21-hydroxylase deficiency. An the observation in MEN1 tumors that Men1 mutations lead to menin increased rate of infertility of female patients with 21-hydroxy- unstable and complete loss of menin protein and its functions. lase deficiency (21-OHD) has been reported. Approximately 50% of untreated patients are reported to be infertile, but the rate is dra- matically decreased to just 10% with glucocorticoid (GC) therapy. The hypothesis that excessive androgen production in patients with 21-OHD negatively affects ovulation is supported by the finding that GC treatment can correct the ovulatory disturbances in these patients. Similarly, an increased rate of infertility has been reported in males with 21-OHD. The most important cause of infertility in Meet-the-Professor (MTP) S211

MTP30-2 MTP31-2 Multiple endocrine neoplasia type 1 (MEN1) Percutaneous thermal ablation procedures for the treatment Stephen J. Marx (1) of benign and malignant thyroid lesions (1)Metabolic Diseases Branch, NIDDK/NIH, Bethesda, MD, USA Enrico Papini (1), Rinaldo Guglielmi (1), Irene Misischi (1), Laura Papini (2), Claudio M Pacella (1) Definitions: MEN1 is a case with tumor in two of three main tis- sues (parathyroid, pituitary, pancreatico-duodenum); familial MEN1 (1)Regina Apostolorum Hospital Rome, Italy, (2)La Sapienza University Rome is MEN1 plus a first degree relative with tumor in one of the three Mini-invasive procedures with use of thermal energy sources such as tissues. Expression and Management: MEN1 can express tumor in laser, radiofrequency, microwave, high-intensity focused ultrasound some 25 endocrine or non-endocrine tissues. Typically, an affected and cryotherapy are currently under evaluation for the non surgical tissue expresses multiple tumors. Tumor multiplicity requires spe- therapy of thyroid lesions. Laser ablation (PLA) and Radiofrequency cial clinical managements, unlike common solitary tumor. These (RFA) have been clinically tested. PLA is based on the conversion vary from total excision (thymus), to subtotal excision (parathy- by the tissue into heat of the light produced by sources such as a roid), to no excision (gastrinoma). Other features needing special ND-YAG laser or a continuous wave infrared diode laser. Two ran- management include earlier onset (parathyroid) and larger size (pitu- domized clinical trials confirmed that a single PLA treatment induces itary). Though an endocrinopathy, MEN1 is eventually lethal from a nodule reduction >40%. Local symptoms and volume decrease an MEN1-related cancer in 25% of carriers.MEN1 gene: The MEN1 were stable at follow-up. A randomized study compared PLA with gene is widely used for carrier diagnosis. The two most common radioiodine treatment in patients with a hot nodule. Both treatments subjects are a proband with undefined syndrome or an asymptom- reduced nodule volume but TSH remained suppressed in 50% of atic relative of a proband with proven MEN1 mutation. The MEN1 PLA-treated patients. RFA induces the ablation of a nodule placing gene test rarely guides an intervention (unlike the RET gene test for into the lesion under US guidance, a 14 to18G needle-like electrode. MEN2). Rather the MEN1 gene test gives important information A few uncontrolled series demonstrated an up to 78% decrease in to patient and to caretakers. Inactivation of the MEN1 gene is the size of thyroid nodules after RFA. The procedure was well tolerated cause also of many common variety, non-hereditary tumors. When and thyroid nodules and related symptoms were steadily controlled the MEN1/menin molecular pathway is defined, it should lead to during a 2-year period.PLA has been tested for the palliative treat- new interventions for many endocrine tumors, hereditary and not. ment of poorly differentiated thyroid carcinomas, local recurrences CDKI genes: MEN1 mutation is not identifiable in 30% of MEN1 or distant metastases. A few cases of anaplastic carcinoma or local cases or families. Most have occult MEN1 mutation or mutation recurrences from poorly differentiated thyroid carcinoma have been in other genes. Any one of four cyclin dependent kinase inhibi- treated to date. PLA and RFA may be considered for a rapid cytore- tor (CDKI) genes can be another cause of MEN1 (Agarwal S et al duction of tumor burden prior to external radiation therapy or che- JCEM 94:1826, 2009). motherapy of local recurrences of thyroid malignancy that are not amenable to surgical or radioiodine treatment. Meet-the- Professor MTP31 Treatment for thyroid nodule MTP32 Cardiovascular hormones: Adrenomedullin and March 29 (Mon.) 11:10-12:00 Room 14 March 29 (Mon.) 11:10-12:00 Room 15 MTP31-1 Minimally invasive thyroidectomy MTP32-1 Hiroshi Takami (1) Adrenomedullins and urocortins: Potent vasodilator and cardioprotective peptides (1)Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan Kazuhiro Takahashi (1) Technologic innovations have rapidly and dramatically improved minimally invasive thyroid surgery, and improvements in ultrasound (1)The Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, Sendai, Japan and ultrasound-guided FNA have contributed to the development of minimally invasive surgery . Minimally invasive thyroid procedures Adrenomedullin (AM) is a 52 amino acid peptide originally isolated can be classified into “pure” endoscopic approaches (completely from pheochromocytoma, and belongs to the calcitonin/CGRP fam- closed approaches), video-assisted endoscopic approaches, and ily. AM has a potent vasodilator action and other various biological minimally invasive mini-incision approaches. “Pure” endoscopic actions, such as cell proliferation, hormone secretion, an anti-oxida- approaches can be subclassified into a supraclavicular approach, tive stress action, and neurotransmitter actions. There are at least five anterior chest approach, axillary approach, and breast approach. The genes for AM family peptides in fish (AM1-5). Adrenomedullin 2/ axillary, anterior chest, and breast approaches avoid skin incisions in intermedin (AM2/IMD) has been identified in the mammals includ- the neck. Whether these three approaches will be accepted in west- ing human. CGRP, AM and AM2/IMD activate - ern countries is unclear, but the surgical concept is appealing from like receptor (CRLR)/receptor activity-modifying protein (RAMP) the standpoint of improved cosmesis. The purpose of endoscopic system. AM preferentially interacts with CRLR/RAMP 2 or 3, and thyroid surgery is not only to improve the cosmetic results, but to CGRP with CRLR/RAMP 1, whereas AM2/IMD interacts with achieve minimally invasive surgery. In terms of invasiveness, how- CRLR/RAMP 1, 2, or 3 non-selectively. ever, these approaches are inferior to the video-assisted endoscopic Urocortin 1 has been identified as a mammalian homologue of approach. The supraclavicular approach allows access to both sides urotensin I, a fish CRF-like peptide. There are at least three urocor- of the neck, and if bleeding occurs, it allows rapid access to the thy- tin in the mammalians; urocortin1, urocortin2 and urocortin3 (stress- roid basin. The video-assisted approach is performed under direct copin). The actions of the CRF-family peptides are mediated by two and endoscopic vision using conventional instruments and permits types of G protein-coupled receptors: CRF type 1 receptor and type much smaller incision in the neck than conventional thyroidectomy. 2 receptor. CRF type 1 receptor mediates ACTH responses to stress, Video-assisted endoscopic procedures are easily mastered by sur- whereas type 2 receptor mediates stress-coping responses including geons who are familiar with conventional thyroidectomy. Ordinary anxiolysis, anorexia, vasodilatation, a positive inotropic action on instruments are used to reach the target mass. The new minimally myocardium, and dearousal. CRF and urocortin1 bind to both CRF invasive technique described above is expected to lead to improved type 1 receptor and type 2 receptor, whereas urocortin2 and urocor- patient comfort, shorter hospital stays, and favorable cosmetic tin 2 are specific ligands for CRF2 receptor. results in a select group of patients, and this operative procedure may AMs and urocortins are expressed in various organs, including be performed on an outpatient basis. brain and heart. Particularly, these biologically active peptides are synthesized and secreted by the cardiovascular organs and may reg- S212 14th International Congress of Endocrinology ulate the cardiovascular function as autocrine/paracrine regulators via respective specific receptors. MTP32-2 Adrenomedullins and urocortins: Therapeutic potential in cardiovascular disease Christopher J. Charles (1) (1)Christchurch Cardioendocrine Research Group, University of Otago, Christchurch, New Zealand The adrenomedullin (AM) and urocortin (Ucn) peptides are two families of hormones discovered in the past two decades that have undergone extensive pre-clinical and early clinical investigations elucidating their role in cardiovascular physiology. Evidence sug- gests that AM peptides play a role in the pathophysiology of heart failure. Plasma levels of AM are raised in cardiovascular disease in proportion to severity of cardiac dysfunction. AM administration in both experimental and human heart failure reduces arterial and atrial pressures, improves cardiac output, inhibition of plasma aldoster- one and preservation or augmentation of urinary sodium excretion. Manipulating the AM systems may prove beneficial as an adjunctive therapeutic strategy in cardiac disease. Co-localization of Ucn pep- tides and their receptors in peripheral tissues, including the heart and vasculature, suggests an important role for the peptides as regula- tors of cardiovascular function. Administration of Ucn1 and Ucn2 in experimental and human heart failure induces beneficial cardiovas- cular (reduced cardiac preload and afterload and increased cardiac output), hormonal and renal effects. In addition to their effects on cardiac and vascular function, the Ucn peptides are reported to have potent cardioprotective actions including prevention of cardiomyo- cyte death in ischaemic models, reducing infarct size, inhibition of cardiac sympathetic nerve activity and anti-arrhythmic actions sug- gesting therapeutic potential in acute cardiac injury. There is a need for development of novel strategies for targeting AM and Ucn mech- anisms.