- Robert L Rosenfield, MD
Robert L Rosenfield, MD
- Professor 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
- National Institute of Child Health and Human Development
- 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 that becomes biochemically apparent as a rise in dehydroepiandrosterone sulfate (DHEA-S) at about six years of age in both girls and boys (figure 1). It represents a gradual change in the pattern of adrenal secretory response to corticotropin (adrenocorticotropic hormone, ACTH), characterized by a disproportionate rise of 17-hydroxypregnenolone and dehydroepiandrosterone (DHEA) relative to cortisol. This change primarily occurs in the zona reticularis of the adrenal cortex, the cells of which express a unique pattern of steroidogenic enzymes that includes expression of sulfotransferase 2A1 (SULT2A1), which catalyzes the formation of DHEA-S, the major adrenarchal steroid (figure 2). (See "Normal adrenarche".)
The causes, diagnosis, and management of premature adrenarche will be reviewed here. It is useful, however, to begin with a review of definitions used to describe the various aspects of premature sexual development as they relate to adrenarche.
The definitions used to describe normal and premature puberty and pubarche are as follows:
Puberty — Puberty is the stage of development during which secondary sexual characteristics appear and there is a transition from the sexually immature to the sexually mature stage. True puberty results from activation of the hypothalamic-pituitary-gonadal (HPG) axis. Testicular enlargement is the usual first sign of gonadal activation (gonadarche) in boys, and breast development (thelarche) is the first sign in girls, with sexual hair development ordinarily occurring later. The physiology and clinical stages of puberty are discussed in a separate topic review. (See "Normal puberty".)
Premature puberty — The exact age at which puberty is abnormally early (precocious) is not well defined. In general, signs of secondary sexual development occurring before the age of eight years in girls and the age of nine years in boys are considered premature and warrant careful evaluation. This practice is supported by data in girls, though breast budding is normal during the seventh year in Black and Mexican-American girls , while good data are still lacking in boys . Gonadotropin-dependent precocious puberty (also termed "central," "true," or "complete" precocity) results from activation of the normal HPG axis. Gonadotropin-independent precocious puberty (also termed "peripheral" precocious puberty) results from excess exposure to androgens or estrogens derived from the gonads, adrenal glands, exogenous sources, or ectopic production of human chorionic gonadotropin (hCG) by a tumor. (See "Definition, etiology, and evaluation of precocious puberty".)
- Rosenfield RL, Lipton RB, Drum ML. Thelarche, pubarche, and menarche attainment in children with normal and elevated body mass index. Pediatrics 2009; 123:84.
- Bordini B, Rosenfield RL. Normal pubertal development: part II: clinical aspects of puberty. Pediatr Rev 2011; 32:281.
- Rosenfield RL. Clinical review: Identifying children at risk for polycystic ovary syndrome. J Clin Endocrinol Metab 2007; 92:787.
- Charkaluk ML, Trivin C, Brauner R. Premature pubarche as an indicator of how body weight influences the onset of adrenarche. Eur J Pediatr 2004; 163:89.
- Williams RM, Ward CE, Hughes IA. Premature adrenarche. Arch Dis Child 2012; 97:250.
- Herman-Giddens ME, Slora EJ, Wasserman RC, et al. 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.
- Utriainen P, Jääskeläinen J, Romppanen J, Voutilainen R. Childhood metabolic syndrome and its components in premature adrenarche. J Clin Endocrinol Metab 2007; 92:4282.
- Denburg MR, Silfen ME, Manibo AM, et al. Insulin sensitivity and the insulin-like growth factor system in prepubertal boys with premature adrenarche. J Clin Endocrinol Metab 2002; 87:5604.
- Kaplowitz P, Soldin SJ. Steroid profiles in serum by liquid chromatography-tandem mass spectrometry in infants with genital hair. J Pediatr Endocrinol Metab 2007; 20:597.
- Rich BH, Rosenfield RL, Lucky AW, et al. Adrenarche: changing adrenal response to adrenocorticotropin. J Clin Endocrinol Metab 1981; 52:1129.
- Rosenfield RL, Rich BH, Lucky AW. Adrenarche as a cause of benign pseudopuberty in boys. J Pediatr 1982; 101:1005.
- Idkowiak J, Lavery GG, Dhir V, et al. Premature adrenarche: novel lessons from early onset androgen excess. Eur J Endocrinol 2011; 165:189.
- Rosenfield RL. Ovarian and adrenal function in polycystic ovary syndrome. Endocrinol Metab Clin North Am 1999; 28:265.
- Utriainen P, Voutilainen R, Jääskeläinen J. Continuum of phenotypes and sympathoadrenal function in premature adrenarche. Eur J Endocrinol 2009; 160:657.
- Sopher AB, Thornton JC, Silfen ME, et al. Prepubertal girls with premature adrenarche have greater bone mineral content and density than controls. J Clin Endocrinol Metab 2001; 86:5269.
- Ibáñez L, Jiménez R, de Zegher F. Early puberty-menarche after precocious pubarche: relation to prenatal growth. Pediatrics 2006; 117:117.
- Oron T, Lebenthal Y, de Vries L, et al. Interrelationship of extent of precocious adrenarche in appropriate for gestational age girls with clinical outcome. J Pediatr 2012; 160:308.
- Rappaport R, Forest MG, Bayard F, et al. Plasma androgens and LH in scoliotic patients with premature pubarche. J Clin Endocrinol Metab 1974; 38:401.
- Neville KA, Walker JL. Precocious pubarche is associated with SGA, prematurity, weight gain, and obesity. Arch Dis Child 2005; 90:258.
- 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.
- von Oettingen J, Sola Pou J, Levitsky LL, Misra M. Clinical presentation of children with premature adrenarche. Clin Pediatr (Phila) 2012; 51:1140.
- Uçar A, Yackobovitch-Gavan M, Erol OB, et al. Associations of size at birth and postnatal catch-up growth status with clinical and biomedical characteristics in prepubertal girls with precocious adrenarche: preliminary results. J Clin Endocrinol Metab 2014; 99:2878.
- Paterson WF, Ahmed SF, Bath L, et al. Exaggerated adrenarche in a cohort of Scottish children: clinical features and biochemistry. Clin Endocrinol (Oxf) 2010; 72:496.
- Ibáñez 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.
- Nayak S, Lee PA, Witchel SF. Variants of the type II 3beta-hydroxysteroid dehydrogenase gene in children with premature pubic hair and hyperandrogenic adolescents. Mol Genet Metab 1998; 64:184.
- Witchel SF, Lee PA, Suda-Hartman M, Hoffman EP. Hyperandrogenism and manifesting heterozygotes for 21-hydroxylase deficiency. Biochem Mol Med 1997; 62:151.
- Zhou R, Bird IM, Dumesic DA, Abbott DH. Adrenal hyperandrogenism is induced by fetal androgen excess in a rhesus monkey model of polycystic ovary syndrome. J Clin Endocrinol Metab 2005; 90:6630.
- Deplewski D, Rosenfield RL. Role of hormones in pilosebaceous unit development. Endocr Rev 2000; 21:363.
- Rosenfield RL. Normal and almost normal precocious variations in pubertal development premature pubarche and premature thelarche revisited. Horm Res 1994; 41 Suppl 2:7.
- Vottero A, Capelletti M, Giuliodori S, et al. Decreased androgen receptor gene methylation in premature pubarche: a novel pathogenetic mechanism? J Clin Endocrinol Metab 2006; 91:968.
- Lappalainen S, Utriainen P, Kuulasmaa T, et al. Androgen receptor gene CAG repeat polymorphism and X-chromosome inactivation in children with premature adrenarche. J Clin Endocrinol Metab 2008; 93:1304.
- Bordini B, Littlejohn E, Rosenfield RL. LH Dynamics in Overweight Girls with Premature Adrenarche and Slowly Progressive Sexual Precocity. Int J Pediatr Endocrinol 2010; 2010.
- Rosenfeld RG, Reitz RE, King AB, Hintz RL. Familial precocious puberty associated with isolated elevation of luteinizing hormone. N Engl J Med 1980; 303:859.
- Joehrer K, Geley S, Strasser-Wozak EM, et al. CYP11B1 mutations causing non-classic adrenal hyperplasia due to 11 beta-hydroxylase deficiency. Hum Mol Genet 1997; 6:1829.
- Tonetto-Fernandes V, Lemos-Marini SH, Kuperman H, et al. Serum 21-Deoxycortisol, 17-Hydroxyprogesterone, and 11-deoxycortisol in classic congenital adrenal hyperplasia: clinical and hormonal correlations and identification of patients with 11beta-hydroxylase deficiency among a large group with alleged 21-hydroxylase deficiency. J Clin Endocrinol Metab 2006; 91:2179.
- Charmandari E, Kino T, Ichijo T, Chrousos GP. Generalized glucocorticoid resistance: clinical aspects, molecular mechanisms, and implications of a rare genetic disorder. J Clin Endocrinol Metab 2008; 93:1563.
- Lawson AJ, Walker EA, Lavery GG, et al. Cortisone-reductase deficiency associated with heterozygous mutations in 11beta-hydroxysteroid dehydrogenase type 1. Proc Natl Acad Sci U S A 2011; 108:4111.
- Lavery GG, Idkowiak J, Sherlock M, et al. Novel H6PDH mutations in two girls with premature adrenarche: 'apparent' and 'true' CRD can be differentiated by urinary steroid profiling. Eur J Endocrinol 2013; 168:K19.
- Noordam C, Dhir V, McNelis JC, et al. Inactivating PAPSS2 mutations in a patient with premature pubarche. N Engl J Med 2009; 360:2310.
- Oostdijk W, Idkowiak J, Mueller JW, et al. PAPSS2 deficiency causes androgen excess via impaired DHEA sulfation--in vitro and in vivo studies in a family harboring two novel PAPSS2 mutations. J Clin Endocrinol Metab 2015; 100:E672.
- Kunz GJ, Klein KO, Clemons RD, et al. Virilization of young children after topical androgen use by their parents. Pediatrics 2004; 114:282.
- Bas S, Guran T, Atay Z, et al. Premature pubarche, hyperinsulinemia and hypothyroxinemia: novel manifestations of congenital portosystemic shunts (abernethy malformation) in children. Horm Res Paediatr 2015; 83:282.
- Kreiter M, Burstein S, Rosenfield RL, et al. Preserving adult height potential in girls with idiopathic true precocious puberty. J Pediatr 1990; 117:364.
- Speiser PW, Dupont B, Rubinstein P, et al. High frequency of nonclassical steroid 21-hydroxylase deficiency. Am J Hum Genet 1985; 37:650.
- Armengaud JB, Charkaluk ML, Trivin C, et al. Precocious pubarche: distinguishing late-onset congenital adrenal hyperplasia from premature adrenarche. J Clin Endocrinol Metab 2009; 94:2835.
- Rosenfield RL, Lucky AW. Acne, hirsutism, and alopecia in adolescent girls. Clinical expressions of androgen excess. Endocrinol Metab Clin North Am 1993; 22:507.
- Bidet M, Bellanné-Chantelot C, Galand-Portier MB, et al. Clinical and molecular characterization of a cohort of 161 unrelated women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency and 330 family members. J Clin Endocrinol Metab 2009; 94:1570.
- Escobar-Morreale HF, Sanchón R, San Millán JL. A prospective study of the prevalence of nonclassical congenital adrenal hyperplasia among women presenting with hyperandrogenic symptoms and signs. J Clin Endocrinol Metab 2008; 93:527.
- Livadas S, Dracopoulou M, Dastamani A, et al. The spectrum of clinical, hormonal and molecular findings in 280 individuals with nonclassical congenital adrenal hyperplasia caused by mutations of the CYP21A2 gene. Clin Endocrinol (Oxf) 2015; 82:543.
- Lutfallah C, Wang W, Mason JI, et al. Newly proposed hormonal criteria via genotypic proof for type II 3beta-hydroxysteroid dehydrogenase deficiency. J Clin Endocrinol Metab 2002; 87:2611.
- Rosenfield RL, Cohen RM, Talerman A. Lipid cell tumor of the ovary in reference to adult-onset congenital adrenal hyperplasia and polycystic ovary syndrome. A case report. J Reprod Med 1987; 32:363.
- Rosner W, Auchus RJ, Azziz R, et al. Position statement: Utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement. J Clin Endocrinol Metab 2007; 92:405.
- Abraham GE. Ovarian and adrenal contribution to peripheral androgens during the menstrual cycle. J Clin Endocrinol Metab 1974; 39:340.
- Rosenfeld RS, Rosenberg BJ, Fukushima DK, Hellman L. 24-Hour secretory pattern of dehydroisoandrosterone and dehydroisoandrosterone sulfate. J Clin Endocrinol Metab 1975; 40:850.
- Balassy C, Navarro OM, Daneman A. Adrenal masses in children. Radiol Clin North Am 2011; 49:711.
- Shah RU, Lawrence C, Fickenscher KA, et al. Imaging of pediatric pelvic neoplasms. Radiol Clin North Am 2011; 49:729.
- Pascale MM, Pugeat M, Roberts M, et al. Androgen suppressive effect of GnRH agonist in ovarian hyperthecosis and virilizing tumours. Clin Endocrinol (Oxf) 1994; 41:571.
- Sontag-Padilla LM, Dorn LD, Tissot A, et al. Executive functioning, cortisol reactivity, and symptoms of psychopathology in girls with premature adrenarche. Dev Psychopathol 2012; 24:211.
- Premature puberty
- Premature pubarche
- Premature adrenarche
- Exaggerated adrenarche
- DIFFERENTIAL DIAGNOSIS OF PREMATURE PUBARCHE
- Idiopathic premature pubarche
- Gonadotropin-dependent precocious puberty
- Virilizing disorders
- - Virilizing congenital adrenal hyperplasia
- - Related congenital ACTH-dependent forms of adrenal hyperandrogenism
- - Cushing's syndrome
- - Virilizing tumors
- - Exogenous androgen exposure
- - Peripheral androgen metabolic disorder
- EVALUATION OF PREMATURE PUBARCHE
- History and physical examination
- Bone age
- Hormonal measurements
- ACTH stimulation test
- Dexamethasone androgen-suppression test
- MANAGEMENT OF PREMATURE ADRENARCHE
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS