Adrenarche: Physiology, Biochemistry and Human Disease

Richard J. Auchus; William E. Rainey

Disclosures

Clin Endocrinol. 2004;60(3) 

In This Article

Adrenarche in Human Physiology

Body hair growth can be dichotomized as androgen-independent (head, lower arms and legs) or androgen-dependent (face, chest, groin, axilla). The androgen-dependent regions vary in their sensitivity to androgens, with the axillary and pubic hair being the most sensitive. Peripheral conversion of adrenal DHEA-S to testosterone and then to dihydrotestosterone is sufficient to stimulate some axillary and pubic hair growth in most children of either sex, and this early androgen-dependent hair growth is a nearly universal clinical manifestation of adrenarche. Local production of these androgens also stimulates the development of apocrine glands within this skin, which can lead to body odour. Conversion of DHEA to active androgens within sebaceous glands can also lead to acne in some children.

The developmental and age-related changes in DHEA-S are not paralleled by any of the major adrenal or gonadal steroids (Fig. 1). Robust production of DHEA-S by the foetal adrenal glands fuels the dramatic rise in oestrogens that proceeds through normal pregnancies, and DHEA-S concentrations are high in the newborn (Yuen & Mincey, 1987). By age 1, the foetal adrenal is replaced by the definitive adrenal cortex, which initially makes little DHEA-S. Hence, DHEA-S production declines precipitously during the first months of life and remains low until adrenarche commences at about age 6 (dePeretti & Forest, 1976). This rise in the circulating concentrations of DHEA and DHEA-S is the biochemical hallmark of adrenarche (Smith et al., 1975). Importantly, the rise in DHEA-S occurs prior to the increase of either oestrogens or androgens associated with puberty (Ducharme et al., 1976). Circulating DHEA-S concentrations continue to rise and peak during the second decade of life, with levels being higher in males than in females (Smith et al., 1975; Orentreich et al., 1984). While circulating concentrations of DHEA and DHEA-S rise progressively, cortisol and ACTH concentrations do not change significantly, indicating that adrenarche is not simply a global activation of the pituitary-adrenal axis.

Variation in circulating dehydroepiandrosterone sulphate (DHEA-S) concentrations throughout human life. DHEA-S concentrations in the foetal circulation rise progressively to reach a peak at term; following birth, there is a rapid decline. At about 6 years of age, DHEA-S concentrations rise again (adrenarche) and reach a peak during early adulthood, declining thereafter in a process often called adrenopause.

Some adrenal DHEA-S must be converted to dihydrotestosterone to yield axillary and pubic hair growth; however, circulating concentrations of active androgens rise little during adrenarche. This discrepancy is a consequence of both the capacity of peripheral and target tissues to metabolize DHEA and the exquisite sensitivity of the skin in these regions to androgens. Expression of the enzymes that can effectively convert DHEA to dihydrotestosterone has been studied in the hair follicle and dermal exocrine glands, indicating that it is the local conversion of DHEA that is important for pubarche (Hay & Hodgins, 1978; Sato et al., 1998; Labrie et al., 2000).

Adrenarche occurs independently of gonads and of puberty such that even children with gonadal dysgenesis and hypothalamic hypogonadism undergo adrenarche (Sklar et al., 1980). By analogy to the release of gonadotrophins as the initiator of puberty, it was long thought that a pituitary hormone, possibly a fragment of the proopiomelanocortin (POMC) molecule, was the initiator of adrenarche (Parker & Odell, 1979), but work in model systems has not supported this theory (Mellon et al., 1991; Penhoat et al., 1991). While the role of novel POMC-derived peptides remains questionable, ACTH is needed for normal adrenarche to occur, as is illustrated in patients with familial glucocorticoid deficiency with mutations in the melanocortin type 2 receptor (MC2R, ACTH receptor) (Weber et al., 1997). This observation, considered with the fact that circulating ACTH concentrations do not rise during the process of adrenarche, support the hypothesis that ACTH plays a permissive but not a causative role in adrenarche. A role for corticotrophin releasing hormone (CRH) has also been proposed in the regulation of DHEA production, particularly in the human foetal adrenal (Smith et al., 1998). Infusion of CRH into adolescent girls and young adults acutely activates adrenal C19 steroid production (Ibanez et al., 1999a,b), but the interpretation of these in vivo studies with CRH is problematic due to concomitant stimulation of ACTH secretion. More recently, candidate hormones related to body mass, such as insulin and leptin, have been suggested as the triggers of adrenal growth and adrenarche (Biason-Lauber et al., 2000). The existing evidence suggests that these hormones may modify the onset and rate of progression through adrenarche, but no single factor has been proven to be the proximal signal solely responsible for the onset of adrenarche.

Foetal adrenal production of DHEA-S is high due to the presence of a specialized 'foetal' zone that appears to be unique to primates. With the postnatal involution of the foetal zone there is a drop in DHEA-S production (Fig. 1). In these preadrenarchal infants, there is a poorly developed adrenal reticularis that does not express the enzymes needed to maintain high levels of DHEA-S production (Dhom, 1973; Suzuki et al., 2000). Dhom (1973) observed that children at about age 3 had adrenals with only focal islands of zona reticularis, while a continuous reticularis did not begin until age 6, coinciding with detectable increases in circulating DHEA-S. This expansion of the zona reticularis is also manifest by the differential expression of steroid-metabolizing enzymes compared to the adjacent fasciculata (Fig. 2). A recent longitudinal study of children proceeding through adrenarche while under gonadal suppression suggested that adrenal steroid production may be modified as early as 3 years of age (Palmert et al., 2001), supporting the idea that there is a slowly progressive 'emergence' of a functional reticularis.

Expression pattern for cytochrome b5, DHEA-sulphotransferase (SULT2A1) and 3β-hydroxysteroid dehydrogenase type 2 (3βHSD) in adrenal glands at the time of adrenarche. (a) Immunohistochemistry for cytochrome b5 in the adrenal at age 8·4 years, demonstrating marked expression in the zona reticularis but limited expression in the zona fasciculata. (b) Immunohistochemistry for SULT2A1 in an adrenal at age 8·4 years, showing selective expression in the zona reticularis. (c) Immunohistochemistry for 3βHSD in an adrenal gland at age 9 years. Immunoreactivity of 3βHSD was marked in the zona glomerulosa and fasciculata but was almost negative in the zona reticularis. Reproduced, with permission, from Clinical Endocrinology (Suzuki et al., 2000).

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