Abstract
The genetic mechanisms underlying the regulation of adrenarche are unknown. The aim of the study was to find out whether ACTH receptor (MC2R) promoter polymorphism associates with premature adrenarche (PA) and its characteristics. DNA samples of 74 prepubertal children with PA and their age- and gender-matched 97 healthy controls were genotyped for the −2 bp T/C diallelic MC2R promoter polymorphism (MC2R −2 T>C) All children were examined clinically, and hormonal measurements after an overnight fast and a low-dose ACTH stimulation test were performed. In controls, the baseline ACTH/cortisol ratio was significantly higher (p = 0.002) in subjects with the polymorphism than in the T/T group indicating decreased ACTH sensitivity. The frequency of the MC2R −2 T>C polymorphism was significantly higher in PA children with premature pubarche than in those with milder signs of PA or in control children (p = 0.04). In children with PA, the polymorphism associated with higher baseline serum dehydroepiandrosterone (p = 0.03), androstenedione (p = 0.02), plasma ACTH (p = 0.03) levels and with lower birth weight (p = 0.02). Our study provides evidence that the MC2R promoter polymorphism modulates the hypothalamo-pituitary-adrenal axis in children and may play a role in altered regulation of adrenarche.
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Abbreviations
- Δ4-A:
-
androstenedione
- DHEA:
-
dehydroepiandrosterone
- DHEAS:
-
dehydroepiandrosterone sulfate
- MC2R:
-
melanocortin-2 receptor, ACTH receptor
- nonPP-PA:
-
premature adrenarche without pubarche
- PA:
-
premature adrenarche
- PP:
-
premature pubarche
- PP-PA:
-
premature adrenarche with premature pubarche
References
Voutilainen R, Perheentupa J, Apter D 1983 Benign premature adrenarche: clinical features and serum steroid levels. Acta Paediatr Scand 72: 707–711
Ibanez L, Dimartino-Nardi J, Potau N, Saenger P 2000 Premature adrenarche–normal variant or forerunner of adult disease?. Endocr Rev 21: 671–696
Ehrhart-Bornstein M, Hinson J, Bornstein S, Scherbaum W, Vinson G 1998 Intraadrenal interactions in the regulation of adrenocortical steroidogenesis. Endocr Rev 19: 101–143
Apter D, Pakarinen A, Hammond G, Vihko R 1979 Adrenocortical function in puberty - serum ACTH, cortisol and dehydroepiandrosterone in girls and boys. Acta Paediatr Scand 68: 599–604
Weber A, Clark A, Perry L, Honour J, Savage M 1997 Diminished adrenal androgen secretion in familial glucocorticoid deficiency implicates a significant role for ACTH in the induction of adrenarche. Clin Endocrinol (Oxf) 46: 431–437
Azziz R, Fox LM, Zacur HA, Parker CR, Boots LR 2001 Adrenocortical secretion of dehydroepiandrosterone in healthy women: highly variable response to adrenocorticotropin. J Clin Endocrinol Metab 86: 2513–2517
Rotter JI, Wong FL, Lifrak ET, Parker LN 1985 A genetic component to the variation of dehydroepiandrosterone sulfate. Metabolism 34: 731–736
Yildiz BO, Goodarzi MO, Guo X, Rotter JI, Azziz R 2006 Heritability of dehydroepiandrosterone sulfate in women with polycystic ovary syndrome and their sisters. Fertil Steril 86: 1688–1693
Legro RS, Driscoll D, Strauss JF III, Fox J, Dunaif A 1998 Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. Proc Natl Acad Sci USA 95: 14956–14960
Buckley DI, Ramachandran J 1981 Characterization of corticotropin receptors on adrenocortical cells. Proc Natl Acad Sci USA 78: 7431–7435
Gantz I, Fong T 2003 The melanocortin system. Am J Physiol Endocrinol Metab 284: E468–E474
Mountjoy KG, Robbins LS, Mortrud MT, Cone RD 1992 The cloning of a family of genes that encode the melanocortin receptors. Science 257: 1248–1251
Naville D, Jaillard C, Barjhoux L, Durand P, Begeot M 1997 Genomic structure and promoter characterization of the human ACTH receptor gene. Biochem Biophys Res Commun 230: 7–12
Slawik M, Reisch N, Zwermann O, Maser-Gluth C, Stahl M, Klink A, Reincke M, Beuschlein F 2004 Characterization of an adrenocorticotropin (ACTH) receptor promoter polymorphism leading to decreased adrenal responsiveness to ACTH. J Clin Endocrinol Metab 89: 3131–3137
Reisch N, Slawik M, Zwermann O, Beuschlein F, Reincke M 2005 Genetic influence of an ACTH receptor promoter polymorphism on adrenal androgen secretion. Eur J Endocrinol 153: 711–715
Utriainen P, Jääskeläinen J, Romppanen J, Voutilainen R 2007 Metabolic syndrome and its components in children with premature adrenarche. J Clin Endocrinol Metab 92: 4282–4285
Pihkala J, Hakala T, Voutilainen P, Raivio K 1989 [Characteristic of recent fetal growth curves in Finland]. Duodecim 105: 1540–1546
Sorva R, Perheentupa J, Lankinen S, Tolppanen EM 1990 Variation of growth in height and weight of children. II. After infancy. Acta Paediatr Scand 79: 498–506
Sanders EB, Aston CE, Ferrell RE, Witchel SF 2002 Inter- and intrafamilial variability in premature pubarche and polycystic ovary syndrome. Fertil Steril 78: 473–478
Witchel SF, Smith R, Tomboc M, Aston CE 2001 Candidate gene analysis in premature pubarche and adolescent hyperandrogenism. Fertil Steril 75: 724–730
Petry CJ, Ong KK, Michelmore KF, Artigas S, Wingate DL, Balen AH, de Zegher F, Ibáñez L, Dunger DB 2005 Association of aromatase (CYP 19) gene variation with features of hyperandrogenism in two populations of young women. Hum Reprod 20: 1837–1843
Ibanez L, Ong K, Mongan N, Jääskeläinen J, Marcos M, Hughes I, De Zegher F, Dunger D 2003 Androgen receptor gene CAG repeat polymorphism in the development of ovarian hyperandrogenism. J Clin Endocrinol Metab 88: 3333–3338
Vottero A, Capelletti M, Giuliodori S, Viani I, Ziveri M, Neri T, Bernasconi S, Ghizzoni L 2006 Decreased androgen receptor gene methylation in premature pubarche: A novel pathogenetic mechanism?. J Clin Endocrinol Metab 91: 968–972
Auchus RJ, Rainey WE 2004 Adrenarche—physiology, biochemistry and human disease. Clin Endocrinol (Oxf) 60: 288–296
Ibanez L, Potau N, Chacon P, Pascual C, Carrascosa A 1998 Hyperinsulinaemia, dyslipaemia and cardiovascular risk in girls with a history of premature pubarche. Diabetologia 41: 1057–1063
Ibanez L, Potau N, Francois I, de Zegher F 1998 Precocious pubarche, hyperinsulinism, and ovarian hyperandrogenism in girls: relation to reduced fetal growth. J Clin Endocrinol Metab 83: 3558–3562
Ong KK, Potau N, Petry CJ, Jones R, Ness AR, Honour JW, de Zegher F, Ibanez L, Dunger DB 2004 Opposing influences of prenatal and postnatal weight gain on adrenarche in normal boys and girls. J Clin Endocrinol Metab 89: 2647–2651
van Montfoort N, Finken MJ, le Cessie S, Dekker FW, Wit JM 2005 Could cortisol explain the association between birth weight and cardiovascular disease in later life? A meta-analysis. Eur J Endocrinol 153: 811–817
Hauffa BP, Kaplan SL, Grumbach MM 1984 Dissociation between plasma adrenal androgens and cortisol in Cushing's disease and ectopic ACTH-producing tumour: relation to adrenarche. Lancet 1: 1373–1376
Watts AG 2005 Glucocorticoid regulation of peptide genes in neuroendocrine CRH neurons: a complexity beyond negative feedback. Front Neuroendocrinol 26: 109–130
Morris DG, Kola B, Borboli N, Kaltsas GA, Gueorguiev M, McNicol AM, Ferrier R, Jones TH, Baldeweg S, Powell M, Czirjak S, Hanzely Z, Johansson JO, Korbonits M, Grossman AB 2003 Identification of adrenocorticotropin receptor messenger ribonucleic acid in the human pituitary and its loss of expression in pituitary adenomas. J Clin Endocrinol Metab 88: 6080–6087
Boscaro M, Sonino N, Paoletta A, Rampazzo A, Mantero F 1988 Evidence for ultra-short loop autoregulation of adrenocorticotropin secretion in man. J Clin Endocrinol Metab 66: 255–257
Lebrethon MC, Naville D, Begeot M, Saez JM 1994 Regulation of corticotropin receptor number and messenger RNA in cultured human adrenocortical cells by corticotropin and angiotensin II. J Clin Invest 93: 1828–1833
Mesiano S, Fujimoto VY, Nelson LR, Lee JY, Voytek CC, Jaffe RB 1996 Localization and regulation of corticotropin receptor expression in the midgestation human fetal adrenal cortex: implications for in utero homeostasis. J Clin Endocrinol Metab 81: 340–345
Picard-Hagen N, Penhoat A, Hue D, Jaillard C, Durand P 1997 Glucocorticoids enhance corticotropin receptor mRNA levels in ovine adrenocortical cells. J Mol Endocrinol 19: 29–36
Luppa P, Munker R, Nagel D, Weber M, Engelhardt D 1991 Serum androgens in intensive-care patients: correlations with clinical findings. Clin Endocrinol (Oxf) 34: 305–310
Beishuizen A, Thijs L, Vermes I 2002 Decreased levels of dehydroepiandrosterone sulphate in severe critical illness: a sign of exhausted adrenal reserve?. Crit Care 6: 434–438
Dimopoulou I, Stamoulis K, Ilias I, Tzanela M, Lyberopoulos P, Orfanos S, Armaganidis A, Theodorakopoulou M, Tsagarakis S 2007 A prospective study on adrenal cortex responses and outcome prediction in acute critical illness: results from a large cohort of 203 mixed ICU patients. Intensive Care Med 33: 2116–2121
Bomba M, Gambera A, Bonini L, Peroni M, Neri F, Scagliola P, Nacinovich R 2007 Endocrine profiles and neuropsychologic correlates of functional hypothalamic amenorrhea in adolescents. Fertil Steril 87: 876–885
Bornstein SR, Chrousos GP 1999 Clinical review 104: adrenocorticotropin (ACTH)- and non-ACTH-mediated regulation of the adrenal cortex: neural and immune inputs. J Clin Endocrinol Metab 84: 1729–1736
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Ms Mari Tuovinen and Ms Minna Heiskanen are thanked for their skilful assistance.
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Supported by Kuopio University Hospital, Pediatric Research Foundation, Academy of Finland, The Finnish Medical Foundation and Sigrid Jusélius Foundation.
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Lappalainen, S., Utriainen, P., Kuulasmaa, T. et al. ACTH Receptor Promoter Polymorphism Associates With Severity of Premature Adrenarche and Modulates Hypothalamo-Pituitary-Adrenal Axis in Children. Pediatr Res 63, 410–414 (2008). https://doi.org/10.1203/PDR.0b013e3181659c14
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DOI: https://doi.org/10.1203/PDR.0b013e3181659c14
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