- Robert L Rosenfield, MD
Robert L Rosenfield, MD
- Professor Emeritus of Pediatrics and Medicine
- Pritzker School of Medicine of the University of Chicago
- Section Editors
- Lynnette K Nieman, MD
Lynnette K Nieman, MD
- Section Editor — Adrenal Disease
- Senior Investigator
- Bethesda, MD
- Mitchell Geffner, MD
Mitchell Geffner, MD
- Section Editor — Pediatric Endocrinology
- Professor of Pediatrics
- Keck School of Medicine, University of Southern California
Adrenarche is the term for the maturational increase in adrenal androgen production, which becomes biochemically apparent at about six years of age in both girls and boys (figure 1) [1,2]. It is characterized by production of increasing amounts of weak androgens by the adrenal cortex, which contribute to the development of pubic hair. Although the clinical manifestations of adrenarche ordinarily closely follow true puberty, the two phenomena may be dissociated, as occurs in the presence of hypogonadism [3,4]. Thus, adrenarche seems to be unrelated to the pubertal maturation of the hypothalamic-pituitary-gonadal axis. Adrenarche is a unique phenomenon confined to a few higher primates [5-7]. (See 'Clinical manifestations of adrenarche' below.)
Premature adrenarche is an incomplete, benign, slowly progressive form of premature puberty that is an extreme variant of normal or nearly normal. The term is used to designate a very mild form of androgen excess, most often manifest as premature pubarche (the isolated appearance of sexual hair before the age of eight years in girls and nine years in boys). The evaluation of a child with premature adrenarche is discussed in a separate topic review. (See "Premature adrenarche".)
Adrenarche is the result of a developmental change in the pattern of adrenal secretory response to adrenocorticotropic hormone (ACTH) . During adrenarche the baseline pattern of adrenal steroid levels changes in a unique way (table 1). In the preadrenarchal child, ACTH stimulates cortisol secretion but has very little effect on 17-ketosteroid secretion. During adrenarche, 17-ketosteroid responsiveness to ACTH gradually increases in a selective manner, while cortisol responsiveness to ACTH remains unchanged (figure 2). The adrenarchal secretory pattern is characterized by disproportionate responsiveness of Δ5-steroid intermediates (17-hydroxypregnenolone and dehydroepiandrosterone, DHEA) relative to Δ4-steroid intermediates (eg, 17-hydroxyprogesterone and androstenedione) in the presence of stable responses of cortisol (figure 3) . As a result, dehydroepiandrosterone sulfate (DHEA-S) becomes the predominant 17-ketosteroid of blood and serves as a marker of adrenarche.
These adrenarchal changes are ACTH-dependent [8,9], but they are caused by changes in response to ACTH rather than a change in ACTH secretion. This pattern of steroid secretion is very different from that caused by excessive ACTH stimulation in the preadrenarchal child . After adrenarche, glucocorticoid administration suppresses adrenal androgens more easily than cortisol, providing further evidence that these hormones are differentially regulated [11,12].
Anatomic site and mechanism of biochemical changes — The zona reticularis of the adrenal cortex seems to be a major source of the adrenarchal steroids (figure 3) [3,5,13,14]. The increased synthesis of 17-hydroxypregnenolone, DHEA, and DHEA-S during adrenarche is a byproduct of ACTH stimulation of cortisol synthesis [8,9].
- Korth-Schutz S, Levine LS, New MI. Dehydroepiandrosterone sulfate (DS) levels, a rapid test for abnormal adrenal androgen secretion. J Clin Endocrinol Metab 1976; 42:1005.
- de Peretti E, Forest MG. Pattern of plasma dehydroepiandrosterone sulfate levels in humans from birth to adulthood: evidence for testicular production. J Clin Endocrinol Metab 1978; 47:572.
- Grumbach M, Richards C, Conte F, Kaplan S. Clinical 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 stimulating hormone. In: The endocrine function of the human adrenal cortex, James V, Serio M, Giusti C, Martini L (Eds), Academic Press, London 1978. p.583.
- Ibáñez L, Dimartino-Nardi J, Potau N, Saenger P. Premature adrenarche--normal variant or forerunner of adult disease? Endocr Rev 2000; 21:671.
- Nakamura Y, Gang HX, Suzuki T, et al. Adrenal changes associated with adrenarche. Rev Endocr Metab Disord 2009; 10:19.
- Nguyen AD, Mapes SM, Corbin CJ, Conley AJ. Morphological adrenarche in rhesus macaques: development of the zona reticularis is concurrent with fetal zone regression in the early neonatal period. J Endocrinol 2008; 199:367.
- Conley AJ, Plant TM, Abbott DH, et al. Adrenal androgen concentrations increase during infancy in male rhesus macaques (Macaca mulatta). Am J Physiol Endocrinol Metab 2011; 301:E1229.
- Rich BH, Rosenfield RL, Lucky AW, et al. Adrenarche: changing adrenal response to adrenocorticotropin. J Clin Endocrinol Metab 1981; 52:1129.
- Weber A, Clark AJ, Perry LA, et al. Diminished adrenal androgen secretion in familial glucocorticoid deficiency implicates a significant role for ACTH in the induction of adrenarche. Clin Endocrinol (Oxf) 1997; 46:431.
- Rosenfield RL. Plasma 17-ketosteroids and 17-beta hydroxysteroids in girls with premature development of sexual hair. J Pediatr 1971; 79:260.
- Rittmaster RS, Givner ML. Effect of daily and alternate day low dose prednisone on serum cortisol and adrenal androgens in hirsute women. J Clin Endocrinol Metab 1988; 67:400.
- Brigell DF, Fang VS, Rosenfield RL. Recovery of responses to ovine corticotropin-releasing hormone after withdrawal of a short course of glucocorticoid. J Clin Endocrinol Metab 1992; 74:1036.
- Endoh A, Kristiansen SB, Casson PR, et al. The zona reticularis is the site of biosynthesis of dehydroepiandrosterone and dehydroepiandrosterone sulfate in the adult human adrenal cortex resulting from its low expression of 3 beta-hydroxysteroid dehydrogenase. J Clin Endocrinol Metab 1996; 81:3558.
- Miller WL, Auchus RJ. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev 2011; 32:81.
- Hui XG, Akahira J, Suzuki T, et al. Development of the human adrenal zona reticularis: morphometric and immunohistochemical studies from birth to adolescence. J Endocrinol 2009; 203:241.
- Xing Y, Lerario AM, Rainey W, Hammer GD. Development of adrenal cortex zonation. Endocrinol Metab Clin North Am 2015; 44:243.
- Blackman, SJ. Concerning the function and origin of the reticular zone of the adrenal cortex. Bull Hopkins Hosp 1946; 78:180.
- Rainey WE, Carr BR, Sasano H, et al. Dissecting human adrenal androgen production. Trends Endocrinol Metab 2002; 13:234.
- Dickerman Z, Grant DR, Faiman C, Winter JS. Intraadrenal steroid concentrations in man: zonal differences and developmental changes. J Clin Endocrinol Metab 1984; 59:1031.
- Byrne GC, Perry YS, Winter JS. Kinetic analysis of adrenal 3 beta-hydroxysteroid dehydrogenase activity during human development. J Clin Endocrinol Metab 1985; 60:934.
- Thomas JL, Rajapaksha M, Mack VL, et al. Regulation of human 3β-hydroxysteroid dehydrogenase type 2 by adrenal corticosteroids and product-feedback by androstenedione in human adrenarche. J Pharmacol Exp Ther 2015; 352:67.
- Winter JS, Smail PJ. Effects of ACTH and estradiol on steroid production by cultured adrenal cells from an anencephalic fetus and from normal adults. Steroids 1983; 42:677.
- Bellanger S, Battista MC, Fink GD, Baillargeon JP. Saturated fatty acid exposure induces androgen overproduction in bovine adrenal cells. Steroids 2012; 77:347.
- Schiebinger RJ, Albertson BD, Cassorla FG, et al. 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.
- Noordam C, Dhir V, McNelis JC, et al. Inactivating PAPSS2 mutations in a patient with premature pubarche. N Engl J Med 2009; 360:2310.
- Nakamura Y, Hornsby PJ, Casson P, et al. Type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3) contributes to testosterone production in the adrenal reticularis. J Clin Endocrinol Metab 2009; 94:2192.
- Mills I, Brooks R, Prunty F. The relationship between the production of cortisol and androgen by the human adrenal. In: The human adrenal cortex, Currie A, Symington T, Grant J (Eds), Williams & Wilkins, Baltimore 1962.
- Parker LN. Adrenarche. Endocrinol Metab Clin North Am 1991; 20:71.
- Taha D, Mullis PE, Ibáñez L, de Zegher F. Absent or delayed adrenarche in Pit-1/POU1F1 deficiency. Horm Res 2005; 64:175.
- Topor LS, Asai M, Dunn J, Majzoub JA. Cortisol stimulates secretion of dehydroepiandrosterone in human adrenocortical cells through inhibition of 3betaHSD2. J Clin Endocrinol Metab 2011; 96:E31.
- Ehrhart-Bornstein M, Hinson JP, Bornstein SR, et al. Intraadrenal interactions in the regulation of adrenocortical steroidogenesis. Endocr Rev 1998; 19:101.
- Ong KK, Potau N, Petry CJ, et al. Opposing influences of prenatal and postnatal weight gain on adrenarche in normal boys and girls. J Clin Endocrinol Metab 2004; 89:2647.
- Corvalán C, Uauy R, Mericq V. Obesity is positively associated with dehydroepiandrosterone sulfate concentrations at 7 y in Chilean children of normal birth weight. Am J Clin Nutr 2013; 97:318.
- Smith CP, Dunger DB, Williams AJ, et al. Relationship between insulin, insulin-like growth factor I, and dehydroepiandrosterone sulfate concentrations during childhood, puberty, and adult life. J Clin Endocrinol Metab 1989; 68:932.
- Błogowska A, Rzepka-Górska I, Krzyzanowska-Swiniarska B. Body composition, dehydroepiandrosterone sulfate and leptin concentrations in girls approaching menarche. J Pediatr Endocrinol Metab 2005; 18:975.
- 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.
- Guercio G, Rivarola MA, Chaler E, et al. Relationship between the growth hormone/insulin-like growth factor-I axis, insulin sensitivity, and adrenal androgens in normal prepubertal and pubertal girls. J Clin Endocrinol Metab 2003; 88:1389.
- Baquedano MS, Berensztein E, Saraco N, et al. Expression of the IGF system in human adrenal tissues from early infancy to late puberty: implications for the development of adrenarche. Pediatr Res 2005; 58:451.
- Martin DD, Schweizer R, Schwarze CP, et al. The early dehydroepiandrosterone sulfate rise of adrenarche and the delay of pubarche indicate primary ovarian failure in Turner syndrome. J Clin Endocrinol Metab 2004; 89:1164.
- Cumming DC, Rebar RW, Hopper BR, Yen SS. Evidence for an influence of the ovary on circulating dehydroepiandrosterone sulfate levels. J Clin Endocrinol Metab 1982; 54:1069.
- Laatikainen T, Laitinen EA, Vihko R. Secretion of free and sulfate-conjugated neutral steroids by the human testis. Effect of administration of human chorionic gonadotropin. J Clin Endocrinol Metab 1971; 32:59.
- Rosenfield RL. Clinical practice. Hirsutism. N Engl J Med 2005; 353:2578.
- Rosenfield RL, Fang VS. The effects of prolonged physiologic estradiol therapy on the maturation of hypogonadal teen-agers. J Pediatr 1974; 85:830.
- Remer T, Boye KR, Hartmann M, et al. Adrenarche and bone modeling and remodeling at the proximal radius: weak androgens make stronger cortical bone in healthy children. J Bone Miner Res 2003; 18:1539.
- Remer T, Shi L, Buyken AE, et al. Prepubertal adrenarchal androgens and animal protein intake independently and differentially influence pubertal timing. J Clin Endocrinol Metab 2010; 95:3002.
- Thankamony A, Ong KK, Ahmed ML, et al. Higher levels of IGF-I and adrenal androgens at age 8 years are associated with earlier age at menarche in girls. J Clin Endocrinol Metab 2012; 97:E786.
- Haning RV Jr, Hackett RJ, Flood CA, et al. Plasma dehydroepiandrosterone sulfate serves as a prehormone for 48% of follicular fluid testosterone during treatment with menotropins. J Clin Endocrinol Metab 1993; 76:1301.
- Paul SM, Purdy RH. Neuroactive steroids. FASEB J 1992; 6:2311.
- Asaba H, Hosoya K, Takanaga H, et al. Blood-brain barrier is involved in the efflux transport of a neuroactive steroid, dehydroepiandrosterone sulfate, via organic anion transporting polypeptide 2. J Neurochem 2000; 75:1907.
- Campbell BC. Adrenarche and middle childhood. Hum Nat 2011; 22:327.
- Del Giudice M. Sex, attachment, and the development of reproductive strategies. Behav Brain Sci 2009; 32:1.
- Herdt G, McClintock M. The magical age of 10. Arch Sex Behav 2000; 29:587.
- Brooke AM, Kalingag LA, Miraki-Moud F, et al. Dehydroepiandrosterone improves psychological well-being in male and female hypopituitary patients on maintenance growth hormone replacement. J Clin Endocrinol Metab 2006; 91:3773.
- Mortola JF, Yen SS. The effects of oral dehydroepiandrosterone on endocrine-metabolic parameters in postmenopausal women. J Clin Endocrinol Metab 1990; 71:696.
- Nair KS, Rizza RA, O'Brien P, et al. DHEA in elderly women and DHEA or testosterone in elderly men. N Engl J Med 2006; 355:1647.
- Davis SR, Panjari M, Stanczyk FZ. Clinical review: DHEA replacement for postmenopausal women. J Clin Endocrinol Metab 2011; 96:1642.