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VOLUME 1 | NUMBER 3 | 2006

Growth, Growth Hormone, & Metabolism

ADVISORY BOARD CLINICAL EDITORS

PINCHAS COHEN CARLO ACERINI University of California Los Angeles, University of Cambridge, Los Angeles, CA, USA Addenbrooke’s Hospital, Cambridge, UK

DEREK LEROITH CHARLES BUCHANAN Mount Sinai School of Medicine, King’s College Hospital, London, UK New York, NY, USA HIRALAL MAHESHWARI EDWARD REITER Northwestern University Medical School, Tufts University School of Medicine, Chicago, IL, USA Springfield, MA, USA

RICHARD ROSS University of Sheffield, Sheffield, UK

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CURRENT MEDICAL LITERATURE JOURNALS

Current Medical Literature journals are designed to solve the problem of information overload for healthcare professionals. Each journal is compiled by an editorial team of clinicians from an ongoing review of the international literature, and articles are selected for citation and review on the basis of their relevance to clinical practice. Other titles in the series are listed below. For additional information on any of these titles, please contact us at the address below.

CML – Breast Cancer CML – Nephrology & Hypertension CML – Cardiology CML – Neurology CML – Clinical Nutrition CML – Ophthalmology CML – Dermatology CML – Pain Medicine CML – Diabetes CML – Pediatrics CML – Gastroenterology CML – Psychiatry CML – Gynecology & Obstetrics CML – Respiratory Medicine CML – Interventional Cardiology Monitor CML – Rheumatology CML – Leukemia & Lymphoma CML – Stroke Review CML – Lysosomal Storage Diseases CML – Urology

PRIORITY JOURNALS

In the preparation of this journal, over 2500 journals are reviewed for content relevant to the target audience. The following journals are treated on a priority basis by the Editors.

Am J Physiol Endocrinol Metab JAMA Metab Clin Exp Ann Endocrinol J Biol Chem Mol Endocrinol BMJ J Clin Endocrinol Metab Nat Med Clin Endocrinol (Oxf) J Endocrinol Nature Endocrinology J Pediatr Endocrinol Metab N Engl J Med Eur J Endocrinol J Paediatr Child Health Pediatr Res Eur J Pediatr J Pediatr Pediatrics Horm Res Lancet

CORRESPONDENCE

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ISSN 1750-8673

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III

Contents

Foreword IV

Leading Articles

Dose Titration of Growth Hormone in 63 Growth Hormone Deficient Adults MJ Bell and WM Drake Department of Endocrinology, St Bartholomew’s Hospital, London, UK

Effect of Standard Insulin Tolerance Test on 68 Plasma Leptin Levels in Children with and without Growth Hormone Deficiency H Zotter1, R Kerbl2, and M Borkenstein2 1Division of Neonatology, and 2Division of General Pediatrics, Department of Pediatrics, Medical University of Graz, Graz, Austria

Citations and Editors’ Notes

• GH Treatment in Non-GH-Deficient Indications 71

• GH Deficiency 84

• Surgery 89 R7973_3_Growth_1_3_06.qxd 16/11/06 17:30 Page 4

IV Foreword

BY RICHARD ROSS University of Sheffield, Sheffield, UK

The production of recombinant growth hormone (GH) in the mid-1980s and its use to replace GH-deficient adults in the 1990s has led to an explosion in our understanding of the hormones that regulate body composition. Over the next decade, it is likely that new growth factors and metabolic treatments will continue to expand our therapeutic options for treating patients with growth disorders.

Embracing new developments is essential in any medical specialty, but the growing volume of literature in the field of growth medicine places an increasing burden on healthcare professionals.

We are delighted to bring you the third issue in the new Current Medical Literature series Growth, Growth Hormone, and Metabolism, a review journal providing commentary and analysis on the most important advances in the field of growth medicine. Each issue of this journal presents specially commissioned review articles exploring issues of current and emerging clinical importance, in addition to a systematic review of the recent international literature.

The first Leading Article in this issue, by Marcia Bell and William Drake from St Bartholomew’s Hospital, London, UK, reviews the latest literature supporting individualized dose titration of GH during GH replacement in adult patients. In the second article, Heinz Zotter, from the Medical University of Graz, Austria, and colleagues discuss the recent literature concerning leptin responses to insulin administration in children with and without GH deficiency.

Future issues of the journal will explore a wide range of topics including the role of GH and insulin-like growth factor 1 (IGF-1) in the treatment of idiopathic short stature, IGF-1 treatment of Laron Dwarfism, and IGF and IGFBP-3 therapy for diabetes.

Please take a moment to visit our website (www.currentmedicalliterature.com), where you can access new and archived content, activate your personalized literature search engine (the CML Compass), and review the ‘Paper of the Month’, selected by the Editorial Board as THE paper that you should read that month.

For our readers in the USA, CME/CNE credits can be earned by reading and answering questions on these articles. The questionnaire is available at the back of the journal and online at www.currentmedicalliterature.com.

We look forward to providing you with an interesting and valuable publication. We welcome your feedback and your suggestions for future content. R7973_3_Growth_1_3_06.qxd 16/11/06 17:30 Page 63

63 Leading Article Dose Titration of Growth Hormone in Growth Hormone Deficient Adults

MJ BELL AND WM DRAKE Department of Endocrinology, St Bartholomew’s Hospital, London, UK

Growth hormone (GH) deficiency in adults response, and tolerability [7–10]. The aim of has become a recognized clinical entity. this article is to review the latest literature The clinical syndrome is characterized by supporting the individualized dose titration increased truncal and visceral fat, decreased of GH during GH replacement in lean body mass, decreased muscle strength, hypopituitary patients. impaired exercise tolerance, and osteopenia [1–3]. It is associated with a lipid profile Dosing by weight consistent with increased atherogenic risk, In the early studies of GH replacement in insulin resistance, altered cardiac structure adults, the dose of GH adopted was and function, and reduced quality of life [4]. extrapolated from that used in pediatric Adults with hypopituitarism are known to practice and was based on body weight or have an overall increased mortality rate [4–6]; surface area [2,3,11,12]. The dose of rhGH it is possible that this may relate to untreated replacement was adjusted if side effects GH deficiency, although there is no direct occurred, and not in response to biochemical evidence to support this at present. The or clinical markers of GH action. As a result, availability of recombinant human GH many patients in these studies reported (rhGH) has made the treatment of GH adverse events and had supraphysiological deficiency a reality, and many patients with serum IGF-1 levels [6,13]. Side effects were symptomatic and biochemically severe GH more frequently reported in older patients deficiency are considered for GH and in those with a higher body mass index replacement. Decreased serum levels of (BMI) [14]. It soon became apparent that the insulin-like growth factor 1 (IGF-1) and dose of GH needed to treat children and subnormal GH responses to stimuli, such as adolescents was far greater than that required insulin-induced hypoglycemia, have been to treat GH deficiency in adults, and as a used as the gold standard for diagnosis of GH result, lower doses of GH were used in later deficiency, and the Endocrine Society has studies of adult GH deficiency [15–17]. recently published updated guidelines on Evidence suggests that spontaneous GH how to best diagnose GH deficiency [7]. release correlates negatively with BMI and Attention is currently being focused on increasing age [18,19]. Carroll et al. compared optimizing dosing schedules of rhGH in high- and low-dose GH replacement regimens order to maximize its efficacy and minimize and found that lower weight-based doses any potential adverse effects of therapy. Many of GH, sufficient to normalize serum experts in the management of pituitary IGF-1, resulted in similar improvements in disease believe that GH replacement is most waist: hip ratio and psychological well-being effectively achieved by dose titration against scores compared with higher doses [20]. a combination of serum markers of GH action Johannsson et al. demonstrated that baseline such as IGF-1, measurements of clinical characteristics such as BMI, age, gender, and R7973_3_Growth_1_3_06.qxd 16/11/06 17:30 Page 64

64 MJ Bell and WM Drake

the level of GH binding protein were more IGF-1 level does not rule out GH deficiency, important than the actual dose administered particularly in older patients [29]. IGFBP-3 when determining an individual’s response to and ALS have been shown to correlate poorly GH treatment [12]. Overall, dose regimens with adult GH deficiency [30–32]; however, based on weight are now believed by many to there is some evidence that IGFBP-3 is useful be unphysiological and can result in excessive in determining GH deficiency in childhood dosing, particularly in obese or older patients. [33], and correlates more closely with growth response than IGF-1 during therapy [34]. Gender differences in Markers of bone turnover are significantly response to GH increased in response to rhGH, but this Healthy, fertile females are known to secrete response is highly variable and so far has greater amounts of GH than aged-matched found little use outside the clinical trials males [21–23], and GH deficient males are setting [35]. Serum IGF-1 is currently more responsive to rhGH therapy compared regarded as the most accurate biochemical with females [24]. Several studies have also marker of GH replacement in adults [29,32], shown that oral, but not transdermal, estrogen but its production, in response to a given GH replacement therapy results in relative GH stimulus, is affected by many variables [36]. resistance [25–27]. Conversely, androgen Clinically active acromegaly is known to be replacement has been shown to enhance associated with supraphysiological IGF-1 IGF-1 generation [28], supporting the clinical levels [37]; however, symptoms of GH excess concept that GH replacement in GH deficient during rhGH replacement are not invariably patients should take these factors into associated with elevations of serum account. Therefore, a weight-based dosing IGF-1 [29]. Therefore, in agreement with regimen is likely to result in relative GH Johannsson [10] and others, the current under-replacement in females, particularly in authors believe that several markers of those taking oral estrogen. Recently published efficacy and safety should be measured during guidelines by the Endocrine Society suggest GH dose titration and maintenance to avoid that women who discontinue estrogen the adverse effects of long-term treatment. therapy, or who switch from oral to transdermal estrogen preparations, should GH titration regimen have their maintenance dose of rhGH reduced Drake et al. were the first to report an [7]. Gender differences in response to GH individualized rhGH titration regimen based replacement emphasize the need for on a defined target range of IGF-1 in a large individualized GH dose titration. patient cohort [8]. The investigators altered the rhGH dose to maintain serum IGF-1 Markers for GH replacement between the median and upper limit of the It is generally acknowledged that no precise age-related reference range. This target marker of ideal GH replacement exists, and it IGF-1 level was chosen in order to avoid the is unlikely that GH replacement can be possible adverse effects associated with monitored adequately by clinical means chronic exposure to supraphysiological IGF-1 alone. Potential biochemical markers of GH levels, and to take into account the fact that a action include serum IGF-1, IGF binding substantial proportion of adult-onset GH protein-3 (IGFBP-3), the acid-labile subunit deficient patients have IGF-1 levels in the (ALS), and markers of bone turnover [29]. In normal reference range. The group reported order to be of use in assessing GH an overall reduction in dose requirements in replacement, a biochemical marker of GH the dose-titration group when compared with action must reflect the GH-deficient state historical series where patients were treated [29]. Although low serum IGF-1 in an with a weight-based regimen. There was a otherwise healthy individual is strongly consequent reduction in the incidence of suggestive of GH deficiency, a normal serum adverse events, with maintenance of efficacy, R7973_3_Growth_1_3_06.qxd 16/11/06 17:30 Page 65

Dose Titration of GH in GH Deficient Adults 65

as determined by favorable changes in body demonstrated the greatest deviation from composition and general well-being. Female normal. Both study groups showed similar patients were found to require larger doses of responses to treatment with respect to body rhGH to achieve the desired IGF-1 levels, and composition and to the majority of metabolic took longer to achieve a maintenance dose parameters, with significantly fewer side compared with their male counterparts effects seen in the dose-titration group. The (median 8 weeks in females vs. 4 weeks in final dose of GH in the weight-based dosing males). It was therefore suggested that larger group was significantly higher compared increments in dose during initial treatment with that of the dose-titration group. It was would likely be appropriate in females. also found that women were given more GH Simultaneous monitoring of IGFBP-3 and per body weight than men, and older patients ALS in this study demonstrated their relative were given significantly less GH per body insensitivity to changes in GH doses. The weight than younger patients. Serum IGF-1 group concluded that GH replacement could was higher in the weight-based group effectively be administered using a dose- throughout the study period, but was also titration regimen in order to achieve a good elevated above the reference range in clinical response to treatment and avoid approximately 20% of patients in the dose excess GH exposure. titration group as a result of dose increments Work by other groups endorses the use of being made in some of this group on the basis a dose-titration regimen for GH replacement. of persistently abnormal body composition. Murray et al. used a dose-titration regimen This observation highlights individual aimed at normalizing serum IGF-1 in 65 responsiveness to rhGH therapy and outlines adult patients with severe GH deficiency [9]. the importance of carefully monitoring GH Although this group was unable to show any replacement by various modalities in a significant difference in metabolic setting where no ideal marker for response to parameters or body composition at baseline treatment exists. and following 8 months of GH replacement, More recently, the results of a large they reported a significant improvement in international, randomized controlled trial quality of life, as reflected by improvements comparing a weight-based rhGH dosing in two separate self-rating questionnaires regimen with an individualized dosing used to assess quality of life (the regimen were reported [38]. GH dose was Psychological General Well-Being Schedule titrated against clinical response and serum [PGWB] and the Adult Growth Hormone IGF-1. The investigators showed that an Deficiency Assessment [AGHDA]). This individualized dosing regimen had similar study also showed that the degree of efficacy, but greater tolerability than a improvement in quality of life was dependant weight-based regimen. When both groups on the level of quality-of-life impairment were compared, the patients in the dose- before GH was commenced. The group did titration group received a significantly lower not comment on the incidence of adverse final dose of rhGH than those in the weight- events in the study population. based group. Johannsson et al. compared weight-based Overall, data from these studies using rhGH dosing with an individualized dose individualized dose-titration regimens have titration approach that was independent of shown that women were given more GH per kg body weight [10]. In this study, dose of body weight compared with men, and older adjustments in the individualized dosing patients who were given less GH per kg of group were guided by clinical response and body weight, than those who were younger. measurements of body composition, and This reflects the normal physiology of normalization of serum IGF-1 levels. When GH secretion in healthy adults [18,21–23]. adjusting the rhGH dose in the dose-titration Individualized regimens have consistently group, priority was given to the factor that shown a reduction in the overall rhGH dose R7973_3_Growth_1_3_06.qxd 16/11/06 17:30 Page 66

66 MJ Bell and WM Drake

required in order to normalize serum IGF-1 hypopituitarism it is important to optimize levels and achieve a similar clinical response. anterior pituitary therapy prior to commencing Adverse events also occurred less frequently GH treatment. Treatment of GH deficient in the dose titration groups. adults with rhGH is known to improve body composition, lipid profiles, and quality of life, Neoplasia in but it is not known whether long-term rhGH hypopituitary patients therapy restores life expectancy to normal in Concerns exist about the risk of neoplasia in adult hypopituitary patients. Against this hypopituitary patients receiving long-term background, it is essential that GH GH treatment. Experience from long-term replacement protocols minimize any potential surveillance studies of pediatric patients is adverse effects of therapy; thus, patients on reassuring, with no published evidence to life-long GH replacement require careful date of an increased risk of new or recurrent follow-up. In the curent authors’ unit, among tumor growth. GH deficiency occurring in others, it has become routine to image the adulthood is predominantly due to pituitary hypothalamo-pituitary region immediately or peripituitary tumors and their associated before commencing GH replacement and at therapy, and the risk of recurrence of these regular intervals thereafter. GH replacement is tumors on GH replacement has been raised. most appropriately commenced at a low Recent studies have, however, suggested starting dose and titrated according to clinical that rhGH replacement does not cause a response, and age-and sex- adjusted values for recurrence of pituitary or peripituitary serum IGF-1. There is a growing body of tumors. An observational study by Frajese evidence to support the safety and efficacy of et al. of 100 patients with adult-onset GH individualized dose titration of GH therapy, deficiency treated with rhGH using dose such that recent experience in adult clinical titration against serum IGF-1 reported no practice is likely to result in a degree of re- obvious increase in the rate of hypothalamo- evaluation of traditional weight and surface pituitary tumor recurrence [39]. It is of area-based dosing in the pediatric setting [36]. interest to note that 91% of patients in this Address for correspondence: William Drake, Department of series had received pituitary radiotherapy. Endocrinology, St Bartholomew’s Hospital, West Smithfield, Chung et al. also reported safety data on London, EC1A 7BE, UK. Email: [email protected] 50 patients with non-anterior pituitary parasellar tumors treated with GH by dose References titration who underwent rigorous surveillance 1. Cuneo RC, Salomon F, McGauley GA et al. The growth hormone deficiency syndrome in adults. imaging [40]. Again, 70% of this patient Clin Endocrinol (Oxf) 1992;37:387–97. group had received pituitary radiotherapy as 2. Jorgensen JO, Pedersen SA, Thuesen L et al. Beneficial effects of growth hormone treatment in GH-deficient adults. part of the original management of their Lancet 1989;1:1221–5. tumor. Both of these studies also provide data 3. Salomon F, Cuneo RD, Hesp R et al. The effects of treatment with recombinant human growth hormone on body that supports the safety and efficacy of the composition and metabolism in adults with growth hormone rhGH dose-titration regimen [39,40]. deficiency. N Engl J Med 1989;321:1797–803. 4. Carroll PV, Christ ER, Bengtsson BA et al. Growth hormone deficiency in adulthood and the effects of growth hormone Treatment of GH deficiency replacement: a review. Growth Hormone Research Society Scientific Committee. J Clin Endocrinol Metab 1998;83:382–95. Determining which patients with GH 5. Rosen T, Bengtsson BA. Premature mortality due to deficiency will benefit most from GH cardiovascular disease in hypopituitarism. Lancet 1990;336:285–8. replacement is difficult. However, it is clear 6. Shahi M, Beshyah SA, Hackett D et al. Myocardial dysfunction that this decision needs to be made on an in treated adult hypopituitarism: a possible explanation for increased cardiovascular mortality. Br Heart J 1992;67:92–6. individual patient basis, and at present rhGH 7. Molitch ME, Clemmons DR, Malozowski S et al. Evaluation and replacement is usually offered to those patients treatment of adult growth hormone deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab with significant clinical manifestations of GH 2006;91:1621–34. deficiency syndrome and biochemically proven 8. Drake WM, Coyte D, Camacho-Hubner C et al. Optimizing growth hormone replacement therapy by dose titration in severe GH deficiency [7]. In adult patients with hypopituitary adults. J Clin Endocrinol Metab 1998;83:3913–9. R7973_3_Growth_1_3_06.qxd 16/11/06 17:30 Page 67

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9. Murray RD, Skillicorn CJ, Howell SJ et al. Dose titration and patient 25. Cook DM, Ludlam WH, Cook MB. Route of estrogen selection increases the efficacy of GH replacement in severely administration helps to determine growth hormone (GH) GH deficient adults. Clin Endocrinol (Oxf) 1999;50:749–57. replacement dose in GH-deficient adults. J Clin Endocrinol 10. Johannsson G, Rosen T, Bengtsson BA. Individualized dose Metab 1999;84:3956–60. titration of growth hormone (GH) during GH replacement in 26. Janssen YJ, Helmerhorst F, Frolich M et al. A switch from oral hypopituitary adults. Clin Endocrinol (Oxf) 1997;47:571–81. (2 mg/day) 17-ß-estradiol therapy increases serum insulin- 11. Moller J, Jorgensen JO, Lauersen T et al. Growth hormone dose like growth factor I levels in recombinant growth hormone regimens in adult GH deficiency: effects on biochemical (GH) substituted women with growth hormone deficiency. growth markers and metabolic parameters. Clin Endocrinol J Clin Endocrinol Metab 2000;85:464–7. (Oxf) 1993;39:403–8. 27. Kam GY, Leung KC, Baxter RC et al. Estrogens exert route 12. Johannsson G, Bjarnason R, Bramnert M et al. The individual and dose-dependent effects on insulin-like growth factor responsiveness to growth hormone (GH) treatment in (IGF)-binding protein-3 and the acid labile subunit of the IGF GH-deficient adults is dependent on the level of GH-binding ternary complex. J Clin Endocrinol Metab 2000;85:1918–22. protein, body mass index, age, and gender. J Clin Endocrinol Metab 1996;81:1575–81. 28. Span JP, Pieters GF, Sweep CG et al. Gender difference in insulin-like growth factor I response to growth hormone (GH) 13. Murray RD, Shalet SM. Adult growth hormone replacement: treatment in GH-deficient adults: role of sex hormone lessons learned and future direction. J Clin Endocrinol Metab replacement. J Clin Endocrinol Metab 2000;85:1121–5. 2002;87:4427–8. 29. Monson JP. Biochemical markers of individual response 14. Holmes SJ, Shalet SM. Which adults develop side-effects of growth hormone replacement? Clin Endocrinol (Oxf) to growth hormone replacement in adults. Horm Res 1995;43:143–9. 2001;55:49–54. 15. Amato G, Carella C, Fazio S et al. Body composition, bone 30. Hoffman DM, Nguyen TV, O’Sullivan AJ et al. Diagnosis of metabolism, and heart structure and function in growth growth hormone deficiency in adults. Lancet 1994;344:482–3. hormone-deficient adults before and after GH replacement 31. Shalet SM, Toogood A, Rahim A et al. The diagnosis of therapy at low doses. J Clin Endocrinol Metab 1993;77:1671–6. growth hormone deficiency in children and adults. 16. Orme SM, Sebastian JP, Oldroyd B et al. Comparison of measures Endocr Rev 1998;19:203–23. of body composition in a trial of low dose growth hormone 32. Gibney J, Johannsson G. Long-term monitoring of insulin-like replacement therapy. Clin Endocrinol (Oxf) 1992;37:453–9. growth factor I in adult growth hormone deficiency: a critical 17. O’Halloran DJ, Tsatsoulis A, Whitehouse RW et al. Increased appraisal. Horm Res 2004;62:66–72. bone density after recombinant human growth hormone 33. Tillmann V, Buckler JM, Kibirige MS et al. Biochemical tests therapy in adults with isolated GH deficiency. J Clin Endocrinol Metab 1993;76:1344–8. in the diagnosis of childhood growth hormone deficiency. J Clin Endocrinol Metab 1997;82:531–5. 18. Iranmanesh A, Lizarralde G, Veldhuis JD. Age and relative adiposity are specific negative determinants of the frequency 34. Mandel S, Moreland E, Nichols V et al. Changes in insulin-like and amplitude of growth hormone (GH) secretory bursts growth factor-I (IGF-I), IGF-binding protein-3, growth hormone and the half-life of endogenous GH in healthy men. (GH)-binding protein, erythrocyte IGF-I receptors, and growth rate J Clin Endocrinol Metab 1991;73:1081–8. during GH treatment. J Clin Endocrinol Metab 1995;80:190–4. 19. Rudman D, Kutner MH, Rogers CM et al. Impaired growth 35. Drake WM, Rodriguez-Arnao J, Weaver JU et al. The effect hormone secretion in the adult population: relation to age of long term GH replacement on bone mineral density and and adiposity. J Clin Invest 1981;67:1361–9. metabolism in hypopituitary adults. Clin Endocrinol (Oxf) 20. Carroll PV, Littlewood R, Weissberger AJ et al. The effects of 2001;54:525–32. two doses of replacement growth hormone on the biochemical, 36. Drake WM, Howell SJ, Monson JP et al. Optimizing GH therapy body composition and psychological profiles of growth in adults and children. Endocr Rev 2001;22:425–50. hormone-deficient adults. Eur J Endocrinol 1997;137:146–53. 37. Arosio M, Ronchi CL, Epaminonda P et al. New therapeutic 21. Chapman IM, Hartman ML, Straume M et al. Enhanced options for acromegaly. Minerva Endocrinol 2004;29:225–39. sensitivity growth hormone (GH) chemiluminescence assay reveals lower post glucose nadir GH concentrations in men 38. Hoffman AR, Strasburger CJ, Zagar A et al. Efficacy and than women. J Clin Endocrinol Metab 1994;78:1312–9. tolerability of an individualized dosing regimen for adult growth hormone replacement therapy in comparison with 22. Veldhuis JD. Gender differences in secretory activity of the fixed body weight-based dosing. J Clin Endocrinol Metab human somatotropic (growth hormone) axis. Eur J Endocrinol 1996;134:287–95. 2004;89:3224–33. 23. Ho KY, Evans WS, Blizzard RM et al. Effects of sex and age 39. Frajese G, Drake WM, Loureiro RA et al. Hypothalamo-pituitary on the 24-hour profile of growth hormone secretion in man: surveillance imaging in hypopituitary patients receiving importance of endogenous estradiol concentrations. long-term GH replacement therapy. J Clin Endocrinol Metab J Clin Endocrinol Metab 1987;64:51–8. 2001;86:5172–5. 24. Burman P, Johansson AG, Siegbahn A et al. Growth hormone 40. Chung TT, Drake WM, Evanson J et al. Tumour surveillance (GH)-deficient men are more responsive to GH replacement imaging in patients with extrapituitary tumours receiving growth therapy than women. J Clin Endocrinol Metab 1997;82:550–5. hormone replacement. Clin Endocrinol (Oxf) 2005;63:274–9. R7973_3_Growth_1_3_06.qxd 16/11/06 17:30 Page 68

68 Leading Article Effect of Standard Insulin Tolerance Test on Plasma Leptin Levels in Children with and without Growth Hormone Deficiency

H ZOTTER1, R KERBL2, AND M BORKENSTEIN2 1Division of Neonatology, and 2Division of General Pediatrics, Department of Pediatrics, Medical University of Graz, Graz, Austria

Leptin is an adipocyte-derived hormone that The studies are discussed, with special enhances satiety and reduces food intake, and regard to children with and without growth is involved in the maintenance of energy hormone (GH) deficiency. balance and body weight [1–4]. In humans, plasma leptin concentration is strongly Discussion correlated to the amount of body fat and body Since the discovery of leptin, the mass index [3–7]. understanding of its physiological role has The discovery of the obese gene and evolved from a satiety signal to that of an leptin [2] has provided a relevant clue to the integrative hormone that responds to, and understanding of interactions between regulates, different endocrine pathways, with hypothalamic regions that control food direct metabolic effects on peripheral tissues intake and peripheral energy stores [8,9]. [4,7,9,14]. Leptin plays an integral role in It has been postulated that insulin induces energy homeostasis and may even be obese gene expression in vivo in rats and in fat important during stress [15]. Although it is cell cultures [10,11]. Moreover, in adults it evident that caloric deprivation decreases has been shown that insulin stimulation plasma leptin levels [16,17], responses of the produces modifications of plasma leptin hormone during repeated episodes of levels [12,13]. physiological stress, such as hypoglycemia, Studies describing leptin responses to remain undetermined. A confounding hyperinsulinemia have been conflicting, variable when studying the impact of with reports of both an increase and a hypoglycemia on plasma leptin levels is that decrease of plasma leptin levels. Therefore, it experimental hypoglycemia may cause both was the aim of this article to review the an increase and a decrease in plasma leptin literature concerning leptin responses to levels in adults [18–21]. insulin administration in children born with Recently, the current authors have shown short stature. that insulin administration in children with short stature decreases plasma leptin levels Methods 60 and 120 min after intravenous insulin In order to find the literature, a PubMed injection [18]. In this study, this effect was search was carried out using the following independent of GH deficiency. Furthermore, keywords: leptin, insulin, hyperinsulinemia, no statistically significant difference was hypoglycemia, hyperglycemia, euglycemia, found in plasma leptin levels before insulin children, short stature, growth hormone, and administration, 1 h and 2 h thereafter, or in idiopathic short stature. percentage leptin decrease (in percentage) R7973_3_Growth_1_3_06.qxd 16/11/06 17:30 Page 69

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when comparing patients with GH deficiency contribute to a shift towards carbohydrate and children with idiopathic short stature utilization, allowing quicker generation of [18]. Concerning the effect of insulin ATP [17]. administration on plasma leptin levels, it Leptin levels have been shown to be is essential to take into consideration inversely related to pituitary–adrenal function whether hyperinsulinemia is accompanied [26]. In adults and in children with short by hypoglycemia. Whereas in the above stature, no obvious differences between study glucose levels fell below a defined patients with and without GH deficiency were hypoglycemia threshold of 2.2 mmol/L in all found [18,26]. This indicates that GH has no subjects (with a nadir of 1.4±0.1 mmol/L) direct effect on short-term leptin regulation, as [18], other studies have shown that prolonged found by others [27,28]. Although it has also elevations of insulin under euglycemic been reported that in adults with GH conditions may increase plasma leptin levels deficiency there was no difference in leptin [19–21]. It has been demonstrated that a 6-h levels when adjusted for body mass index and hyperinsulinemic euglycemic clamp caused a gender compared with healthy subjects [29], in 147±7% increase over baseline in plasma adolescents with GH deficiency, GH treatment leptin levels in healthy lean males, but 6 h of caused a substantial increase in the nocturnal hyperinsulinemia with graded hypoglycemia leptin peak during the second night after blunted the increase in plasma leptin levels commencing substitution [30,31]. Whether [20]. In response to hypoglycemia, plasma this effect was due to an increase in insulin or leptin levels decreased in healthy adults, but directly caused by GH remains unclear. In not in patients with insulin-dependent children with isolated GH deficiency, leptin diabetes [17]. Wellhoener et al. exposed levels were normal before therapy and subjects to four different conditions: high decreased after 4 weeks of GH therapy, which insulin, with either euglycemia or graded could not be explained by changes in body hypoglycemia, and low insulin, with either composition [32]. In vitro, GH led to a euglycemia or graded hypoglycemia [21]. moderate reduction in leptin release from With both high and low insulin levels, the human adipocytes. This inhibitory effect was insulin-induced increase in plasma leptin only observed in the presence of insulin, levels was attenuated by 50% during suggesting that GH interacts with the hypoglycemia [21]. Thus, hypoglycemia stimulatory effect of insulin [33]. counteracts the stimulatory effect of hyperinsulinemia on plasma leptin levels. Summary The evidence that hypoglycemia induced by A confounding variable when studying the hyperinsulinemia inhibits rises in plasma impact of insulin on plasma leptin levels is leptin levels, supports the hypothesis that low that experimental hyperinsulinemia may glucose levels during a prolonged fast, cause both an increase and a decrease in directly or indirectly, signal the adipocyte to plasma leptin levels in humans. Therefore, it reduce leptin secretion [17]. was the aim of the present study to review the It is well established that changes in leptin literature concerning leptin responses to have marked effects on metabolism. Increases insulin administration in children born with in leptin can elevate hepatic glucose short stature. production in rats in the post-absorptive state For this purpose, a PubMed search was [22]. Reports also demonstrate leptin-induced carried out and the literature was discussed, fat mobilization and fatty acid oxidation in with special regard to children with and mice [23]. Therefore, a major function of without GH deficiency. leptin may be to switch fuel utilization In summary, the literature indicates that from carbohydrates to fat [24,25]. This insulin administration may increase and metabolic impact could be important during decrease plasma leptin levels in humans hypoglycemia, where leptin decrease could depending on the presence of hypoglycemia. R7973_3_Growth_1_3_06.qxd 16/11/06 17:30 Page 70

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In children with short stature, a standard 15. Bornstein SR. Is leptin a stress related peptide? Nat Med insulin tolerance test that is accompanied by 1997;3:937. 16. Maccario M, Aimaretti G, Corneli G et al. Short-term fasting hypoglycemia leads to a decrease in plasma abolishes the sex-related difference in GH and leptin secretion leptin levels in those with and without in humans. Am J Physiol Endocrinol Metab 2000;279:411–6. 17. Sandoval DA, Galassetti P, Tate D et al. Leptin responses to GH deficiency. antecedent exercise and hypoglycemia in healthy and type 1 diabetes mellitus men and women. J Diabetes Complications Address for correspondence: H Zotter, Division of Neonatology, 2003;17:301–6. Department of Pediatrics, Medical University of Graz, 18. Zotter H, Kerbl R, Gallistl S et al. Leptin responses to insulin Auenbruggerplatz 30, A-8036 Graz, Austria. administration in children with short stature. Metabolism Email: [email protected] 2005;54:862–5. 19. Boden G, Chen X, Kolaczynski JW et al. Effects of prolonged hyperinsulinemia on serum leptin in normal human subjects. References J Clin Invest 1997;100:1107–13. 20. Schmitz O, Fisker S, Orskov L et al. Effects of hyperinsulinaemia 1. Tartaglia LA. The leptin receptor. J Biol Chem 1997;272:6093–6. and hypoglycaemia on circulating leptin levels in healthy lean 2. Zhang Y, Proenca R, Maffei M et al. Positional cloning of the males. Diabetes Metab 1997;23:80–3. mouse obese gene and its human homologue. Nature 21. Wellhoener P, Fruehwald-Schultes B, Kern W et al. Glucose 1994;372:425–32. metabolism rather than insulin is a main determinant of leptin 3. Campfield LA, Smith FJ, Burn P. The OB protein (leptin) secretion in humans. J Clin Endocrinol Metab 2000;85:1267–71. pathway – a link between adipose tissue mass and central 22. Nemecz M, Preininger K, Englisch R et al. Acute effect of neural networks. Horm Metab Res 1996;28:619–32. leptin on hepatic glycogenolysis and gluconeogenesis in 4. Sudi KM, Gallistl S, Tafeit E et al. The relationship between perfused rat liver. Hepatology 1999;29:166–72. different subcutaneous adipose tissue layers, fat mass and 23. Bryson JM, Phuyal JL, Swan V et al. Leptin has acute effects leptin in obese children and adolescents. J Pediatr Endocrinol on glucose and lipid metabolism in both lean and gold Metab 2000;13:505–12. thioglucose-obese mice. Am J Physiol 1999;277:417–22. 5. Considine RV, Sinha MK, Heiman ML et al. Serum 24. Gutierrez-Juarez R, Obici S, Rossetti L. Melanocortin- immunoreactive-leptin concentrations in normal-weight and independent effects of leptin on hepatic glucose fluxes. obese humans. N Engl J Med 1996;334:292–5. J Biol Chem 2004;279:49704–15. 6. Sudi KM, Gallistl S, Trobinger M et al. Subcutaneous adipose 25. Rossetti L, Massillon D, Barzilai N et al. Short term effects of tissue layers as a stable correlate of leptin in response to leptin on hepatic gluconeogenesis and in vivo insulin action. short term energy restriction in obese girls. Int J Obes Relat J Biol Chem 1997;272:27758–63. Metab Disord 2001;25:43–5. 26. Licinio J, Mantzoros C, Negrao AB et al. Human leptin levels 7. Sudi K, Gallistl S, Trobinger M et al. Insulin and insulin are pulsatile and inversely related to pituitary-adrenal resistance index are not independent determinants for the function. Nat Med 1997;3:575–9. variation in leptin in obese children and adolescents. J Pediatr 27. Wolthers T, Grofte T, Norrelund H et al. Differential effects of Endocrinol Metab 2000;13:923–32. growth hormone and prednisolone on energy metabolism and 8. Rohner-Jeanrenaud F. A neuroendocrine reappraisal of the leptin levels in humans. Metabolism 1998;47:83–8. dual-centre hypothesis: its implications for obesity and insulin 28. Kousta E, Chrisoulidou A, Lawrence NJ et al. The circadian resistance. Int J Obes Relat Metab Disord 1995;19:517–34. rhythm of leptin is preserved in growth hormone deficient 9. Zotter H, Gallistl S, Kerbl R et al. Effects of TRH hypopituitary adults. Clin Endocrinol 1998;48:685–90. administration on plasma leptin levels in infants, children and 29. Blum WF, Englaro P, Hanitsch S et al. Plasma leptin levels in adolescents. J Pediatr Endocrinol Metab 2004;17:1001–6. healthy children and adolescents: dependence on body mass 10. Cusin I, Sainsbury A, Doyle P et al. The ob gene and insulin. A index, body fat mass, gender, pubertal stage, and relationship leading to clues to the understanding of obesity. testosterone. J Clin Endocrinol Metab 1997;82:2904–10. Diabetes 1995;44:1467–70. 30. Blum WF, Jorgensen JO, Englaro P et al. Nocturnal serum leptin 11. Saladin R, De Vos P, Guerre-Millo M et al. Transient increase in increase after short-term but not during long-term treatment obese gene expression after food intake or insulin with growth hormone. Endocrinol Metab 1997;4:22–9. administration. Nature 1995;377:527–9. 31. Vestergaard ET, Hansen TK, Nielsen S et al. Effects of GH 12. Malmstrom R, Taskinen MR, Karonen SL et al. Insulin increases replacement therapy in adults on serum levels of leptin and plasma leptin concentrations in normal subjects and patients ghrelin: the role of lipolysis. Eur J Endocrinol 2005;153:545–9. with NIDDM. Diabetologia 1996;39:993–6. 32. Rauch F, Westermann F, Englaro P et al. Serum leptin is 13. Schafroth U, Godang K, Ueland T et al. Leptin response to suppressed by growth hormone therapy in growth hormone- endogenous acute stress is independent of pituitary deficient children. Horm Res 1998;50:18–21. function. Eur J Endocrinol 2001;145:295–301. 33. Wabitsch M, Jensen PB, Blum WF et al: Insulin and cortisol 14. Sandoval DA, Davis SN. Leptin: metabolic control and promote leptin production in cultured human fat cells. regulation. J Diabetes Complications 2003;17:108–13. Diabetes 1996;45:1435–8. R7973_3_Growth_1_3_06.qxd 16/11/06 17:30 Page 71

71 Citations and Editor’s Notes GH Treatment in Non-GH-Deficient Indications

Aortic distensibility and dimensions • The ascending aorta. and the effects of growth hormone • The descending aorta. treatment in the turner syndrome. • The level of the diaphragm. van den Berg J, Bannink EM, Wielopolski PA et al. • The abdominal aorta. Erasmus MC–Sophia Children’s Hospital, Rotterdam, The Netherlands. TS patients had larger aortic diameters Am J Cardiol 2006 97:1644–9. and reduced aortic distensibility compared with controls. In general, GH treatment Editor’s note: There has been concern that increased distensibility except in TS patients growth hormone (GH) treatment for non- who received the lowest dose of GH, who GH-deficient indications might be associated had larger aortic diameters and reduced with a variety of physical and long-term distensibility compared with control subjects. metabolic consequences. Such consequences These findings do not meet with might be difficult to identify in short-term theoretical expectations, and it may be that studies and will naturally require long-term individual patients have followed a natural surveillance of patients in these cohorts. progression of their aortic anatomy with age, A problem facing researchers conducting independent of GH treatment, and thus long-term studies is the recruitment of confounded the observations. In other untreated control patients to match with groups of children treated with GH (e.g. for treated patients, particularly as more congenital heart disease with short stature individuals with disorders eligible for GH or Noonan syndrome), no adverse effects of treatment are attracted to that option GH treatment have been observed on cardiac for management. size and function. Thus, the adolescent with Turner syndrome (TS) poses a particular TS is clearly an important focus for investigative and management dilemma, as cardiovascular assessment. cardiovascular anatomical (structural) and functional (e.g. hypertension) problems have Inflammatory markers in adults with been under-evaluated in the past. However, Prader-Willi syndrome before and during improved research resources and imaging 12 months growth hormone treatment. techniques indicate that structural Hoybye C. cardiovascular malformations are present in Karolinska University Hospital, ≤76% of patients with TS. Stockholm, Sweden. The present authors compared 38 TS Horm Res 2006;66:27–32. women who received GH treatment at a variety of doses during childhood with Editor’s note: Growth hormone (GH) 27 TS women who did not receive GH treatment for patients with Prader–Willi treatment. Four aortic dimensions and syndrome (PWS) is primarily licensed for distensibility were assessed using magnetic children on the basis of its ability to reduce resonance imaging: fat mass when used in association with an R7973_3_Growth_1_3_06.qxd 16/11/06 17:30 Page 72

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appropriate calorie-constrained diet. The a non-significant reduction in IL-6 and majority of PWS patients are believed to be HCRP levels for the whole group at both functionally GH deficient to some degree. 6 and 12 months. Notably, the diabetic This idea is partly supported by the improved patient was able to stop treatment for linear growth that is observed in response to diabetes after starting GH treatment. treatment. Thus, the long-term morbidity This small study clearly needs to be due to cardiovascular disorders found in expanded with a larger cohort of patients to adult PWS patients may not simply be a disentangle the many clinical variables that result of obesity and obstructive respiratory might influence inflammatory marker disorders, but may be exacerbated by partial profiles, and show possible situations in which GH deficiency. GH treatment may have a therapeutic role. The present study sought to define whether or not PWS adults show abnormal levels of the Self-esteem and social adjustment inflammatory markers interleukin-6 (IL-6), in young women with Turner syndrome – tumor necrosis factor-α (TNF-α), high influence of pubertal management and sensitive C-reactive protein (HCRP), and sexuality: population-based cohort study. cholesterol, triglycerides, leptin, adiponectin, Carel JC, Elie C, Ecosse E et al. and glucose and insulin status levels associated Hôpital Robert Debré, Paris, France. with obesity and GH deficiency. Body fat levels J Clin Endocrinol Metab 2006;91:2972–9. were determined by dual X-ray absorptiometry. The authors recruited 12 PWS adults, aged Editor’s note: This remarkable study reports 17–37 years, with a median body mass index of the evaluation of the impact of pubertal 34 kg/m2 (range 21–50 kg/m2). The patients management (timing of induction) on were assessed at baseline and after 6 and 566 French adult women with Turner 12 months of GH treatment, which was dose syndrome (TS). Throughout childhood and titrated to keep serum insulin-like growth adolescence, data regarding TS, growth, and factor-1 (IGF-1) within the normal age-related treatment were collected, and at a mean age of reference range. Daily calorie intake was 22 years (range 18–31) the studied TS patients continued at 1000 kcal/day, which had been were invited to complete a questionnaire. The maintained for several years in these patients survey included: using a strict diet. Baseline leptin levels were appropriate • The Cooperman’s Self-Esteem for individual degrees of adiposity, one Inventory (SEI). patient had overt diabetes and half of the • The Social Adjustment Scale patients had insulin resistance (calculated Self-Report (SAS-SR). using the homeostasis model assessment • Short Form 36 (SF-36) of the Medical index). Four patients were hypertensive and Outcome Study. receiving appropriate antihypertensive • The General Health Questionnaire agents, and eight patients were hypogonadal. 12 (GHQ-12), which measures These varied clinical circumstances may have psychological distress. impacted in different ways on the observed inflammatory markers. However, baseline Patients also answered questions regarding IL-6 was elevated in nine patients, HCRP demographic characteristics, sexual experience, elevated in seven patients, and TNF-α levels current health status, and expectations from were within the normal range in all patients. growth hormone (GH) treatment. After 12 months of GH treatment, median The most important observations from a IGF-1 levels increased approximately two- life-style perspective were that a low self- fold, median body fat was reduced by 10%, esteem was associated with limited sexual and median lean body mass increased by 20% experience, with impaired auditory function, (p<0.05). GH treatment was associated with and with persistent otological abnormalities. R7973_3_Growth_1_3_06.qxd 16/11/06 17:30 Page 73

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Auditory and otological problems have This randomized, double-blinded, placebo- become increasingly apparent in recent years controlled crossover study of five MAS patients in adult women with TS. In addition, low aged 13–39 years was comprised of: social adjustment was associated with low paternal socio-economic class. Late age at • An initial 12-week washout period, first kiss was associated with late induction of in which GH excess treatments puberty, which in itself might be related were discontinued. through medical management as being a • A first 12-week treatment period, causal association with cardiac disorders. Not in which patients received 20 mg/day surprisingly, age at first sexual intercourse pegvisomant or a placebo, was related to age at puberty, and delayed administered subcutaneously. induction of puberty had “a long-lasting • A 6-week washout period. effect on sex life”. However, the finding most • A second 12-week treatment course, relevant to growth management was that final in which pegvisomant and placebo adult height and height gain due to GH had regimens were crossed-over. no effect on psychological outcomes, and the authors question the value of GH treatment The recruited patients had GH that did in TS patients. not suppress below 1 ng/mL on a standard oral glucose test. The primary measure of drug Pegvisomant for the treatment of efficacy was normalization of serum insulin- gsp-mediated growth hormone excess in like growth factor-1 (IGF-1) to age-specific patients with McCune-Albright syndrome. and gender-specific references, and this was Akintoye SO, Kelly MH, Brillante B et al. successfully achieved by 6 weeks in four of the University of Pennsylvania, Philadelphia, PA, USA. patients when treated with pegvisomant. The J Clin Endocrinol Metab 2006;91:2960–6. other patient was subsequently controlled with a combination of lanreotide and pegvisomant. Editor’s note: Hypersecretion of growth In addition, a more modest reduction in IGF hormone (GH) may occur in approximately binding protein-3 was achieved, without 20% of patients with McCune–Albright change in random serum GH levels. Pituitary syndrome (MAS), arising in childhood or magnetic resonance imaging showed no developing later in life. A proportion of these evidence of increased pituitary volume from patients will have identifiable pituitary baseline to 12 months for the cohort as a adenomas, whereas others may have more whole, although one patient did show an generalized somatotrophic hypersecretion increase in pituitary volume (clinical without tumor. Many have coexistent significance not reported). A standard panel of polyostotic fibrous dysplasia (PFD), which, bone metabolism markers showed no change when affecting the skull bones, will render during pegvisomant treatment and there was trans-sphenoidal surgery impractical. Pituitary no overall change in subjective, reported bone irradiation is contra-indicated because of a pain (scored on a weekly basis throughout the predisposition of PFD to undergo sarcomatous study). This suggests that there was no positive transformation. Long-term medical therapy or negative effect of pegvisomant on PFD. with somatostatin (or analogue), with or Interestingly, pegvisomant had no effect without dopamine receptor agonists, has on symptoms of fatigue and sweating, hitherto been the treatment of preference in possibly because the authors targeted IGF-1 these thankfully rare cases. The development of suppression as the endpoint rather than the GH receptor antagonist “pegvisomant” titrating pegvisomant dose to symptoms offers a similar opportunity for control in such removal. Whilst pegvisomant is clearly MAS patients as has been shown in recent years effective in MAS-associated GH excess, for symptomatic control of GH excess in factors such as cost and optimal injection acromegaly resistant to other treatment options. frequency will determine clinical utility. R7973_3_Growth_1_3_06.qxd 16/11/06 17:30 Page 74

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New growth factor therapies aimed units (UK) that focus on the dietary at improving intestinal adaptation determinants of serum insulin-like growth in short bowel syndrome. factor-1 (IGF-1) and its relationship with Pereira PM, Bines JE. IGF binding protein 3 (IGFBP-3) and Royal Children’s Hospital, Melbourne, childhood growth, and the potential VIC, Australia. association of higher (free) IGF-1 levels with J Gastroenterol Hepatol 2006;21:932–40. certain types of cancer in late life. The first study found an association Editor’s note: There has been extensive between leg length, IGF-1, IGFBP-3, and animal-based research over the last 15 years cancer risk, and the authors attributed this to evaluating the role of a variety of growth the milk protein content of diet [1]. However, factors as trophic agents. They may have dairy product intake was correlated with clinical applications in adaptive recovery increased leg length in boys, but with or treatment for malabsorption and decreased leg length in girls. malnutrition resulting from massive small In females, early onset of puberty and its bowel resection due to a variety of congenital association with tall stature, constitutional intestinal disorders and acquired conditions. advanced development, and earlier estrogen The most likely candidates for treatment of exposure has been clearly linked with short bowel syndrome (SBS) at present increased risk of breast cancer. However, the are growth hormone (GH), glucagon-like second study, unusually, focused on males, for peptide-2 (GLP-2), epidermal growth factor whom good retrospective data on pubertal (EGF), and insulin-like growth factor-1 timing were available [2]. Age at peak height (IGF-1) and its binding proteins or analogues. velocity (APHV) in puberty was inversely The present review provides a concise associated with adult IGF-1 levels and body update on the progress to date within this mass index (BMI), as were prepubertal field, and highlights the lack of data within childhood height and BMI. In contrast, APHV clinical settings due to the relative rarity of was positively associated with adult height. SBS. The role of GH in pediatric cases is summarized by considering just five patients Does long-term GH replacement in three case studies. If significant progress is therapy in hypopituitary adults with to be made at clinical level then careful GH deficiency normalise quality of life? multicenter trials with appropriate protocols Koltowska-Haggstrom M, Mattsson AF, and outcome measures are clearly essential Monson JP et al. for any single agent or combined treatments. Pfizer, Sollentuna, Sweden. Eur J Endocrinol 2006;155:109–19. [1] Milk as a food for growth? The insulin-like growth factors link. Editor’s note: Impairment of quality of life Rogers I, Emmett P, Gunnell D et al. (QoL) in adult patients with growth University of Bristol, Bristol, UK. hormone (GH) deficiency caused by Public Health Nutr 2006;9:359–68. hypopituitarism is a well-recognized phenomenon that was first reported over [2] Timing of puberty determines 40 years ago. Whilst many studies have serum insulin-like growth factor-I confirmed this impairment, the benefit of in late adulthood. recombinant human GH (rhGH) replace- Sandhu J, Davey Smith G, Holly J et al. ment therapy on QoL measures remains University of Bristol, Bristol, UK. controversial, with recent clinical trials J Clin Endocrinol Metab 2006;91:3150–7. producing conflicting results. This may be because the studies concerned have tended to Editor’s note: These two papers are linked be quite small in size, and have not by common interests within Bristol-based compared the impact of rhGH therapy on R7973_3_Growth_1_3_06.qxd 16/11/06 17:30 Page 75

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QoL with normative data obtained from local step in studying the physiology of hormone reference populations. action in vivo. Using adenoviral-mediated In this report, the large Kabi gene delivery systems in combination with International Metabolic Study (KIMS) sensitive, non-invasive imaging on animal database is utilized and QoL data obtained experimental models may offer a number of for those all those patients (n=1686) advantages, including the ability to perform registered in four participating European serial measurements or experiments within countries. These data were compared with the same animal. This would allow more QoL data taken from corresponding general relevant biological endpoints of hormone population samples for each country action to be determined. (England & Wales n=892, The Netherlands The present paper reports on the n=1038, Spain n=868, and Sweden n=1682). development of a novel, non-invasive Change in total QoL scores and responses bioluminescence technique for the imaging to treatment (using 4–6 years follow-up data) and assessment of in vivo hepatic growth were evaluated, and revealed that long-term hormone (GH) action. Taking advantage of rhGH replacement therapy in GH deficient the new gene delivery systems and imaging adults improved QoL to nearly country-specific techniques, the authors coupled a signal normative levels. This was especially evident transducer and activation of transcription-5B during the first 12 months of treatment, with a (STAT-5B)-dependent GH response element steady and gradual improvement over time to a luciferase reporter. STAT-5-driven until the general population reference range transcriptional activation of the fused was reached. Problems with memory and upstream coding region for firefly luciferase tiredness were the most debilitating symptoms enabled measurement of light emission in for patients prior to starting rhGH therapy, response to GH. followed by problems with tenseness, self- The GH–luciferase response element was confidence, and difficulties with socialization. incorporated into an adenoviral vector and Interestingly, treatment with rhGH improved injected into female nude mice, GH was all these problems in reverse order, a novel administered exogenously, and the in vivo observation that was consistent across the four effects of hepatic GH signaling were studied. countries. Furthermore, the degree of baseline Luminescence responses in the region of the impairment in QoL did not appear to liver were detected by gamma camera, and were determine the extent of sustained and lasting evident within 1 h of GH injection, peaking improvement in QoL, or the observed pattern of after 3 h. The dose–response effects of GH treatment response. In conclusion, the authors administration were also tested, and suggested that the results supported the statistically significant dose-dependent effects hypothesis that GH deficiency alone might be of GH were observed in liver luciferase signal the direct cause for the psychological problems following GH injection, confirming that the experienced by many GH deficient patients. ability of this system to detect graded responses. Subsequently, similar patterns of GH dose- In vivo imaging of hepatic growth dependent responsiveness were observed when hormone signaling. the GH injection experiments were repeated on Frank SJ, Wang X, He K et al. four other occasions over a 10-day period in the University of Alabama at Birmingham, same mice. Experiments in which there was co- Birmingham, AL, USA. administration of GH receptor with GH Mol Endocrinol 2006;20;2819–30. significantly enhanced the GH responses as detected using bioluminescence. Editor’s note: The development of novel, The preliminary work presented in this non-invasive experimental techniques that do paper potentially heralds a new era of in vivo not involve the use of animals or the hormone study, and the technique described harvesting of tissue samples may be the next may serve as an important blueprint for R7973_3_Growth_1_3_06.qxd 16/11/06 17:30 Page 76

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non-invasive and repeated studies of the induce OSA in GH deficient patients. In effects of hormone signaling via receptors contrast, OSA may be present before the onset expressed in the liver and in other tissues. of therapy. Thus, the authors concluded that OSA should not be a major concern if Sleep apnoea and quality of life in appropriate rhGH therapy is performed, and growth hormone (GH)-deficient adults may indeed benefit overall sleep quality. before and after 6 months of GH replacement therapy. The d3/growth hormone (GH) receptor Peker Y, Svensson J, Hedner J et al. polymorphism does not influence the Skaraborg Hospital, Skoevde, Sweden. effect of GH treatment (66 μg/k/day) Clin Endocrinol (Oxf) 2006;65:98–105. or the spontaneous growth in short non-GH-deficient small-for-gestational-age Editor’s note: Growth hormone (GH) is children: results from a two-year controlled known to have complex effects on sleep by prospective study in 170 Spanish patients. acting on the central nervous system and the Carrascosa A, Esteban C, Espadero R et al. upper airways, affecting both sleep quality Hospital Maternoinfantil Vall d’Hebron, and breathing patterns. In patients with Barcelona, Spain. untreated acromegaly, and thus GH excess, J Clin Endocrinol Metab 2006;91:3281–6. obstructive sleep apnea (OSA) is frequently observed. Therefore, concerns have been Editor’s note: The d3 growth hormone raised that recombinant human GH (rhGH) receptor gene (d3-GHR) polymorphism has replacement therapy may induce OSA and recently been the focus of much attention, other disturbances in sleep architecture in with a number of research groups reporting GH deficient patients. significant relationships between d3-GHR Peker and colleagues report what appears genotype and responsiveness to GH therapy. to be the first prospective observational study These relationships have been observed in GH of a small cohort of GH deficient adult deficient patients, Turner syndrome patients, subjects (n=19, mean age of 53 years). and small-for-gestational-age (SGA) patients, Detailed polysomnographic and quality of life but have not been consistently observed in assessments (including electroencephalogram, different categories of recombinant human electromyography, electrocardiogram, electro- GH (rhGH) treatment recipients. oculography, body position detector, and In a 2-year, prospective, randomized respiratory monitoring) were conducted before controlled trial of rhGH therapy for children and immediately after 6 months of daily with short stature attributed to SGA, treatment with rhGH. Treatment with rhGH 86 subjects received treatment (mean dose (dose range 0.14–0.33 mg/day) was not 66 μg/kg/day) whilst 84 untreated subjects associated with a significant change in mean served as controls. Genotypic frequencies for total sleep time, or the proportions of slow wave the three d3-GHR genotypes (d3/d3; d3/fl; sleep (SWS) and rapid eye movement (REM) fl/fl) were determined for the entire cohort, sleep. It is noteworthy that 12/19 subjects had and data pertinent to growth were recorded evidence of OSA at baseline, before the onset of and analyzed. Data regarding patients who rhGH therapy. This was associated with having remained prepubertal during the study a higher body mass index, waist:hip ratio, (group 1: 68 GH-treated, 72 non-GH-treated), and age. Subjects with OSA at baseline had were compared with data for the entire cohort evidence of less SWS and REM sleep compared (group 2). with the remaining seven subjects without As expected, height velocity and height OSA at baseline. The OSA symptoms were standard deviation for stature (SDS) significantly improved with rhGH therapy. increased in the rhGH-treated children, but Although this was a small study, the results not in the non-rhGH-treated controls. In challenge suggestions that rhGH therapy may both untreated and treated groups, height R7973_3_Growth_1_3_06.qxd 16/11/06 17:30 Page 77

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velocity, change in height SDS, and other Furthermore, homozygous mice exhibited auxological parameters did not differ delays in bone mineralization and defects in between the three d3-GHR genotypes. cartilage formation that persisted into early Furthermore, there was no correlation post-natal life. Hepatic glycogen stores were between genotype and pubertal status during significantly lower in homozygous mice the study. during fetal life compared with non- These results are at odds with an earlier transgenic mice. This lower energetic study in children receiving rhGH reservoir was also found in the homozygous (30 μg/kg/day) for SGA, in which d3-GHR newborn animals, together with lower mean genotype significantly determined rhGH blood glucose levels (1.9 mM in homozygous therapy responsiveness. Patients with d3/d3 mice vs. 3.0 mM in non-transgenic mice). and d3/fl genotypes grew more compared The effects of maternal IGBFP-1 over- with the fl/fl genotype patients (Nat Genet expression were also studied, and heterozygous 2004;36:720–24). The authors of the present pups from homozygous mothers had paper speculated that the use of higher doses significantly smaller birth weights compared of rhGH in their study might explain the with heterozygous pups from non-transgenic different results in the two studies. However, mothers. Taken together, the authors although the authors add to the d3-GHR concluded that the antenatal growth literature, they fail to answer the question as retardation and reduced fetal carbohydrate to whether or not the d3-GHR polymorphism reserves observed in transgenic mice were has an effect on growth rate response to related to over-expressed fetal and maternal GH therapy. circulating IGFBP-1. Thus, excess IGFBP-1 may be an important contributing factor in IGFBP-1 involvement in intra-uterine growth retardation and delayed bone growth retardation: study on IGFBP-1 development in severe cases of human overexpressing transgenic mice. intrauterine growth retardation. Ben Lagha N, Seurin D, Le Bouc Y et al. Hôpital St-Antoine, Paris, France. Neurobehavioral and quality of life Endocrinology 2006;147:4730–7. changes associated with growth hormone insufficiency after complicated mild, Editor’s note: Gene targeting studies have moderate, or severe traumatic brain injury. conclusively shown that both insulin-like Kelly DF, McArthur DL, Levin H et al. growth factor-1 (IGF-1), IGF-2, their UCLA School of Medicine, Los Angeles, CA, USA. receptors, and their binding proteins J Neurotrauma 2006;23:928–42. (IGFBPs) are important determinants of both prenatal and post-natal growth. It is also Editor’s note: During the last 6 years, a recognized that the IGF system has number of studies have reported that important effects on bone growth and the frequency of hypothalamic–pituitary development, although the endocrine role of dysfunction evident several months or years IGFBP-1 in regulating this process has not following moderate to severe traumatic brain been specifically studied to date. injury (TBI) may be as high as 25–40%. The In the present study, the endocrine effects growth hormone (GH) axis appears to be the of IGFBP-1 on fetal bone development and most vulnerable region to injury, with GH on carbohydrate metabolism were studied deficiency estimates of 6–25% observed in using a transgenic mouse model that over- tested TBI patients. Furthermore, many TBI expressed human IGFBP-1. Homozygous survivors experience significant morbidity in mice for IGFBP-1 over-expression had neurocognitive function and quality of life evidence of growth restriction from (QoL) perceptions, and many of these embryonic day (E) 17.5, and had a birth symptoms are very similar to symptoms weight 20% lower than non-transgenic mice. observed in untreated GH deficient adult R7973_3_Growth_1_3_06.qxd 16/11/06 17:30 Page 78

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patients. Thus, there is much speculation C-type natriuretic peptide in growth: that the neurocognitive and QoL morbidity a new paradigm. observed in TBI survivors may be secondary Olney RC. to underlying undiagnosed GH deficiency. Nemours Children’s Clnic, Jacksonville, FL, USA. This prospective study tested the Growth Horm IGF Res 2006;16:S6–14. hypothesis that TBI survivors with GH deficiency or GH insufficiency would Editor’s note: The present review draws exhibit greater neurocognitive and QoL together recent observations in animal models impairment compared with those without that provide the basis for our understanding GH deficiency. Survivors of moderate to of the clinical impact of mutations in the severe TBI (median Glasgow Coma Scale=7, natriuretic peptide receptor-B (NPR-B). n=44) aged 32±18 years were recruited, and In humans, homozygous NPR-B mutations studied 6–9 months following head injury manifest as acromesomelic dysplasia using dynamic anterior pituitary function (Maroteaux type). Although this condition is tests (GH axis assessment by growth very rare, affecting only 1 in 2 000 000 of the hormone-releasing hormone plus arginine general population, the heterozygous carrier stimulation), and neurocognitive and state may be more common and contribute to QoL tests. non-dysmorphic “idiopathic” short stature Eight patients (18%) had evidence of GH (J Clin Endocrinol Metab 2006;91:1229–32). deficiency or GH insufficiency. With the exception of one patient with evidence of Intravenous insulin-like growth hypogonadism, no other anterior pituitary factor-I receptor antisense treatment deficits were detected. Compared with reduces angiotensin receptor expression patients that were GH sufficient, the GH and function in spontaneously deficient and GH insufficient patients hypertensive rats. exhibited significantly higher rates of Nguyen TT, Cao N, Short JL et al. depression (p<0.01) and lower QoL scores in Monash University, Parkville, VIC, Australia. perceptions of: J Pharmacol Exp Ther 2006;318:1171–7.

• Physical health (p=0.02). Editor’s note: Insulin-like growth factor-1 • Energy and fatigue (p=0.02). (IGF-1) is known to have important effects • Pain (p=0.01). on the cardiovascular system. In terms of • Emotional well-being (p=0.02). blood pressure modulation, IGF-1 appears to • General health (p=0.05). have pressor-inducing effects (vascular smooth muscle cell proliferation) and nitric Notably, the GH deficient and GH oxide-dependent vasodilatory effects. Both insufficient patients had similar overall injury of these effects are altered in hypertensive characteristics to the 36 GH sufficient patients, animal models. However, there are although there was a weak, non-significant interactions between IGF-1 and the trend in aggregate computed tomography score renin–angiotensin system (RAS) that are that suggests that the GH deficient and GH associated with vascular resistance and are insufficient groups may have experienced a also thought to be important. greater degree of parenchymal brain damage The authors of the present article recently than the GH-sufficient group. Nevertheless, reported IGF-1 receptor (IGF-1R) “knock- this study supports the hypothesis that GH down” experiments utilizing a specific deficiency itself may be the primary IGF-1R antisense oligonucleotide product, underlying cause of the neurocognitive and that revealed a reduction in pressor responses QoL deficits observed in the chronic post-TBI to angiotensin-II and decreased angiotensin period, or is acting in synergy with the residual receptor (AT-1R) expression in normotensive effects of the brain injury. rats. The study used a hypertensive animal R7973_3_Growth_1_3_06.qxd 16/11/06 17:30 Page 79

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model to investigate the effects of IGF-1R • Spontaneous growth. antisense on AT-1R expression, resting blood • Height gain responses to pressure, and on blood pressure responses to ecombinant human growth norepinephrine and angiotensin-II. hormone (rhGH) treatment. Alternate-day intravenous administration • The frequency of sensorineural of IGF-1R antisense to spontaneously deafness. hypertensive rats (SHR) for 2 weeks resulted in significantly reduced IGF-1R expression Subjects aged 10.0±1.7 years (n=54) within aortic and tail arteries when compared participating in an ongoing, randomized, with controls (untreated and mismatched control trial of rhGH therapy had parent-of- treated animals). IGF-1R antisense treatment origin of the intact X chromosome resulted in reduced AT-1R expression analyses conducted. within the vasculature and in reduced In terms of baseline clinical indices, pressor responses to both angiotensin-II X chromosome parent-of-origin status did not and norepinephrine. This response to appear to have any bearing on birth weight, IGF-1R antisense was significantly greater in birth length, or on the height, age, or bone the SHR group when compared with age at the time of study entry. However, in normotensive rats. IGF-1R antisense patients with Xmat, height standard deviation treatment had no significant effect on resting score before the initiation of rhGH therapy blood pressure. correlated with both mid-parental height Taken together, these IGF-1R knock- (r=0.535; p=0.001) and maternal height down experiments suggested that inhibition (r=0.574; p=<0.001), but not with paternal of the local effect of IGF-1 within blood height. When subjected to analysis using a vessels produced a profound effect on linear regression model, subjects with Xmat vascular responses to vasoconstrictor agents. demonstrated a greater mean height gain than The large IGF-1R antisense effect observed those with Xpat, and 36–53% of the response to in the SHR group compared with the rhGH was attributed to X-linked imprinting. normotensive rat group is probably due to Furthermore, Xmat subjects had a greater mean the greater impact of IGF-1 inhibition on the response to rhGH therapy compared with Xpat RAS and on the sympathetic nervous subjects (p=0.017; 95% confidence interval systems, which was observed in the 0.66–6.09). In terms of sensorineural hearing SHR group. impairment, Xmat subjects were less likely to have hearing loss compared with Xpat subjects Genomic imprinting in Turner syndrome: (p=0.040). effects on response to growth hormone Overall, this study provides further and on risk of sensorineural hearing loss. evidence of significant X chromosome Hamelin CE, Anglin G, Quigley CA et al. imprinting effects on subjects with TS. McGill University, Montreal, QC, Canada. J Clin Endocrinol Metab 2006;91:3002–10. A variable degree of intrauterine and postnatal growth retardation in a family Editor’s note: In Turner Syndrome (TS) there with a missense mutation in the insulin- is evidence to suggest that an X chromosome like growth factor I receptor. parent-of-origin effect exists. For example, Walenkamp MJ, van der Kamp HJ, Pereira AM et al. phenotypic and neurocognitive profiles Leiden University Medical Center, RC Leiden, appear to differ between those with an intact The Netherlands. maternal X chromosome (Xmat) and those with J Clin Endocrinol Metab 2006;91:3062–70. an intact paternal X chromososome (Xpat). In the present study, the authors Editor’s note: The importance of insulin-like investigated the parent-of-origin effect of the growth factor-1 (IGF-1) in the regulation of intact X chromosome on: intrauterine development and in post-natal R7973_3_Growth_1_3_06.qxd 16/11/06 17:30 Page 80

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growth and metabolism is well established. • Mental performance (reduced Nevertheless, animal knock-out and other in mother, normal in child). experimental models and gene mutation • Dysmorphic features (absent discoveries in humans continue to provide in mother, present in child). insights into the key roles played by the • Birth length (–0.3 SDS in mother, various individual components of the IGF-1 –4.2 SDS in child). system. Human IGF-1 deficiency due to homozygous gene deletion or mutation is The authors speculated that this characterized by severe intrauterine growth heterogeneity in phenotype might reflect the retardation (IUGR), post-natal failure, mental degree of remaining IGF-1 signaling within retardation, and deafness. However, the tissues. Furthermore, they hypothesized that clinical features and phenotype of humans the presence or absence of maternal IGF-1 presenting with mutations of type 1 IGF-1 resistance may partially determine birth receptor gene (IGF1R) are less well defined. weight, and might explain the variance in The present authors described a mother IUGR evident in those offspring that are also and daughter from the same family (aged heterozygotes for the IGF1R mutation. 35 years and approximately 16 months, respectively) with a novel heterozygous GH secretory pattern in young adults mutation of the IGF1R gene (G3148>A who discontinued GH treatment for GH substitution). This missense mutation is deficiency and decreased longitudinal associated with IUGR and post-natal growth growth in childhood. retardation, and is located in the Svensson J, Johannsson G, Iranmanesh A et al. intracellular tyrosine kinase domain of the Sahlgrenska University Hospital, IGF1R gene. The mutation results in a Goteborg, Sweden. partial resistance to IGF-1, which has been Eur J Endocrinol 2006;155:91–9. confirmed by in vitro studies that demonstrated normal IGF-1 binding to the Editor’s note: It is well established that some receptor, but reduced activation of the patients diagnosed with growth hormone downstream signaling cascades. (GH) deficiency during childhood no longer The phenotypes of the mother and appear to be GH deficient when retested at daughter were similar to the few (n=8) completion of linear growth in mid to late previously reported cases of mutations of adolescence. The vast majority of the patients IGF1R, with respect to: falling into this category appear to have been diagnosed with so-called idiopathic GH • Degree of IUGR (maternal birth- deficiency, with no obvious structural weight standard deviation score [SDS] abnormalities or pathology of the = –2.1, child SDS = –3.3). hypothalamic–pituitary structures to account • Reduced post-natal growth (maternal for their GH deficient status. It is suspected, height SDS = –4.0, child height SDS but not yet confirmed, that these patients = –2.3). may have a neuroendocrine defect in the • Head circumference (maternal SDS spontaneous pattern of GH release. = –3.0, child SDS = –5.6 SDS). The present authors conducted a study in which 24-h GH profiles were performed in a By comparison with the previous group of 37 adolescent (mean age 19 years) reports, which described mutations affecting diagnosed with poor growth velocity secondary the extracellular domain of IGF1R, the to GH deficiency during childhood. Subjects authors highlight the high degree of were grouped according to whether retesting variability that appears to be evident within in late adolescence revealed persisting GH and between the IGF1R mutation deficiency (GH deficiency n=19, of whom 10 categories in: had an organic cause of GH deficiency) or GH R7973_3_Growth_1_3_06.qxd 16/11/06 17:30 Page 81

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sufficiency (n=18, of whom 17 had previously period of 32 months (range 4–108 months). been diagnosed with “idiopathic” GH Actuarial progression-free survival was 99% deficiency). GH profiles were assessed 1 year at 1 year, 98% at 3 years, and 98% at 5 years. following discontinuation of recombinant Treatment was deemed to be well tolerated. human GH (rhGH) therapy, and were The most frequent long-term effect was compared with the GH profiles of 16 age- hypopituarism, which was seen in 76% matched healthy controls. of participants. Assessment of GH secretion patterns The authors state that the results with (using deconvolution analysis) in the GH SCRT are equivalent to those seen using deficiency group revealed significantly lower conventional radiotherapy. Longer follow-up basal, pulsatile, and total GH secretion rates, is required to see if this high-precision, with increased frequency of GH pulses, but localized irradiation technique has benefits lower mean pulse area when compared with over conventional radiotherapy on morbidity. healthy controls. In contrast, adolescents in the Effects on long-term cognitive function also GH sufficiency group had a pattern of 24-h GH require testing. secretion that was similar to controls. Whilst this study distinguishes patterns Insulinlike growth factor I affects of GH secretion in adolescents and young ocular development: a study of adults following discontinuation of rhGH untreated and treated patients therapy initiated for apparent GH deficiency with Laron syndrome. in childhood, it cannot explain why those Bourla DH, Laron Z, Snir M et al. subsequently found to be GH sufficient University of California, Los Angeles, CA, USA (almost exclusively those with a previous Ophthalmology 2006;113:1197–1200. diagnosis of idiopathic GH deficiency) had evidence of inappropriate GH secretion and Editor’s note: In brief, Laron syndrome (LS) poor growth velocity in childhood. is a dwarfism that is associated with low serum levels of insulin-like growth factor 1 Fractionated stereotactic conformal (IGF-1), despite subjects having elevated radiotherapy for secreting and growth hormone (GH) levels. nonsecreting pituitary adenomas. It has been reported by previous studies Minniti G, Traish D, Ashley S et al. that there is a relationship between decreased Institute of Cancer Research and Royal Marsden ocular pathological features in children with NHS Foundation Trust, Sutton, UK. GH deficiency and LS. Clin Endocrinol 2006;64:542–8. In this study, the authors investigated the relationship between ocular dimensions and Editor’s note: As an update to previously LS, and the effect of IGF-1 on ocular growth reported early experience of fractionated in LS patients. In order to evaluate this, stereotactic conformal radiotherapy (SCRT) the authors recruited 12 patients with LS, in patients with pituitary adenomas, the 8 of whom were untreated (LS group; average authors detail medium-term outcomes in a age 46 years) and 4 who were treated with cohort with secreting and non-secreting IGF-1(LS-T group; average age 15.2 years), adenomas. The cohort comprised 92 patients and 30 control patients (average age given treatment from 1995 to 2003. Treatment 45.2 years). All patients were subjected to a was via four non-coplanar conformal fixed full ophthalmic examination, which fields. A 6 MV linear accelerator was used to included, for example, best-corrected Snellen deliver a dose of 45 Gy in 25 fractions. visual acuity, automated corneal keratometry Two years after treatment, a mean and refractometry, and ultrasound biometry. reduction in growth hormone of 45% from Their results showed that the average the baseline level was recorded. Overall axial length (AXL) of eyes of the LS group survival was 98% after a median follow-up was significantly lower (p<0.01) compared R7973_3_Growth_1_3_06.qxd 16/11/06 17:30 Page 82

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with AXL for the control group. The LS-T and the myofiber cross-sectional areas of group also had a higher average AXL mutant mice were 36–40% smaller than those compared with LS patients; however, this was of wild-type (WT) mice. However, the not statistically significant. The average number of myofibers present in muscle was chamber depth (ACD) was found to be 2.55, the same for the two groups. This indicated 3.48, and 3.84 mm in the LS, LS-T, and control that GHR deletion does not affect myofiber groups, respectively, showing a significant formation during embryogenesis, but does statistical difference only between the LS inhibit postnatal myofiber growth. and LS-T groups (p<0.001). Average lens Furthermore, the differentiation of muscle thickness for each group was 4.56 mm in the into oxidative type 1 myofibers and glycolytic LS patients, 3.77 mm in the LS-T patients, type 2 myofibers was affected. In GHR–/– and 3.51 mm for the control patients, showing mice, a 26% decrease in type 1 fiber number a significant statistical difference between the and a 16% increase in type 2 fiber number LS and LS-T groups and also between the LS was observed in soleus muscle. An increase in and control groups (p<0.001). Furthermore, hybrid fibers was also found. The authors there was a statistically significant difference concluded that GH has a positive affect on of average corneal curvature between the LS type 1 fiber specification. and LS-T groups versus the control groups Further investigation, using WT and (p<0.001). GHR–/– murine cell cultures, showed that Overall, the results indicate that LS myotubule size was controlled in a patients treated with IGF-1 had better ocular cell-autonomous manner by GH, and GHR–/– growth compared with LS patients who cells formed myotubules that were 25% weren’t treated with IGF-1, although this was smaller than those in WT cells. Conversely, not mirrored when IGF-1-treated LS patients GH stimulation of WT cells increased were compared with healthy controls. myotube size by 20%. These size differences In conclusion, the authors found that were comparable at 48, 72, and 96 h after IGF-1 was important in regulating ocular transferring cells to mitogen-poor growth in LS patients, although the differentiation medium (DM), indicating that mechanisms involved in this have not yet GH controls myotubule size during early been fully elucidated. The latter should be differentiation. However, GH had no effect on more fully investigated in further studies. myoblast precursor cell size, proliferation, or differentiation. Nascent myotubes are formed Growth hormone promotes skeletal by myoblast–myoblast fusion, and rapid muscle cell fusion independent of growth occurs when myoblasts subsequently insulin-like growth factor 1 up-regulation. fuse with myotubes. After 48 h in DM there Sotiropoulos A, Ohanna M, Kedzia X et al. was no difference in the number of fused cells Institut National de la Santé et de la Recherche (as a proportion of total cell number) in WT Médicale, Paris, France. and GHR–/– cultures, indicating that myotube Proc Natl Acad Sci USA 2006;103:7315–20. formation was not controlled by GHR signaling. However, GHR–/– myotubes had Editor’s note: Although postnatal growth fewer nuclei compared with WT myotubes. of skeletal muscle is coordinated by growth Therefore, the authors suggested that GH may hormone (GH), the underlying mechanism of increase muscle cell size by recruiting new this process has not been fully described. nuclei to existing myotubules. The present study used a growth hormone Insulin-like growth factor 1 (IGF-1) gene receptor (GHR)-minus (GHR–/–) mouse expression did not correlate with GHR model to investigate the way in which skeletal activation or with GH mediation of myotube muscle responds to GH. A disproportionate size. This finding, when looked at in the reduction in muscle mass was observed in context of previous studies, indicates that GHR–/– mice compared with control mice, local IGF-1 upregulation does not mediate R7973_3_Growth_1_3_06.qxd 16/11/06 17:30 Page 83

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the GH-controlled skeletal muscle fusion no data suggesting that IGF-1 was more and size. strongly associated with one particular Further investigation into the influence growth component (p=0.34 for adjusted of GH on myotube size may have analysis). On the other hand, girls were found implications for stem cell transfer therapies to have a strong positive association between and future treatment of muscle disorders, IGF-1 and growth in trunk length, but the including Duchenne muscular dystrophy. results did not show any association between However, the present article reinforces the IGF-1 and growth in length. No relationship message that the control of cell growth is not was found between IGF binding protein-3 simply a matter of switching a single gene on and height growth between girls and boys and off. (p interaction= 0.21). This study found relationships between Insulin-Like Growth Factor-I and Growth final height and childhood IGF-1 levels, thus in Height, Leg Length, and Trunk Length suggesting that final adult height may be a between Ages 5 and 10 Years. marker for childhood IGF-1. Now, the Rogers I, Metcalfe C, Gunnell D et al.; question arises of whether levels of IGF-1 can Avon Longitudinal Study of Parents be used as the final height outcome and and Children Study Team. initiation of GH or IGF-1 supplement therapy. J Clin Endocrinol Metab 2006;91:2514–9. Stature in children with chronic kidney Editor’s note: Insulin-like growth factor 1 disease: analysis of NAPRTCS database. (IGF-1) being the growth hormone (GH) Seikaly MG, Salhab N, Gipson D et al. mediator, is supposed to be responsible for University of Texas Southwestern Medical the final adult height. As height consists of Center, Dallas, TX, USA. both trunk and leg length, and in the Pediatr Nephrol 2006;21:793–9. prepubertal period a greater proportion of growth in total height results from growth in Editor’s note: Children with chronic kidney leg rather than trunk length, this study was disease experience poor growth of multifactorial conducted with the hypothesis that adult leg etiology. Nutritional, metabolic, and hormonal length may be a marker for IGF-1 levels factors are implicated and the use of during childhood. Serum IGF-1 levels were recombinant human growth hormone has measured in healthy prepubertal children, been shown to improve growth. and subsequently related to growth in height, Seikaly et al. analyzed the NAPRTCS leg length, and trunk length. (North American Pediatric Renal Transplant The study was carried out in >14 000 Cooperative Studies) database, which included pregnancies over a 20 month period. >5000 children, in order to determine the Anthropometric data and blood were relationship between height and a variety of collected for analysis at ages 5, 7–8, and 9–10 parameters. Factors associated with being short years of age. The study comprised 1260 at entry to the database included younger age, children. It was observed that at age 5, IGF-1 lower glomerular filtration rate, and anemia, levels correlated positively with total height, while black patients and those with focal and leg and trunk length in both boys and segmental glomerulosclerosis were at a lower girls. The relationship was not much better in risk. Data of this type are of limited practical leg length compared with trunk length in value and it is clear that growth failure either boys (p=0.3) or girls (p=0.8). Total continues to be a significant problem despite growth in height and trunk length was advances in medical treatment. Traditional positively associated with IGF-1 in both sexes risk factors, including acidosis, calcium, at 8 years of age. Boys, in particular, had a phosphate, albumin, and parathyroid hormone strong association between IGF-1 and growth levels, were poor independent predictors of in leg and trunk length; however, there were short stature. R7973_3_Growth_1_3_06.qxd 16/11/06 17:30 Page 84

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Pituitary stalk compression by the cases of functional GH deficiency. Future dorsum sellae: possible cause for late follow-up studies are indicated to determine childhood onset growth disorders. whether or not the pituitary stalk–dorsum Taoka T, Iwasaki S, Okamoto S et al. sellae relationship changes over time, Nara Medical University, Nara, Japan. possibly with evolution of multiple pituitary Magn Reson Imaging 2006;24:651–6. hormone deficiencies.

Editor’s note: The anatomical and Adult heights in patients with physiological bases for childhood-onset growth permanent growth hormone deficiency hormone (GH) deficiency remain unclear. with and without multiple pituitary Perinatal traumatic events (such as breech hormone deficiencies. delivery) and genetic disorders associated Maghnie M, Ambrosini L, Cappa M et al. with hypothalamo–pituitary embryological University of Genoa, Genoa, Italy. transcription factors are established causes of a J Clin Endocrinol Metab 2006;91:2900–5. variety of pituitary hormone deficiency syndromes. However, there remains a large Editor’s note: The present retrospective study unexplained cohort of GH deficiency and other evaluated factors contributing to differences in pituitary hormone deficiencies. final height in patients with isolated growth This study of 34 GH deficient, short- hormone deficiency (IGHD) compared with stature children and 24 age-matched normal final height in those with multiple pituitary stature children examined the magnetic hormone deficiencies (MPHD). resonance imaging appearances of the Five treatment centers contributed to the pituitary and pituitary stalk. The pituitary study and recruited patients with IGHD stalk appeared to be compressed against the (n=39) and with MPHD (n=49) who had dorsum sellae and distorted in nine of the been diagnosed at mean ages of 7.7 years and GH deficient children, indicating that 6.9 years, respectively. Re-evaluation of GH this anatomical relationship might be status was performed at a median age of causally related to functional GH deficiency. 17.6 years (IGHD) and 19.8 years (MPHD) Conversely, GH deficiency might be to confirm that GH deficiency was present. responsible for the pituitary stalk–dorsum GH deficiency was confirmed if GH peak sellae deformity. The posterior pituitary lobe levels were <3 μg/L after an insulin tolerance had normal signal intensity and localization in test or failed to rise >10 μg/L following all patients. Interestingly, pituitary stalk provocative tests. Fifteen subjects were compression was significantly correlated with designated as having idiopathic IGHD on onset of GH deficiency in children ≥7 years the basis of a normal magnetic resonance old, and was rarely found in children <6 years. image (MRI) of the pituitary, with 73 patients The authors suggest that this may be due to showing congenital hypothalamopituitary the slow growth rate of the dorsum sellae, abnormalities. Five treatment centers which only becomes large enough to compress contributed to this study. the pituitary stalk during late childhood. Median height at onset or induction of Although there is no apparent puberty was similar for the IGHD and MPHD explanation (from medical history) for the patients, although puberty onset for both sequence of developmental events that led to sexes was 1 year later in the MPHD group this anatomical and, presumed, functional than in the IGHD group. Pubertal height gain abnormality, it is reasonable to accept that was similar for the two groups, with median compression and distortion of the pituitary final heights of 168 and 170 cm for IGHD and stalk is an associated cause in late-onset MPHD males, respectively, and 160 and R7973_3_Growth_1_3_06.qxd 16/11/06 17:30 Page 85

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157 cm for IGHD and MPHD females, therapy, and only 23% were treated with respectively. The median GH treatment dose BMT alone. The mean age at BMT was was approximately 0.2 mg/kg/week for 7.3 years (range 0.6–21.5 years) and the mean both groups, although a variety of dosage duration of follow-up after BMT was 6.2 years schedules (3–7 doses per week) were used (range 1–22.5 years). during the overlapping treatment periods for Endocrine side-effects were observed in a these patients. A few patients had received significant number of patients and were pituitary-derived human GH prior to the associated with cranial irradiation and total availability of recombinant GH. body irradiation. Of the BMT patients, The authors suggested that the greater final 10 developed growth hormone deficiency, height of patients with MPHD was due to the 12 developed primary hypothyroidism, and late onset of puberty in this group of patients, one developed papillary thyroid carcinoma. compared with patients with IGHD. They Furthermore, 24 patients (54% of girls aged therefore argued that introducing sex steroid ≥13 years and 29% of boys aged ≥14 years) replacements might be beneficial in patients developed primary gonadal failure by the with MPHD, and not seriously detrimental to time of final evaluation. Gonadal failure was final height attainment. A marginal height more frequent in: gain through delayed induction of puberty may indeed be less important to the long-term well- • Patients who had BMT to treat being of the hypogonadal patient. However, hematological disease. the absence of relevant psychological studies • Patients treated with radiotherapy. of adolescents with MPHD limits the • Patients of advanced pubertal complete understanding of the optimal age at BMT. management pathways. Further concerns for the long-term health Endocrine dysfunction and parameters of childhood cancer survivors included of the metabolic syndrome after bone evidence at follow-up of type 2 diabetes and marrow transplantation during childhood other adult metabolic syndrome parameters. and adolescence. Obesity was present in 4.4%, type 2 diabetes in Shalitin S, Phillip M, Stein J et al. 3.3%, impaired glucose tolerance in 3.3%, and Schneider Children’s Medical Center of Israel, dyslipidemia in 28% of the 43 patients tested. Petach Tikva, Israel. The authors acknowledge important Bone Marrow Transplant 2006;37:1109–17. limitations in their study, including the small size of the cohort, and the small number of Editor’s note: The present authors produced patients who had reached final adult height a comprehensive account of multiple and had entered puberty by the end of the endocrine disorders that arose during long- study. Careful long-term follow-up in an term follow-up of 91 patients after bone appropriate clinical setting is clearly marrow transplantations (BMTs). The mean essential for the growing number of age at diagnosis was 5.6 years (0.1–18.5) and childhood cancer survivors. patients were aged 4–32 years at follow-up. Indications for transplant were: GH replacement does not increase the risk of recurrence in patients • Hematological malignancies (44.2%). with craniopharyngioma. • Solid malignant tumors (28.8%). Karavitaki N, Warner JT, Marland A et al. • Other systemic disorders (26.9%). Churchill Hospital, Oxford, UK. Clinical Endocrinology 2006;64:556–60. Following primary surgical or other therapy, 66% received chemotherapy alone, Editor’s note: Craniopharyngioma is one of 11% received chemotherapy and radio- most common primary intracranial tumors R7973_3_Growth_1_3_06.qxd 16/11/06 17:30 Page 86

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in children. Alhough histologically a benign In fact this is lower than the general pediatric tumor, the craniopharyngioma is known population with craniopharyngioma. The for its recurrence potential even after data available so far are from retrospective apparent successful therapy. The recurrence studies; it is unlikely to have prospective long- is associated with significant morbidity and term studies, as monitoring for recurrence is mortality rates. easily carried out using the imaging studies Endocrine abnormalities, especially while patients are treated with GH therapy growth hormone (GH) deficiency, is commonly for ultimate growth in children, and quality associated with craniopharyngioma. The of life and cardiovascular morbidity and hormone deficiency is attributed to multiple mortality benefits in adults. factors including tumor mass effect, recurrence and/or consequence of therapy of the tumor Effects of growth hormone substitution itself. GH replacement has been beneficial in therapy on cognitive functioning in these patients, and GH therapy has been growth hormone deficient patients: implicated in possible recurrence and tumor a functional MRI study. growth through its direct action or indirect Arwert LI, Veltman DJ, Deijen JB et al. action via insulin-like growth factor-1 (IGF-1). VU University Medical Center, Amsterdam, In this retrospective study, the authors The Netherlands. assessed the effects of GH replacement on Neuroendocrinology 2006;83:12–9. tumor recurrence. The study included all patients with craniopharyngioma who Editor’s note: The identification of growth reported at their institution for over 40 years. hormone (GH) receptors in the brain, and The treatment included surgical resection subsequent demonstration of improved (gross total removal [GTR], partial removal cognitive function in adult GH-deficient [PR]), and surgery with radiotherapy patients receiving GH replacement has (S+RT). The GH deficiency was diagnosed focused research towards establishing with auxiological data in children and GH causally related mechanisms. stimulation tests in children and adults. The This small, but significant, double-blind recurrence of tumor was diagnosed by study examined 13 childhood-onset GH- residual tumor in GTR, and tumor growth in deficient patients who were recruited at a PR. Computed tomography scans and mean age of 27±7 years following a 3-month magnetic resonance imaging were used after washout period without GH treatment. 1980 and 1990, respectively, to visualize the Following washout, five patients received tumor recurrence. active GH treatment and seven patients Of a total of 94 subjects, 41 received GH received a placebo. One patient dropped out replacement therapy, nine patients did not of the study due to protocol violation. All have follow-up imaging studies. patients were confirmed GH deficient prior to Tumor recurrence was observed in the study by repeat testing and had low serum 4 patients who were treated with GH and had insulin-like growth factor-1 (IGF-1) levels. a mean follow up of 0.7–6.8 years of therapy, Serum IGF-1 levels were monitored during and 22 non-GH treated subjects had tumor GH treatment to verify the adequacy of GH recurrence with 0.9–11 years of follow up. replacement. Cognitive assessments were The analysis showed that GH therapy taken at baseline and after 6 months of GH was not a significant independent predictor treatment or placebo, together with functional of tumor recurrence. This study of magnetic resonance imaging (fMRI). approximately 20 years of therapy and long- There was a highly significant term data from Genentech’s National improvement in both long-term and working Cooperative Growth Study (approximately memory function in the GH-treated group 15 years), which showed a recurrence rate of compared with the placebo group (p=0.004). 6.4% in children who were treated with GH. This improvement was associated with R7973_3_Growth_1_3_06.qxd 16/11/06 17:30 Page 87

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fMRI activations during working memory • Hip–waist ratios. tasks of prefrontal, parietal, motor, and • Body fat levels. occipital cortices, as well as in the right • Fasting insulin concentrations. thalamus and anterior cingulated cortex. A • C-peptide concentrations. further interesting observation was the • E-selectin concentrations (2.5-fold). decreased activation in the ventrolateral • Triglyceride concentrations. prefrontal cortex in GH-treated patients compared with control patients. The authors However, after 1 year of GH treatment suggested that this difference indicated there were no changes in biochemical decreased effort and more efficient parameters, fibrinolytic markers, soluble recruitment of the neural systems. adhesion molecules, inflammatory cytokines The preliminary data from this study are or endothelial function. Clearly more interesting and merit more extensive studies extensive studies are required to define the on patients with a spectrum of childhood and GH dependent factors or other life-style adult-onset causes of GH deficiency, using issues that place the GH deficient adult at cross-over groups and sequential studies of increased mortality risk, within or without treatment and withdrawal of GH. the context of GH deficiency itself.

Peripheral fibrinolytic markers, soluble Pathophysiology of radiation-induced adhesion molecules, inflammatory growth hormone deficiency: efficacy cytokines and endothelial function and safety of GH replacement. in hypopituitary adults with growth Darzy H, Shalet SM. hormone deficiency. Christie Hospital NHS Trust, Manchester, Gomez JM, Sahun M, Vila R et al. United Kingdom. Hospital de la Santa Creu i Sant Pau, Growth Hormone & IGF Research Barcelona, Spain. 2006;16:S30–40. Clin Endocrinol (Oxf) 2006;64:632–9. Editor’s note: This is an excellent review of Editor’s note: Growth hormone (GH) the pathophysiology of radiation induced replacement in GH-deficient adults has been growth hormone (GH) deficiency, GH associated with reduced mortality risk. The therapy, and safety. The review is factors responsible for this have not yet been summarized below. adequately identified, and are not necessarily Radiotherapy has been used for related to simple cardiovascular risk factors various childhood malignancies, including and related mortality events. hematological cancers, and brain and skull In this study, 10 patients with GH based tumors. Treatment may involve deficiency (50% male) were studied at baseline brain and/or spinal radiation, and whole and at 1 year following initiation of GH body irradiation, which can damage the replacement therapy. With a mean age of hypothalamus and result in hypothalamic– 46±10 years, these patients were compared pituitary dysfunctions. Within the with nine male and 16 female controls, hypothalamic–pituitary axis (HPA), the matched for body mass index and age. All were somatotropic axis is the most radiosensitive. lifelong non-smokers, normotensive, and Studies in rats have shown that a radiation non-diabetic. A number of variables were dose as little as 3 Gy can damage the recorded, including fibrinolytic markers, somatotrophs and inhibit the production of soluble adhesion molecules, inflammatory GH, whereas it took 10 Gy to inhibit thyroid- cytokines, and endothelial functions. stimulating hormone (TSH)-producing cells. Compared with controls, baseline It follows that GH deficiency is the observations showed that GH deficient commonest neuroendocrine injury following patients had higher: cranial irradiation for non-pituitary brain R7973_3_Growth_1_3_06.qxd 16/11/06 17:30 Page 88

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tumors, with almost all children treated with recurrent malignancy is in fact lower than the >30 Gy showing defective GH responses to normal population. the insulin tolerance test. These radiation- GH therapy is safe in patients with induced hormone deficiencies are time- radiation-induced GH deficiency in both the dependant – both the incidence and severity final height outcome in children and quality of disorders increase with time after of life in adults, and it is efficacious compared radiation. They have also been shown to be with patients who are not treated, as the risks related to the dose and site of radiation. of recurrence or new tumor formation are no Growth deficiencies in cancer patients are more than in the normal population. often attributed to radiation-induced GH deficiency. However, there are many other Healthcare utilization, quality of life and factors associated with cancer and its treatment patient-reported outcomes during two that can influence growth. Growth impairment years of GH replacement therapy in GH- in children treated for brain tumors during deficient adults – comparison between the first year seems unrelated to GH Sweden, The Netherlands and Germany. deficiency, unlike growth impairment seen Saller B, Mattsson AF, Kann PH et al. in hematological malignancy patients. Spinal Pfizer GmbH, Karlsruhe, Germany. irradiation seems to be responsible for growth Eur J Endocrinology 2006;154:843–50. deficiencies in the first few years after radiation therapy, but GH deficiency does Editor’s note: The present study used become important in later years. information derived from the Kabi Response to short-term GH therapy in International Metabolic Study (KIMS) radiation-induced short stature has been database to determine changes in healthcare encouraging. However, in the long term it has utilization and quality of life (QoL) in not been able to produce the catch-up growth adults receiving growth hormone (GH) seen in those with idiopathic short stature. It replacement therapy. has, however, been shown to maintain height QoL assessments were conducted with percentile into adulthood, whereas patients 302 Swedish, 103 Dutch, and 98 German not treated with GH therapy continue to patients at baseline, and after 1 and 2 years of decrease in height percentile. In recent GH replacement. Analysis was made of the studies, height loss has been much lower, as QoL-Assessment in GH-Deficient Adults the dose of GH has been adjusted to age and (QoL-AGHDA) questionnaire and the KIMS weight, as well as the use of gonadotropin- patient Life Situation Form to evaluate releasing hormone (GnRH) analogues to delay healthcare utilization. The cohorts from the the epiphyseal closure and give an extra three countries were demographically window for prolonged GH therapy. similar, with a mean age at enrolment of The children who had pharmacological approximately 50±13 years and a mean body evidence of GH deficiency have the worst mass index of 27. Approximately 50% of the final height of up to 1.7±0.2 standard patients were male. deviation scores compared with 0.9±0.2 in The cause of GH deficiency in most children with normal peak GH response. patients was pituitary adenoma (60–65%), This suggests that final height can be and other causes included craniopharyngioma achieved by instituting GH therapy at an (7–15%). Isolated GH deficiency (IGHD) was earlier stage in these subjects. present in 4–15%, and approximately 90% of There are some safety concerns associated patients from each country had adult-onset with GH therapy due to the risks of new or GH deficiency. Approximately 70% of recurrent tumors and malignancies. Various patients had undergone pituitary surgery, and data, especially from the National time between surgery and study onset varied Cooperative Growth Study of Genentech, so from 0–20 years. The parameter showing the far has suggested that the risk of a second or greatest variation between the three countries R7973_3_Growth_1_3_06.qxd 16/11/06 17:30 Page 89

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was the use of cranial radiotherapy, with 55% evidence to suggest it is important for the of Dutch patients, 37% of Swedish normal functioning of the central nervous patients, and just 7% of German patients system (CNS). At present, most conclusions experiencing radiotherapy. about the existing relationship between GH Patients from the three countries showed deficiency and cognitive function have been very similar responses to the QoL assessments based on cross-sectional comparisons between before and following GH treatment. GH deficient patients and healthy controls. Improvement in QoL was apparent after 1 year, The reliability of such studies is questionable and was sustained at 2 years by approximately in regards to several methodological issues 3 points on the QoL-AGHDA scoring system. (i.e. performance of GH patients is matched The improvement in QoL was associated with to healthy controls). Such issues may a restoration to normal or above average serum reflect secondary consequences of GH insulin-like growth factor 1 levels in both sexes, deficiency rather then primary CNS-related and a reduction in recorded number of days of consequences. The present study sought to sick leave (significant at 63%) compared with improve the understanding of the nature pre-treatment status. and magnitude of cognitive impairment in These data highlight the importance of GH-deficient patients. This was achieved by evaluating the benefit of GH treatment in the performing a meta-analysis of the existing context of daily living experiences. literature, comparing the performance of Furthermore, alternative ways of assessing the patients with GH deficiency and GH treated contribution to society of the GH-treated patients with controls, baseline and treatment adult, through active gainful employment and comparisons, and the measurement of size of reduced demand on the healthcare services, treatment effect. might support the argument for extended GH The authors identified 13 studies that replacement through adult life. met the inclusion criteria, with a total of 64 neuropsychological tests measures used. The effects of growth hormone (GH) GH deficiency showed a moderate-to- deficiency and GH replacement on large impairment of cognition, with a slightly cognitive performance in adults: larger effect on language compared with a meta-analysis of the current literature. other domains. In addition, GH treated Falleti MG, Maruff P, Burman P et al. patients showed impairments in cognitive CogState Ltd, Melbourne, Australia. function (particularly memory function) Psychoneuroendocrinology 2006;31(6):681-91. when compared with controls. Overall, following analysis, the authors Editor’s note: Although the many beneficial conclude that patients with GH deficiency effects of growth hormone (GH) replacement can achieve improvements in cognitive therapy are well known, there is growing function with GH replacement therapy.

Surgery

Gamma knife radiosurgery for treatments of patients with acromegaly. acromegaly – long-term experience. The success of neurosurgery depends on the Jezková J, Marek J, Hána V et al. size of pituitary adenoma and experience Charles University, Prague, Czech Republic. of surgeon. The successful surgery varies Clinical Endocrinology 2006;64:588–95. between 80–90% of microadenoma and up to 50% of macroadenoma removal. The Editors note: Neurosurgery and pharmaco- remainder of patients with residual and therapy are well-established first-line functional tumor may require long-term R7973_3_Growth_1_3_06.qxd 16/11/06 17:30 Page 90

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pharmacotherapy, radiotherapy, or a these patients had conventional irradiation combination of both, and rarely re-surgery. prior to LKG. Twenty-four patients were Primary pharmacotherapy has its own treated primarily with LKG irradiation. The limitation, such as need of life long patients were followed at different times treatment, cost, and variable success on using hormonal analysis, and magnetic hormone secretion and tumor size. resonance imaging scans. Conventional radiotherapy has slow The results of the current study provide a onset, the hormonal normalization is not very positive outlook on the long-term achieved ≥10 years after radiotherapy. There effectiveness of LGK therapy for acromagaly are increased side effects of conventional without any adverse effects, including irradiation locally. absence of peri-pituitary gland. LGK therapy The use of gamma knife radiosurgery for should be considered as a therapeutic tool acromagaly is very recent, and long-term data after neurosurgery in patients with residual are scarce. In this study, the authors studied tumor, as long-term cost may be less with 96 patients with Leksell gamma knife (LGK) LGK compared with pharmacological treatment and followed up to 120 months. treatment. LGK therapy should be The patients included 46 women, aged 16–76 considered as a primary therapy in patients years. Of the 96 patients, 71 had undergone who are not surgical candidates or who do not surgery before LGK treatment, and 11 of want long-term medical therapy.