Version May 2024
INTRODUCTION — Adrenarche is the term for the maturational increase in adrenal androgen production that normally becomes biochemically apparent by a rise in serum levels of the 19-carbon (C19) 17-ketosteroid androgen precursor dehydroepiandrosterone sulfate (DHEAS) at approximately six years of age in both girls and boys (figure 1) [1-3]. It is characterized by production of increasing amounts of androgen precursors and smaller amounts of potent androgens (C19 17-beta-hydroxysteroids) by the zona reticularis of the adrenal cortex, which contribute to the development of pubic hair, sebaceous glands, and apocrine (sweat) glands.
Humans and some higher primates are unique in having an adrenal zone with such structure-function-developmental stage relationships [4-9]. In most children, the first appearance of pubic hair (pubarche) occurs shortly after other signs of pubertal development. In a minority of individuals, pubarche occurs before true puberty (eg, when adrenarche causes pubarche before true puberty begins [10] or in the presence of hypogonadism [1]). Thus, adrenarche is unrelated to the pubertal maturation of the hypothalamic-pituitary-gonadal axis.
Premature adrenarche is the most common cause of premature pubarche, defined as the isolated appearance of sexual hair before the age of eight years in girls and nine years in boys. This subject is discussed in detail in a separate topic review. (See "Premature adrenarche".)
PHYSIOLOGY
Overview — Adrenarche is the result of a developmental change in the pattern of adrenal secretory response to adrenocorticotropic hormone (ACTH) so that serum levels of dehydroepiandrosterone sulfate (DHEAS), 5-androstenediol-3-sulfate, and related 19-carbon (C19) steroids rise, while those of cortisol do not [1,11]. 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 C19 steroids (eg, dehydroepiandrosterone [DHEA]) secretion.
●During adrenarche, the secretory pattern in response to ACTH gradually changes (figure 2) [11]:
•ACTH stimulates secretion of DHEAS and DHEA, their delta-5-steroid precursors (eg, 17-hydroxypregnenolone), and product 5-androstenediol more than it stimulates secretion of testosterone and its delta-4-steroid precursors (eg, 17-hydroxyprogesterone and androstenedione). Meanwhile, cortisol serum levels remain stable (figure 3). In contrast, ACTH stimulation in the preadrenarchal child causes a different adrenal androgen secretory pattern, with a relative predominance of androstenedione over DHEA [12].
•DHEA is sulfated, predominantly within the zona reticularis, to form DHEAS. As a result, DHEAS becomes the predominant 17-ketosteroid in blood and main marker of adrenarche.
•Serum levels of androstenedione and testosterone increase slightly, so that they normally hover near the upper end of the prepubertal range during the early adrenarchal years (six to eight years of age).
These adrenarchal changes are ACTH dependent [11,13]; they recede when ACTH is suppressed (eg, by glucocorticoid therapy) [14,15]. However, they are not due to a change in ACTH secretion; rather, the increase in adrenal C19 steroid production reflects a qualitative change in the adrenal response to ACTH due to the development of the zona reticularis. The changes in the zona reticularis with normal growth and development are summarized in the figure (figure 4) [16].
Differentiation of the adrenal zona reticularis — The zona reticularis is the source of adrenarchal steroids (figure 3) [16,17].
Adrenocortical stem and progenitor cells appear to be located in the capsular and subcapsular (outer zona glomerulosa) regions of the adrenal cortex, and daughter cells then proliferate toward the corticomedullary junction to establish the zones of the definitive adrenal cortex [8,16]. This development is initiated by a number of interactions involving differentiation and transcription factors that are critical for the formation of the zona glomerulosa. ACTH signaling via melanocortin receptor 2 and protein kinase A is critical for differentiation of the zona fasciculata and zona reticularis from precursor cells in the zona glomerulosa [8,13,16,18]. Low cholesterol concentrations in the zona reticularis appear to contribute to its biochemical phenotype [19].
The zona reticularis begins to form in the central adrenal cortex at three to four years of age. It appears in the site of the former fetal zone of the adrenal cortex, which it resembles in its DHEAS production, but develops from a cell type that is distinct from that of the fetal zone. During the preschool years, it continues to develop into a continuous zone, in which zona reticularis cells then proliferate as children grow [20] and adrenal androgen production subtly increases [21]. By six years of age, the adrenarchal increase in serum DHEAS is detectable by immunoassay (table 1). At a younger age, a small increase in serum DHEAS is detectable by liquid chromatography-tandem mass spectrometry [21] and a significant increase of DHEAS and its metabolites is detectable in urine [22].
Centripetal migration of proliferating precursor cells contributes to the enlargement of the zona reticularis [20]. By early adulthood, the cell proliferation wanes [20]. After 40 years of age, zona reticularis cell senescence predominates and the zone partially involutes, with consequent decreases in adrenal-derived production of DHEAS, DHEAS precursors, androstenedione, and testosterone [23,24].
Regulation of zona reticularis/adrenarchal growth, development, and function — ACTH signaling is critical for the maintenance and function of the zona reticularis. Accordingly, ACTH deficiency reverses adrenarchal steroid secretion [25,26]. As an example, DHEA and DHEAS secretion declines rapidly after ACTH withdrawal (eg, due to glucocorticoid therapy) and is slow to resume after ACTH signaling is restored [26].
ACTH effects on adrenal androgen production are modulated by diverse signaling networks [27,28]. 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 overexpressed in theca cells in the setting of polycystic ovary syndrome. In addition, bone morphogenetic protein type 4 has an inhibitory influence. 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 [29,30]. Insulin and insulin-like growth factor 1 (IGF-1) stimulate expression of adrenal P450c17 and 3-beta-hydroxysteroid dehydrogenase type 2 activities [31-33]. Leptin, an adipocyte hormone, stimulates the 17,20-lyase activity of adrenocortical cells [34].
Prolactin may regulate the growth and function of the zona reticularis. This possibility is supported by the observation that adrenarche is severely attenuated in congenital pituitary disorders in which there is prolactin, but not ACTH, deficiency [35,36]. Conversely, hyperprolactinemia is accompanied by adrenal androgen excess [37]. These considerations suggest that an interaction between prolactin and ACTH amplifies adrenarche.
Postnatal body growth is related to adrenarche [38-40]. Nutritional status, in particular, seems to play a role in adrenarchal development, particularly in girls [39,41]. Obesity, particularly commencing with early childhood rapid weight gain, is associated with increased DHEAS levels in normal children [42,43]. Insulin, IGF-1, and leptin may mediate this relationship [33,34,39].
In contrast with postnatal growth, birth weight is inversely associated with adrenarchal DHEAS levels. Infants born small for gestational age have increased DHEAS levels at five to eight years of age, independent of obesity status. Conversely, children born large for gestational age have lower adrenarchal DHEAS levels than those with normal birth weight [42,44].
Ovarian function affects zona reticularis growth and DHEAS levels through unclear mechanisms. Puberty is associated with earlier expansion of the zona reticularis in females compared with males [20]. Ovariectomy precipitates an early decline in DHEAS levels that is unrelated to estrogenic status [45]. Paradoxically, primary ovarian failure is associated with an earlier rise in DHEAS levels (although later pubarche) [46]. The 50 percent higher serum DHEAS levels of men than women [3] seem explicable by higher testicular than ovarian secretion of DHEA, which is peripherally converted to DHEAS [47,48].
Basis of the biochemical changes of adrenarche — The adrenarchal pattern of adrenal secretion in response to ACTH results from a unique steroidogenic enzyme expression profile in the zona reticularis that develops in mid-childhood (figure 3) [28].
Beginning at approximately four to five years of age, zona reticularis cells express decreasing levels of 3-beta-hydroxysteroid dehydrogenase type 2 (encoded by HSD3B2) but increasing levels of cytochrome b5 (encoded by CYB5A) and steroid sulfotransferase 2A1 [49,50], which promote DHEAS formation as follows:
●Low activity of 3-beta-hydroxysteroid dehydrogenase type 2 in the zona reticularis is associated with poor production of cortisol and other delta-4-steroids (eg, androstenedione and testosterone) in favor of formation of DHEAS and other delta-5-steroids (eg, DHEA, 17-hydroxypregnenolone, and pregnenolone). This enzyme activity is low in part because of low HSD3B2 gene expression [49,51] and in part because enzyme activity undergoes end-product inhibition in a dose-related manner, particularly by cortisol [38]. High fatty acid levels also seem to inhibit activity of this enzyme [52].
●Increased 17,20-lyase activity of cytochrome P450c17 in the zona reticularis also contributes to the adrenarchal changes [51]. Cytochrome P450c17 has two actions. The first is 17-alpha-hydroxylase activity, which catalyzes the conversion of pregnenolone to 17-hydroxypregnenolone (an essential precursor of both cortisol and sex steroids). The second is 17,20-lyase activity, which preferentially converts 17-hydroxypregnenolone (a C21 steroid) to DHEA (a C19 steroid) (figure 3) [17]. Preferential expression of CYB5A in the zona reticularis catalyzes this enhancement of lyase activity of P450c17. (See "Adrenal steroid biosynthesis".)
●The above factors favor the formation of DHEA from 17-hydroxypregnenolone by the zona reticularis. Meanwhile, preferential expression of steroid sulfotransferase 2A1 in this zone then converts DHEA to the relatively inert DHEAS, which acts to "trap" it and thus to direct steroidogenesis to this terminal product and to prevent DHEA from being converted into more biologically active androgens [28].
At approximately nine years of age, zona reticularis cells also increasingly express 17-beta-hydroxysteroid dehydrogenase type 5 (encoded by the aldo-keto reductase gene [AKR1C3]) [20,53]. This enzyme appears to account for the small amount of adrenal testosterone secretion [53]. Testosterone and androstenedione are further metabolized within the zona reticularis by 11-beta-hydroxylase (encoded by CYP11B1), which underlies robust adrenal 11-beta-hydroxyandrostenedione and much lesser 11-beta-hydroxytestosterone secretion [54]. Small amounts of estrone are also formed by aromatase (CYP19A1) in the zona reticularis [54,55].
Contribution of adrenarchal hormones to bioactive androgens — The large quantities of C19 steroids, mostly 17-ketosteroid prohormones, secreted by the mature adrenal gland are, to a small extent, converted to more androgenic hormones in the peripheral circulation:
●Testosterone – Approximately one-quarter of the serum testosterone of adult women arises by adrenal testosterone secretion and one-quarter by peripheral conversion of adrenal androstenedione; the remainder arises from the ovary [28].
●11-beta-hydroxyandrostenedione – In the zona reticularis, 11-beta-hydroxylase type 1 efficiently metabolizes androstenedione to 11-beta-hydroxyandrostenedione.
●11-ketoandrostenedione – In the kidney, 11-beta-hydroxyandrostenedione is converted to 11-ketoandrostenedione by 11-beta-hydroxysteroid dehydrogenase type 2 (encoded by HSD11B2).
●11-ketotestosterone – In fat and other peripheral tissues, 11-ketoandrostenetione is efficiently reduced to 11-beta-hydroxytestosterone by 17-beta-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) [56].
●11-beta-hydroxysterosterone – A small amount of 11-beta-hydroxytestosterone, which has weak androgenic activity, is also generated either in the adrenal zona reticularis through 11-beta-hydroxylation of testosterone (by 11-beta-hydroxylase type 1) or more so in extra-adrenal tissues (liver, fat, etc) through reduction of 11-ketotestosterone via 11-beta-hydroxysteroid dehydrogenase type 1.
11-ketotestosterone predominates nearly threefold over testosterone in the serum of healthy young adrenarchal children [57]. 11-ketotestosterone has 33 to 101 percent of the androgenic biopotency of testosterone at physiologic concentrations [54,58]. Thus, 11-ketotestosterone contributes at least as much to serum androgenic bioactivity as testosterone during adrenarche.
Androgen action is often exerted by intracrine effects (ie, conversion to a more bioactive form in target organs). Testosterone is converted to dihydrotestosterone, which is approximately tenfold more potent in activating the androgen receptor, in androgen target organs by 5-alpha-reductase [17]. Although DHEAS is incapable of activating the androgen receptor, androgen-responsive skin expresses all of the enzymes necessary to convert DHEAS to dihydrotestosterone. This is particularly seen in the sebaceous gland, which has high 3-beta-hydroxysteroid dehydrogenase activity [59].
CLINICAL MANIFESTATIONS OF ADRENARCHE — Adrenarchal androgens contribute to the appearance of pubic hair (pubarche) and sebaceous gland and apocrine (sweat) gland development. Androgens are a prerequisite for the growth and development of the pilosebaceous unit (PSU) in "sexual" areas of skin [59,60]. Before puberty, the androgen-dependent PSU consists of a prepubertal vellus follicle in which the hair and sebaceous gland components are virtually invisible to the naked eye. When exposed to increasing androgen levels, the PSUs of sexual hair areas progressively switch to production of a thicker type of terminal hair follicle. In acne-prone areas, androgen causes the prepubertal vellus follicle to develop into a sebaceous gland.
These changes in the PSU lead to the following clinical manifestations of adrenarche:
●Skin – Adrenarchal androgen action on sebaceous glands is first manifested clinically as microcomedonal acne, which is the basis of the change in facial complexion that occurs in mid-childhood.
●Apocrine glands – Adrenarchal androgen action on apocrine glands is manifested as adult-type body odor.
●Pubarche – Pubic hair normally begins after eight years of age in girls and nine years in boys. Axillary hair ordinarily follows when androgen levels become slightly higher but occasionally precedes pubic hair development. Pubarche before eight years of age in girls and nine years in boys is the primary manifestation of premature adrenarche. (See "Premature adrenarche".)
●Other – Other effects of adrenarche have been suggested but are not established:
•Puberty – Adrenarchal androgens may play a role in advancing the onset of puberty. Higher urinary excretion of dehydroepiandrosterone sulfate (DHEAS) and related 19-carbon (C19) steroids one to two years before puberty correlates with earlier onset of puberty [61]. Mid-childhood DHEAS levels are associated with earlier age of menarche independent of insulin-like growth factor 1 (IGF-1) and body mass index [62].
•Bone health – Adrenal androgens may promote bone mineral density and strength in children, as suggested by correlations between adrenal androgen levels and bone mineral parameters [63].
•Lipids – The data regarding a possible effect of the DHEAS elevation in obesity on serum lipids have led to conflicting conclusions [41,64].
•Neurobiologic development – Other observations suggest that adrenarchal steroids might play a role in human neurobiologic development. Serum levels of dehydroepiandrosterone (DHEA) and testosterone differentially correlate with specific structural developmental changes in the cerebral corticolimbic system [65]. DHEAS and its precursor, pregnenolone sulfate, as well as the progesterone metabolite, allopregnanolone, have direct nongenomic neuroactive effects, which include modulation of neurotransmitter signaling and neuroplasticity [2,66,67]. These steroid sulfates are actively transported across the blood-brain barrier [68]. The association of adrenarchal changes with the emergence of sexually dimorphic sexual attraction and stress-adaptive and social maturational behavior during middle childhood, prior to true puberty, has led to the suggestion that adrenarchal steroids play a role in activating these behaviors [69-71].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Normal puberty and puberty-related disorders".)
SUMMARY
●Clinical context – Adrenarche is the maturational increase in adrenal androgens that is indexed by a rise in serum dehydroepiandrosterone sulfate (DHEAS) that becomes measurable by radioimmunoassay at approximately six years of age and earlier by liquid chromatography-tandem mass spectrometry. The clinical manifestations of adrenarche usually occur shortly after puberty begins but occasionally precede puberty because the processes are independent. (See 'Introduction' above.)
●Physiology – The biochemical changes of adrenarche result from qualitative changes in the secretory response to adrenocorticotropic hormone (ACTH) due to the development of the zona reticularis (figure 4). (See 'Physiology' above.)
•After adrenarche, ACTH causes a disproportionate rise in serum dehydroepiandrosterone (DHEA) and its delta-5-3-beta-hydroxysteroid precursors (eg, 17-hydroxypregnenolone) relative to serum testosterone, androstenedione, and their delta-4-3-ketosteroid precursors (eg, 17-hydroxyprogesterone and androstenedione). Conversely, suppression of ACTH by glucocorticoid administration disproportionately suppresses DHEAS more than cortisol. (See 'Overview' above.)
•ACTH signaling is necessary for the development of the zona fasciculata and zona reticularis and for their steroid secretions. Birth weight is inversely related to adrenarchal development. Postnatal body growth, obesity, and prolactin are positively related to adrenarchal development. (See 'Regulation of zona reticularis/adrenarchal growth, development, and function' above.)
•These changes are related to the development of the zona reticularis and its unique steroidogenic enzyme expression pattern of low 3-beta-hydroxysteroid dehydrogenase type 2 (encoded by HSD3B2) with high cytochrome b5 (encoded by CYB5A), sulfotransferase 2A1 (encoded by SULT2A1), and increased 17-beta-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3). (See 'Basis of the biochemical changes of adrenarche' above.)
•The 11-oxygenated 19-carbon (C19) steroids, particularly 11-beta-hydroxyandrostenedione and its active metabolite 11-ketotestosterone, have been identified as adrenarchal steroids. 11-ketotestosterone contributes at least as much to serum androgenic bioactivity as testosterone in young adrenarchal children. (See 'Contribution of adrenarchal hormones to bioactive androgens' above.)
●Clinical manifestations – Adrenarchal androgens normally account for the mid-childhood development of sebaceous and apocrine gland development and contribute to the appearance of pubic hair (pubarche). It is less clear whether adrenarche contributes to increased bone mineral density and prepubertal behavior patterns. (See 'Clinical manifestations of adrenarche' above.)
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