Abstract
Adrenarche is the puberty of the adrenal gland. The descriptive term “pubarche” indicates the appearance of pubic hair, which may be accompanied by axillary hair. This process is considered premature if it occurs before age 8 yr in girls and 9 yr in boys. The chief hormonal products of adrenarche are DHEA and DHEAS. The well-documented evolution of adrenarche in primates and men is incompatible with either a neutral or harmful role for DHEA and implies most likely a positive role for some aspects of young adult pubertal maturation and developmental maturation. Premature adrenarche has no adverse effects on the onset and progression of gonadarche and/or final height. Mechanisms for initiation of adrenal androgen secretion at adrenarche are still not well understood. Maturational increases in 17-hydroxylase and 17,20-lyase are seen together with a lower activity of 3β-hydroxysteroid dehydrogenase (3β-HSD). There is good evidence that the zona reticularis is the source of adrenal androgens. Adrenarche and gonadarche are regulated differently. Although premature adrenarche has been thought to be a benign, normal variant of puberty, our findings indicate that, for certain girls, premature adrenarche represents an early clinical feature of syndrome X (obesity, hypertension, dyslipidemia, insulin resistance). Perhaps the early identification of these patients will permit early therapy, such as lifestyle changes, including dietary and activity level intervention. As insulin resistance is an underlying feature of premature adrenarche, it seems rational to assess the efficacy and safety of using insulin-sensitizing agents to treat these individuals. In the absence of controlled longitudinal studies, the cross-sectional data available from our studies suggest that premature pubarche driven by premature adrenarche and hyperinsulinemia may precede the development of ovarian hyperandrogenism, and this sequence may have an early origin with low birth weight serving as a marker. Premature adrenarche may thus be a forerunner of syndrome X in some girls.
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References
Parker L.N., Sack J., Fisher D.A., Odell W.D. The adrenarche: prolactin. gonadotropins, adrenal androgens, and cortisol. J. Clin. Endocrinol. Metab. 1978, 46: 396–401.
Sklar C.A., Kaplan S.L., Grumbach M.M. Evidence for dissociation between adrenarche and gonadarche: studies in patients with idiopathic precocious puberty, gonadal dysgenesis, isolated gonadotropin deficiency and constitutionally delayed growth and adolescence. J. Clin. Endocrinol. Metab. 1980, 51: 548–556.
Apter D., Pakarinen A., Hammond G.L., Vihko R. Adrenocortical function in puberty. Acta Paediatr. Scand. 1979, 68: 599–604.
Orentreich N., Brind J.L., Rizer R.L., Vogelman J.H. Age changes and sex differences in serum dehydroepiandrostenedione sulfate concentrations throughout adulthood. J. Clin. Endocrinol. Metab. 1984, 59: 551–555.
Miller W.L. The molecular basis of premature adrenarche: an hypothesis. Acta Paediatr. Suppl. 1999, 433: 60–66.
Cutler Jr. G.B., Loriaux D.L. Adrenarche and its relationship to the onset of puberty. Fed. Proc. 1980, 39: 2384–2392.
Smail P.J., Faiman C., Hobson W.C., Fuller G.B., Winter J.S.D. Further studies on adrenarche in non-human primates. Endocrinology 1982, 111: 844–848.
Meusy-Dessolle N., Dang P.C. Plasma concentrations of testosterone, dihydrotesto-sterone, Δ-androstenedione, dihydroepiandrosterone and oestradiol-17 in the crab-eating monkey (Macaca fascicularis) from birth to adulthood. J. Reprod. Fertil. 1985, 74: 347–359.
Lane M.A., Ingram D.K., Ball S.S., Roth G.S. Dehydroepiandrosterone sulfate: a biomarker of primate aging slowed by calorie restriction. J. Clin. Endocrinol. Metab. 1997, 82: 2093–2096.
Hornsby P.J. The biosynthesis of DHEA by the adrenal cortex and its age-related decline. In: Watson R.W. (Ed.), DHEA: health promotion and aging. Academic, Harwood, 1998, p. 1.
Morales A.J., Nolan J.J., Nelson J.C., Yen S.S.C. Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age. J. Clin. Endocrinol. Metab. 1994, 78: 1360–1367.
Baulieu E.E. Dehydroepiandrosterone (DHEA): a fountain of youth? J. Clin. Endocrinol. Metab. 1996, 81: 3147–3151.
Ghizzoni L., Virdis R., Ziveri M., Lamboglini A., Alberini A., Volta C., Bernasconi S. Adrenal steroid, cortisol, adrenocorticotropin and β-endorphin responses to human corticotropin-releasing hormone stimulation test in normal children and children with premature pubarche. J. Clin. Endocrinol. Metab. 1989, 69: 875–880.
Ibáñez L., Potau N., Marcos M.V., DeZegher F. Corticotropin-releasing hormone: a potent androgen secretagogue in girls with hyperandrogenism after precocious pubarche. J. Clin. Endocrinol. Metab. 1999, 84: 4602–4607.
Albertson B., Hobson W., Barnett B., Turner P.T., Clark R.V., Schiebinger R.J., Loriaux, D.L., Cutler G.B. Jr. Dissociation of cortisol and adrenal androgen secretion in the hypophysectomized ACTH-replaced chimpanze. J. Clin. Endocrinol. Metab. 1984, 59: 13–18.
Mills I.H., Brooks R.V., Prunty F.T.G. The relationship between the production of cortisol and of androgen by the human adrenal. In: Currie A.R., Symington T., Grank J.K. (Eds.), The human adrenal cortex. Livingstone, London, 1962, p. 20.
Grumbach M.M., Richard S.G.E., Conte F.A., Kaplan S.I. Clinial disorders of adrenal function and puberty: an assessment of the role of the adrenal cortex in normal and abnormal puberty in man and evidence for an ACTH-like pituitary adrenal androgen stimulation hormone. In: James V.H.T., Serio M., Giusti G., Martini L. (Eds.), The endocrine function of the human adrenal cortex. Serono Symposia 18. Academic Press, London, 1978, p. 583.
Hauffa B.P., Kaplan S.L., Grumbach M.M. Dissociation between plasma adrenal androgens and cortisol in Cushing’s disease and ectopic ACTHproducing tumour: relation to adrenarche. Lancet 1984, 1: 1373–1376.
Suda T., Demura H., Demura R., Jibiki K., Tozawa F., Shizuma F. Anterior pituitary hormones in plasma and pituitary from patients with Cushing’s disease. J. Clin. Endocrinol. Metab. 1980, 51: 1048–1053.
Chan J.S.D., Seidah N.G., Chretien M. Measurement of N-terminal (1–76) proopiomelanocortin in human plasma: correlation with adrenocorticotropin. J. Clin. Endocrinol. Metab. 1983, 56: 791–796.
Parker L.N., Lifrak E.T., Odell W.D. A 60,000 molecular weight human pituitary glycopeptide stimulates adrenal androgen secretion. Endocrinology 1983, 113: 2092–2096.
Parker L., Lifrak E., Shively J., Lee T., Kaplan B., Walker P., Calaycacy J., Florsheim W., Soong-Shiong P. Human gland cortical androgen-stimulating hormone (CASH) is identical with a portion of the joint peptide of pituitary proopiomelanocortin (POMC). Program of the 71st Annual Meeting of The Endocrine Society, Seattle, Washington, 1989, p. 97 (Abstract).
Parker L., Lifrak E., Gelfand R., Shively J., Lee T., Kaplan B., Walker P., Calaycay J., Florsheim W., Mason I., Soong-Shiong P. Isolation, purification, synthesis and binding of human adrenal gland cortical androgen stimulating hormone. Endocr. J. 1993, 1: 441–445.
Mellon S.H., Shively J.E., Miller W.L. Human proopiomelanocortin (79–96), a proposed androgen stimulating hormone, does not affect steroidogenesis in cultured human fetal adrenal cells. J. Clin. Endocrinol. Metab. 1991, 72: 19–22.
Penhoat A., Sanchez P., Jaillard C., Langlois D., Begeot M. Human proopiomelanocortin (79–96), a proposed cortisol adrenal-stimulating hormone, does not affect steroidogenesis in cultured human adult adrenal cells. J. Clin. Endocrinol. Metab. 1991, 72: 23–26.
Robinson P., Bateman A., Mulay S., Spenser S.J., Jaffe R.B. Isolation and characterization of three forms of joining peptide from adult human pituitaries: lack of adrenal androgen-stimulating activity. Endocrinology 1991, 129: 859–867.
Miller W.L., Johnson L.K. Synthesis and glycosylation of proopiomelanocortin by a Cushing tumor. J. Clin. Endocrinol. Metab. 1982, 55: 441–446.
Remer T., Marz F. Role of nutritional status in the regulation of adrenarche. J. Clin. Endocrinol. Metab. 1999, 84: 3936–3944.
Schiebinger R.J., Albertson B.D., Cassorla F.G., Bowyer D.W., Geelhoed G.W., Cutler Jr. G.B., Loriaux D.L. The developmental changes in plasma adrenal androgens during infancy and adrenarche are associated with changing activities of adrenal microsomal 17-hydroxylase and 17,20-desmolase. J. Clin. Invest. 1981, 67: 1177–1182.
Rich B., Rosenfield R., Lucky A., Helke J., Otto P. Adrenarche: changing adrenal response to adrenocorticotropin. J. Clin. Endocrinol. Metab. 1981, 52: 1129–1134.
Kahri A.I., Voutilainen R., Salmenperae M. Different biological action of corticosteroids, corticosterone and cortisol as a basis of zonal function adrenal cortex. Acta Endocrinol. (Copenh.) 1979, 91: 329–337.
Gell J.S., Carr B.R., Sasano H., Atkins B., Margraf L., Mason J.I., Rainey W.E. Adrenarche results from development of a 3β-hydroxysteroid dehydrogenase-deficient adrenal reticularis. J. Clin. Endocrinol. Metab. 1998, 83: 3695–3709.
L’Allemand D., Penhoat A., Lebrethon M.C., Ardevol R., Baeher V., Oelkers W., Saez J.M. 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: 392–397.
Lebrethon M.C., Jaillard C., Naville D., Begeot M., Saez J.M. Effects of transforming growth factor-1 on human adrenocortical fasciculata-reticualris cell differentiated functions. J. Clin. Endocrinol. Metab. 1994, 79: 1033–1039.
Wolkersdörfer G.W., Lohmann T., Marx C., Schröder S., Pfeiffer R., Stahl H.-D., Scherbaum W.A., Chrousos G.P., Bornstein S.R. Lympocytes stimulate dehydroepiandrosterone production through direct cellular contract with adrenal zona reticularis cells: a novel mechanism of immuneendocrine interaction. J. Clin. Endocrinol. Metab. 1999, 84: 4220–4227.
Yanagibashi K., Hall P.F. Role of electron transport in the regulation of the lyase activity of C32 side-chain cleavage P-450 from porcine adrenal and testicular microsomes. J. Biol. Chem. 1980, 261: 8429–8433.
Lin D., Black S.M., Nagahama Y., Miller W.L. Steroid 17-alpha-hydroxylase and 17,20-lyase activities of P450C17:contributions of serion 106 and P450 reductase. Endocrinology 1993, 132: 2498–2506.
Geller D.J., Auchus R.J., Mendonca B.B., Miller W.L. Molecular mechanism of 17,20-lyase deficiency. Horm. Res. 1997, 48 (Suppl. 2): (Abstract).
Miller W.L., Tyrell J.B, The adrenal cortex. In: Felig P., Baxter J.D., Frohman L.A. (Eds.), Endocrinology and metabolism, ed. 3. McGraw-Hill, New York, 1995, p. 555.
Lashansky G., Saenger P., Fishman K., Gautier T., Mayes D., Berg G., DiMartino-Nardi J., Reiter E. Normative data for adrenal steroidogenesis in a healthy pediatric population: age and sex-related changes after ACTH stimulation. J. Clin. Endocrinol. Metab. 1991, 73: 674–686.
Lashansky G., Saenger P., DiMartino-Nardi J., Gautier T., Mayes D., Berg G., Reiter E. Normative data for the steroidogenic response of mineralocorticoids and their precursors to adrenocorticotropin in a healthy pediatric population. J. Clin. Endocrinol. Metab. 1992, 75: 1491–1496.
Zhang L., Rodriguez H., Ohno S., Miller W.L. Serine phosphorylation of human P450C17 increases 17,20-lyase activity: implications for adrenarche and the polycystic ovary syndrome. Proc. Natl. Acad. Sci. USA 1995, 92: 10619–10623.
Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanisms for implications for pathogenesis. Endocr. Rev. 1997, 18: 774–800.
Takayama S., White M.F., Kahn C.R. Phorbol ester-induced serine phosphorylation of the insulin receptor decreases its tyrosine kinase activity. J. Biol. Chem. 1988, 263: 3440–3447.
Chin C.E., Dickens M., Tavare J.M., Roth R.A. Overexpression of protein kinase C isoenzymes a-, b, I, g and e in cells overexpressing the insulin receptor: effects on receptor phosphorylation and signaling. J. Biol. Chem. 1993, 268: 6338–6347.
Saenger P. Turner’s syndrome. N. Engl. J. Med. 1996, 335: 1749–1754.
Counts D.R., Pescovitz O.H., Barnes K.M., Hench K.D., Chrousos G.P., Sherin S.R., Comite F., Loriaux D. L., Cutler G.B. Jr. Dissociation of adrenarche and gonadarche in precocious puberty and in isolated hypogonadotropic hypogonadism. J. Clin. Endocrinol. Metab. 1987, 64: 1174–1178.
Urban M., Lee P.A., Guta J.P., Migeon C.J. Androgens in pubertal males with Addison’s disease. J. Clin. Endocrinol. Metab. 1980, 5: 925–929.
Silverman S.H., Migeon C.J., Rosenberg E., Wilkins L. Precocious growth of sexual hair without other secondary sexual development: “premature pubarche”, a constitutional variation of adolescence. Pediatrics 1952, 10: 426–432.
Sigurjonsdottir T.J., Hayles A.S. Premature pubarche. Clin. Pediatr. (Phil.) 1968, 7: 29–33.
Wilkins L. Abnormalities and variations of sexual development during childhood and adolescence. In: Advances in pediatrics. Interscience, New York, 1948, Vol. 3, p. 159.
Talbot N.B., Sobel E.H., McArthur J.W., Crawford J.D. Precocious adrenarche. In: Case J.P., Lockwood A.S., Brainard M. (Eds.), Functional endocrinology from birth through adolescence. Commonwealth Fund, Harvard University, Cambridge, 1952, p. 247.
Liu N., Grumbach M.M., DeNapoli R.A., Morishi-ma A. Prevalence of electro-encephalographic abnormaltiies in idiopathic precocious puberty and premature pubarche: bearing on pathogenesis and neuroendocrine regulation of puberty. J. Clin. Endocrinol. Metab. 1965, 25: 1296–1308.
Thamdrup E. Premature pubarche: a hypothalamic disorder: Report of 17 cases. Acta Endocrinol. (Copenh.) 1955, 18: 564–567.
Reiter E.O., Kulin H.F. Sexual maturation in the female: normal development and precocious puberty. Pediatr. Clin. North Am. 1972, 19: 581–603.
Rosenbaum M., Leibel R.L. Obesity in Childhood. Pediatr. Rev. 1989, 11: 43–55.
Jabbar M., Pugliese M., Fort P., Becker B., Lifshitz F. Excess weight and precocious pubarche in children: alterations of the adrenocortical hormones. J. Am. Coll. Nutr. 1991, 10: 289–296.
Herman-Giddens M.E., Slora E.J., Wasserman R.C., Bourdony C.J., Bhapkar M.V., Koch G.G., Hasemeier C.M. Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings Network. Pediatrics 1997, 99: 505–512.
Rosenfield R.L., Bachrach L.K., Chernausek S.D., Gertner J.M., Gottschalk G., Hardin D.S., Pescovitz O., Saenger P. Current age of onset of puberty. Pediatrics 2000, 106: 622–623.
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.
DiMartino-Nardi J. Premature adrenarche: findings in prepubertal African-American and Caribbean-Hispanic girls. Acta Paediatr. Suppl. 1999, 443: 67–72.
Nestler J.E., Clore J.N., Blackard W.G. The central role of obesity (hyperinsulinemia) in the pathogenesis of polycystic ovary syndrome. Am. J. Obstet. Gynecol. 1989, 161: 1095–1097.
Vuguin P., Linder B., Rosenfeld R.G., Saenger P., DiMartino-Nardi J. The role of insulin sensitivity, insulin-like growth factor and insulin-like growth factor binding proteins 1 and 3 in the hyperandrogenism of African-American and Caribbean-Hispanic girls with premature adrenarche. J. Clin. Endocrinol. Metab. 1999, 84: 2037–2042.
Legro R.S., Finegood D., Dunaif A. A fasting glucose to insulin ratio is a useful measure of insulin sensitivity in women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 1998, 83: 2694–2698.
Vuguin P., Saenger P., DiMartino-Nardi J. Fasting glucose:insulin ratio: a useful measure of insulin resistance in girls with premature adrenarche. Pediatr. Res. 1999, 45: 99A.
Francois I., de Zegher F. Adrenarche and fetal growth. Pediatr. Res. 1997, 41: 440–442.
Ibanez L., Potau N., Francois I., de Zegher F. Precocious pubarche, hyperinsulinism and ovarian hyperandrogenism in girls: relation to reduced fetal growth. J. Clin. Endocrinol. Metab. 1998, 83: 3558–3562.
Grinstein G.P., Vuguin P., Saenger P., DiMartino-Nardi J. The relationship between birth weight (BW), body mass index (BMI) and insulin sensitivity (SI) in prepubertal Caribbean Hispanic (CH) and black African-American (BAA) girls with premature adrenarche. Pediatr. Res. 1999, 45: 89 (Abstract).
Ghizzoni L., Mastorakos G., Vottero A. Commentary — Adrenal hyperandrogenism in children. J. Clin. Endocrinol. Metab. 1999, 84: 4431–4435.
Ibáñez L., DiMartino-Nardi J., Potau N., Saenger P. Premature adrenarche — Normal variant or forerunner of adult disease? Endocr. Rev. 2000, 21: 671–696.
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Saenger, P., DiMartino-Nardi, J. Premature adrenarche. J Endocrinol Invest 24, 724–733 (2001). https://doi.org/10.1007/BF03343917
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DOI: https://doi.org/10.1007/BF03343917