Background/Aim: Since hyperandrogenism in simple obesity is assumed to arise from hyperinsulinism and/or increased insulin-like growth factor I (IGF-I) or leptin levels, we examined how in patients with Prader-Willi syndrome (PWS), the most frequent form of syndromal obesity, the accelerated adrenarche can be explained despite hypothalamic-pituitary insufficiency with low levels of insulin and IGF-I. Methods: In 23 children with PWS and a mean age of 5.6 years, height, weight, fat mass, fasting insulin concentration, insulin resistance (by HOMA-R; see text), and leptin and IGF-I levels were determined to test whether they explain the variance of the levels of dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), of androstenedione, and of cortisol before and during 42 months of therapy with growth hormone. Results: The baseline DHEAS, DHEA, and androstenedione concentrations were increased as compared with age-related reference values, whereas the cortisol level was always normal. During growth hormone treatment, the DHEA concentration further rose, and the cortisol level decreased significantly. The insulin and IGF-I concentrations were low before therapy, while fat mass and leptin level were elevated. The hormonal covariates provided alone or together between 24 and 60% of the explanation for the variance of adrenal androgen levels, but the anthropometric variables did not correlate with them. Conclusions: In children with PWS, elevated androgen levels correlate with hormones that are usually associated with adiposity. However, the lack of direct correlations between disturbed body composition and androgen levels as well as the increased sensitivity to insulin and IGF-I are abnormalities specific to PWS, potentially caused by the underlying hypothalamic defect.

1.
De Simone M, Farello G, Palumbo M, Gentile T, Ciuffreda M, Olioso P, Cinque M, De Matteis F: Growth charts, growth velocity and bone development in childhood obesity. Int J Obes Relat Metab Disord 1995;19:851–857.
2.
Kaplowitz PB, Slora EJ, Wasserman RC, Pedlow SE, Herman-Giddens ME: Earlier onset of puberty in girls: Relation to increased body mass index and race. Pediatrics 2001;108:347–353.
3.
Genazzani AR, Pintor C, Corda R: Plasma levels of gonadotropins, prolactin, thyroxine, and adrenal and gonadal steroids in obese prepubertal girls. J Clin Endocrinol Metab 1978;47:974–979.
4.
Pintor C, Loche S, Faedda A, Fanni V, Nurchi AM, Corda R: Adrenal androgens in obese boys before and after weight loss. Horm Metab Res 1984;16:544–548.
5.
Katz SH, Hediger ML, Zemel BS, Parks JS: Adrenal androgens, body fat and advanced skeletal age in puberty: New evidence for the relations of adrenarche and gonadarche in males. Hum Biol 1985;57:401–413.
6.
Oppenheimer E, Linder B, DiMartino-Nardi J: Decreased insulin sensitivity in prepubertal girls with premature adrenarche and acanthosis nigricans. J Clin Endocrinol Metab 1995;80:614–618.
7.
Ibanez L, Potau N, Zampolli M, Rique S, Saenger P, Carrascosa A: Hyperinsulinemia and decreased insulin-like growth factor-binding protein-1 are common features in prepubertal and pubertal girls with a history of premature pubarche. J Clin Endocrinol Metab 1997;82:2283–2288.
8.
l’Allemand D, Schmidt S, Rousson V, Brabant G, Gasser T, Gruters A: Associations between body mass, leptin, IGF-I and circulating adrenal androgens in children with obesity and premature adrenarche. Eur J Endocrinol 2002;146:537–543.
9.
Ghizzoni L, Mastorakos G, Street ME, Mazzardo G, Vottero A, Vanelli M, Bernasconi S: Leptin, cortisol, and GH secretion interactions in short normal prepubertal children. J Clin Endocrinol Metab 2001;86:3729–3734.
10.
Biason-Lauber A, Zachmann M, Schoenle EJ: Effect of leptin on CYP17 enzymatic activities in human adrenal cells: New insight in the onset of adrenarche. Endocrinology 2000;141:1446–1454.
11.
Tolis G, Lewis W, Verdy M, Friesen H, Solomon S, Pagalis G: Anterior pituitary function in the Prader-Labhart-Willi (PLW) syndrome. J Clin Endocrinol Metab 1974;39:1061–1066.
12.
Kauli R, Prager-Lewin R, Laron Z: Pubertal development in the Prader-Labhart-Willi syndrome. Acta Paediatr Scand 1978;67:763–767.
13.
Garty B, Shuper A, Mimouni M, Varsano I, Kauli R: Primary gonadal failure and precocious adrenarche in a boy with Prader-Labhart-Willi syndrome. Eur J Pediatr 1982;139:201.
14.
Chasalow FI, Blethen SL, Tobash JG, Myles D, Butler MG: Steroid metabolic disturbances in Prader-Willi syndrome. Am J Med Genet 1987;28:857–864.
15.
Schmidt H, Schwarz H P: Premature adrenarche, increased growth velocity and accelerated bone age in male patients with Prader-Labhart-Willi syndrome. Eur J Pediatr 2001;160:69–70.
16.
Lindgren AC, Hagenas L, Ritzen EM: Growth hormone treatment of children with Prader-Willi syndrome: Effects on glucose and insulin homeostasis. Horm Res 1999;51:157–161.
17.
Eiholzer U, Stutz K, Weinmann C, Torresani T, Molinari L, Prader A: Low insulin, IGF-I and IGFBP-3 levels in children with Prader-Labhart-Willi syndrome. Eur J Pediatr 1998;157:890–893.
18.
Eiholzer U, Bachmann S, l’Allemand D: Is there a growth hormone deficiency in PWS? Six arguments to support the presence of a hypothalamic GHD in PWS. Horm Res 2000;53(suppl 3):44–52.
19.
Rudd BT, Chance GW, Theodoridis CG: Adrenal response to ACTH in patients with Prader-Willi syndrome, simple obesity and constitutional dwarfism. Arch Dis Child 1969;44:244–247.
20.
Goldstone AP, Thomas EL, Brynes AE, Bell JD, Frost G, Saeed N, Hajnal JV, Howard JK, Holland A, Bloom SR: Visceral adipose tissue and metabolic complications of obesity are reduced in Prader-Willi syndrome female adults: Evidence for novel influences on body fat distribution. J Clin Endocrinol Metab 2001;86:4330–4338.
21.
Eiholzer U, l’Allemand D: Growth hormone normalises height, prediction of final height and hand length in children with Prader-Willi syndrome after four years of therapy. Horm Res 2000;53:185–192.
22.
Eiholzer U, l’Allemand D, van der Sluis I, Steinert H, Ellis K: Body composition abnormalities in children with Prader-Willi syndrome and long-term effects of growth hormone therapy. Horm Res 2000;53:200–206.
23.
Prader A, Largo R, Molinari L, Issler C: Physical growth of Swiss children from birth to 20 years of age. Helv Paediatr Acta Suppl 1989;52:1–125.
24.
Blum W, Englaro P, Hanitsch S, Juul A, Hertel N, Müller J, Attanasio A, Kiess W, Rascher W: Plasma leptin levels in healthy children and adolescents: Dependence on body mass index, body fat mass, gender, pubertal stage, and testosterone. J Clin Endocrinol Metab 1997;82:2904–2910.
25.
Zapf J, Walter H, Froesch E: Radioimmunological determination of insulin-like growth factors I and II in normal subjects and in patients with growth disorders and extrapancreatic tumor hypoglycemia. J Clin Invest 1981;68:1321–1330.
26.
Zapf J, Froesch E: Insulin-like growth factor I actions on somatic growth; in Kostyo J, Goodman H (eds): Hormonal Control of Growth. New York, Oxford University Press, 1999, vol V, pp 663–699.
27.
Ellis KJ, Abrams SA, Wong WW: Body composition of a young, multiethnic female population. Am J Clin Nutr 1997;65:724–731.
28.
Boot AM, Bouquet J, de Ridder MA, Krenning EP, De Muinck K: Determinants of body composition measured by dual-energy X-ray absorptiometry in Dutch children and adolescents. Am J Clin Nutr 1997;66:232–238.
29.
Ellis KJ: Body composition of a young, multiethnic, male population. Am J Clin Nutr 1997;66:1323–1331.
30.
Lautala P, Akerblöm H, Viikari J, Louhivouri K, Uhari M, Dahlström S, Dahl M, Lähde P, Pesonen E, Pietikäinen M, Suoninen P, Knip M: Atherosclerosis precursors in Finnish children and adolescents. VII. Serum immunoreactive insulin. Acta Paediatr Scand Suppl 1985;318:127–133.
31.
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC: Homeostasis model assessment: Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412–419.
32.
l’Allemand D, Eiholzer U, Schlumpf M, Torresani T, Girard J: Prader-Willi syndrome (PWS): Glucose homeostasis and insulin secretion remain unchanged after 3 years of treatment with hGh as an effect of improved body composition. Horm Res 2000;53(suppl 2):131.
33.
Ibanez L, DiMartino-Nardi J, Potau N, Saenger P: Premature adrenarche – normal variant or forerunner of adult disease? Endocr Rev 2000;21:671–696.
34.
Vuguin P, Linder B, Rosenfeld RG, Saenger P, DiMartino-Nardi J: The roles of insulin sensitivity, insulin-like growth factor I (IGF-I), and IGF-binding protein-1 and -3 in the hyperandrogenism of African-American and Caribbean Hispanic girls with premature adrenarche. J Clin Endocrinol Metab 1999;84:2037–2042.
35.
Barbieri RL, Smith S, Ryan KJ: The role of hyperinsulinemia in the pathogenesis of ovarian hyperandrogenism. Fertil Steril 1988;50:197–212.
36.
Deschamps I, Giron B, Lestradet H: Blood glucose, insulin, and free fatty acid levels during oral glucose tolerance tests in 158 obese children. Diabetes 1977;26:89–93.
37.
Girgis R, Abrams SA, Castracane VD, Gunn SK, Ellis KJ, Copeland KC: Ethnic differences in androgens, IGF-I and body fat in healthy prepubertal girls. J Pediatr Endocrinol Metab 2000;13:497–503.
38.
Wabitsch M, Blum W, Muche R, Heinze E, Haug C, Mayer H, Teller W: Insulin-like growth factors and their binding proteins before and after weight loss and their associations with hormonal and metabolic parameters in obese adolescent girls. Int J Obes Relat Metab Disord 1996;20:1073–1080.
39.
Kristiansen SB, Endoh A, Casson PR, Buster JE, Hornsby PJ: Induction of steroidogenic enzyme genes by insulin and IGF-I in cultured adult human adrenocortical cells. Steroids 1997;62:258–265.
40.
l’Allemand D, Penhoat A, Lebrethon MC, Ardevol R, Baehr V, Oelkers W, Saez JM: Insulin-like growth factors enhance steroidogenic enzyme and corticotropin receptor messenger ribonucleic acid levels and corticotropin steroidogenic responsiveness in cultured human adrenocortical cells. J Clin Endocrinol Metab 1996;81:3892–3897.
41.
Ibanez L, Potau N, Ong K, Dunger DB, de Zegher F: Increased bone mineral density and serum leptin in non-obese girls with precocious pubarche: Relation to low birth weight and hyperinsulinism. Horm Res 2000;54:192–197.
42.
Chapman IM, Wittert GA, Norman RJ: Circulating leptin concentrations in polycystic ovary syndrome: Relation to anthropometric and metabolic parameters. Clin Endocrinol (Oxf) 1997;46:175–181.
43.
Remer T, Manz F: Role of nutritional status in the regulation of adrenarche. J Clin Endocrinol Metab 1999;84:3936–3944.
44.
Suter KJ, Pohl CR, Wilson ME: Circulating concentrations of nocturnal leptin, growth hormone, and insulin-like growth factor-I increase before the onset of puberty in agonadal male monkeys: Potential signals for the initiation of puberty. J Clin Endocrinol Metab 2000;85:808–814.
45.
Kaplowitz PB, Slora EJ, Wasserman RC, Pedlow SE, Herman-Giddens ME: Earlier onset of puberty in girls: Relation to increased body mass index and race. Pediatrics 2001;108:347–353.
46.
Juricskay Z, Molnar D: Steroid metabolism in obese children. II. Steroid excretion of obese and normal weight children. Acta Paediatr Hung 1988;29:395–403.
47.
Cheek DB, Graystone JE, Seamark RF, McIntosh JE, Phillipou G, Court JM: Urinary steroid metabolites and the overgrowth of lean and fat tissues in obese girls. Am J Clin Nutr 1981;34:1804–1810.
48.
Brambilla P, Bosio L, Manzoni P, Pietrobelli A, Beccaria L, Chiumello G: Peculiar body composition in patients with Prader-Labhart-Willi syndrome. Am J Clin Nutr 1997;65:1369–1374.
49.
l’Allemand D, Eiholzer U, Schlumpf M, Steinert H, Riesen W: Cardiovascular risk factors improve under 3 years of growth hormone therapy in Prader-Willi syndrome. Eur J Pediatr 2000;159:835–842.
50.
Sudi K, Gallistl S, Weinhandl G, Payer C, Cartellieri M, Borkenstein MH: No relationship between leptin and cortisol in obese children and adolescents. J Pediatr Endocrinol Metab 2000;13:913–921.
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