- Robert L Rosenfield, MD
Robert L Rosenfield, MD
- Professor Emeritus of Pediatrics and Medicine
- Pritzker School of Medicine of the University of Chicago
Adrenarche is the term for the maturational increase in adrenal androgen production that normally 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 with rare exceptions to a few higher primates [5-8]. (See 'Clinical manifestations of adrenarche' below.)
Premature adrenarche is an incomplete, benign, slowly progressive form of premature puberty that is usually a common extreme variant of normal development. However, it may be a risk factor for a future hyperandrogenic disorder. 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 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 (DHEAS) becomes the predominant 17-ketosteroid in blood and main marker of adrenarche.
These adrenarchal changes are ACTH-dependent [9,10], ie, they are not manifest in the absence of ACTH. They are caused by changes in response to ACTH rather than a change in ACTH secretion. This pattern of androgen production differs from that caused by excessive ACTH stimulation in the preadrenarchal child, in whom androstenedione becomes relatively prominent . After adrenarche, adrenal androgens are more sensitive than cortisol to suppression by glucocorticoid administration, providing further evidence that these hormones are differentially ACTH-responsive [12,13].
Anatomic site and mechanism of biochemical changes — The zona reticularis of the adrenal cortex is a major source of the adrenarchal steroids (figure 3) [3,5,14,15]. The increased synthesis of 17-hydroxypregnenolone, DHEA, and DHEAS during adrenarche occurs as a byproduct of ACTH stimulation of cortisol synthesis [9,10]. ACTH effects on adrenal androgen production are modulated by diverse signaling networks . Modulators of the androgenic response to ACTH include a stimulatory isoform of DENND1A (DENN/MADD domain-containing protein 1A; DENND1A.V2) that is known to be over-expressed in polycystic ovary syndrome theca cells, and BMP4 (bone morphogenetic protein type 4), which is inhibitory. Leptin, an adipocyte hormone, stimulates the 17,20-lyase activity of adrenocortical cells , which shunts adrenal steroidogenesis away from cortisol and toward DHEAS production. Interleukin-6, which stimulates ACTH secretion, is also strongly expressed in the zona reticularis of the adrenal cortex where it directly stimulates production of all classes of adrenal steroids independently of ACTH [18,19].
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