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133 THEMATIC REVIEW

The metabolome of

Juilee Rege and William E Rainey Department of Physiology, Georgia Health Sciences University, 1120 15th Street, Augusta, Georgia 30912, USA (Correspondence should be addressed to W E Rainey; Email: [email protected])

Abstract

Adrenarche is an endocrine developmental process whereby the biochemical pathways leading to this event have been humans and select nonhuman primates increase adrenal elucidated in detail. There are numerous reviews examining output of a series of , especially DHEA and the process of adrenarche, most of which have focused on DHEAS. The timing of adrenarche varies among primates, the changes within the adrenal as well as the phenotypic but in humans serum levels of DHEAS are seen to increase results of adrenarche. This article reviews the recent and at around 6 years of age. This phenomenon corresponds past studies that show the breadth of changes in the with the development and expansion of the zona reticularis of circulating steroid metabolome that occur during the process the . The physiological phenomena that trigger of adrenarche. the onset of adrenarche are still unknown; however, Journal of Endocrinology (2012) 214, 133–143

Introduction adrenarche, most of which have focused on the adrenarche- associated changes in adrenal steroidogenic enzymes and The human adrenal produces large quantities of the differentiation (Cutler & Loriaux 1980, Parker 1991, Auchus 19-carbon (C19) steroids DHEA and DHEAS during fetal & Rainey 2004, Havelock et al. 2004, Miller 2009, Nakamura development, but the production of these steroids falls rapidly et al. 2009a). Herein, we have reviewed the recent and past after birth and remains low for the first few years of life. studies that show the breadth of changes in the circulating Adrenarche refers to the re-emergence of adrenal C19 steroid steroid metabolome that occur during the process of production at around 6 years of age that results from the adrenarche. expansion and differentiation of the adrenal zona reticularis (ZR; Cutler & Loriaux 1980, Miller 1988, 2009, Parker 1991, Auchus & Rainey 2004; Fig. 1). Neither DHEA nor C steroids and adrenal morphology DHEAS are bioactive , but they act as precursors for 19 production of more potent androgens including While most of our focus will be placed on the adrenarchal rise in peripheral tissues that include hair follicles, genital , and in adrenal production of C19 steroids, it should be noted that (Kaufman et al. 1990, Rosenfield 2005, Pelletier during development the fetal adrenal produces large amounts 2008; Fig. 2). The initiation of -dependent growth of DHEAS. During this period, C19 steroids arise from a of axillary and (pubarche) is the phenotypic developmental specific fetal zone that comprises 80% of the hallmark of adrenarche (Ducharme et al. 1976, Auchus & fetal adrenal. Till birth, the fetal zone continues to secrete Rainey 2004, Havelock et al. 2004). The peripherally dramatic quantities of the C19 steroid DHEAS, which is used converted bioactive androgens also stimulate the development by the placenta for production of remarkably large amounts of of apocrine glands in the skin to produce characteristic adult- during pregnancy (Siiteri & MacDonald 1963, type body odor and can act on the sebaceous glands leading Frandsen & Stakemann 1964, Bolte et al. 1966). to signs of (Rosenfield & Lucky 1993, Zouboulis et al. After birth, there is a dramatic involution of the fetal zone, 2007). There are numerous reviews examining the process of which accounts for the sharp decline in DHEAS synthesis in the first few months of life (Fig. 1). The levels of DHEAS This paper is one of three papers that form part of a thematic review remain low until adrenarche commences as a result of the section on Adrenarche. The Guest Editor for this section was Ian Bird, expansion of the ZR (Dhom 1973, Suzuki et al. 2000, Hui University of Wisconsin, USA. et al. 2009). This phenomenon was first described and given

Journal of Endocrinology (2012) 214, 133–143 DOI: 10.1530/JOE-12-0183 0022–0795/12/0214–133 q 2012 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org

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160 500 expression of key steroidogenic enzymes. The pathway Serum DHEA and DHEAS 140 450 leading to the synthesis of DHEAS is quite simple and levels across adrenarche 400 120 350 requires only three steroidogenic enzymes. However, across 100 300 the period of adrenarche there are changes in the expression 80 250 pattern of the steroidogenic enzymes and cofactors that 60 200 150 facilitates C19 steroid production (Fig. 4A). Immunohisto-

40 DHEA (ng/dL) DHEAS (µg/dL) 100 chemistry studies have demonstrated the varied expression 20 50 0 0 of key steroidogenic enzymes within the cortical zones (Gell 0 1 23456 7 8 9 10 11 12 13 14 15 et al. 1996, 1998, Suzuki et al. 2000, Hui et al. 2009). Age (years) The initial conversion of to is an Figure 1 Serum DHEA and DHEAS levels before and after the onset essential step in all steroidogenic organs and is accomplished of human adrenarche. Based on steroid levels from de Peretti & by the enzyme cytochrome P450 cholesterol side-chain Forest (1976, 1978). cleavage (CYP11A1). This enzyme is expressed in all zones of the adrenal and the expression pattern within the ZR does not change during adrenarche (Nakamura et al. 2009a). the name adrenarche by Albright et al. (1942) when they CYP17A1, a single steroidogenic enzyme localized in the observed the growth of axillary and pubic hair in the absence endoplasmic reticulum, is necessary for production of both of gonadal androgens due to congenital absence or and DHEA as it catalyzes two biosynthetic activities: malformation of ovaries. Dhom (1973) characterized the 17a-hydroxylase and 17,20-lyase (Yanase et al. 1991, Imai morphological changes that occurred in the prepubertal and et al. 1993, Brock & Waterman 1999). Thus, this enzyme is pubertal adrenal. According to this study, the needed for both ZF and ZR functions. However, Suzuki et al. of the infant shows distinct zona glomurerulosa (ZG) and (2000) reported changes in expression of CYP17A1 in the zona fasciculata (ZF) with little ZR. However, in the adrenals adrenal ZF and ZR of pre-adrenarche vs post-adrenarche of children around age 3 years, focal islands of ZR appear, children. Their semiquantitative immunohistochemical which expand at age 4–5 years (Dhom 1973, Hui et al. 2009). analysis showed that after age 5 years, the CYP17A1 protein A continuous layer of ‘functional’ ZR is first seen at age 6, appeared to increase in both zones and reached a plateau level which continues to expand till age 12–13 years (Dhom 1973, after 13 years; suggesting that increased CYP17A1 could Hui, et al. 2009). The emergence of the developed ZR impact the capacity for DHEA synthesis. corresponds with the rise in circulating DHEAS (Dhom 1973). The expression of the flavoprotein mediating the dual It has also been demonstrated that the thickness of the ZR is activity of CYP17A1, namely cytochrome P450 oxido- directly proportional to the production of DHEAS (Dhom reductase (CPR) has also been studied across adrenarche and 1973, Reiter et al.1977; Fig. 3). was found to increase in all the three adrenal zones, especially the ZR (Suzuki, et al. 2000). The increased conversion of 17OHPreg to DHEA due to the elevated 17,20-lyase activity Steroidogenic enzymes and cofactors involved in of CYP17A1 (Katagiri et al. 1995) is central to understanding C19 steroid production the mechanisms underlying adrenarche. The lyase activity of the enzyme is enhanced by the hemoprotein cytochrome b5 Although some steroidogenic enzymes and cofactor proteins CYB5A; Katagiri et al. 1995, Auchus et al. 1998, Brock & are common to all zones of the cortex, the zone-specific Waterman 1999, Dharia et al. 2004). CYB5A expression was production of steroids results in part due to differential detected in the DHEAS-synthesizing fetal zone throughout

Figure 2 Adrenal-derived C19 steroids act as precursors for the production of more potent androgens in peripheral tissues including hair follicles, genital skin, and prostate. The classical pathway for bioactive androgen synthesis as well as a proposed alternative pathway using 11b- hydroxyandrostenedione (11OHA) is shown. A, ; DHT, ; 11OHT, 11b-hydroxytestosterone; 5,11OHT, 5a,11b-hydroxytestosterone; 17bHSDs, 17b-hydroxysteroid dehydrogenases (type 5 or type 3).

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of the poor androgen DHEA into more potent androgens. Numerous studies have demonstrated that the transitional and fetal zones of the human fetal adrenal abundantly express SULT2A1 (Korte et al. 1982, Barker et al. 1994, Parker et al. 1994). Suzuki et al. (2000) carried out immunohistochemical studies in the postnatal period from infancy to old age and established that SULT2A1 became highly discernible in the ZR at ages 5–13 years and reached a plateau thereafter; thus confirming it as marker for ZR development. The sulfonation of steroids by SULT2A1 requires a sulfate donor, namely 30-phosphoadenosine 50-phosphosulfate (PAPS; Weinshilboum et al. 1997, Strott 2002). In humans, PAPS synthesis requires two isoforms of the enzyme PAPS synthase, namely PAPSS1 and PAPSS2. Noordam et al. (2009) examined an 8-year-old girl with early pubic and axillary hair, and concluded that the cause of hyperandrogenism in this subject was a set of compound heterozygous mutations in PAPSS2. Mutated PAPSS2 generated a decreased amount of PAPS, which is a prerequisite for steroid sulfonation. This was consistent with impaired DHEA sulfonation; thereby making the unconjugated DHEA pool available for conver- sion into bioactive androgens such as testosterone. During adrenarche, as the ZR expands, this zone was found to have substantially lower levels of HSD3B2 compared with the adjacent ZF (Fig. 4B). The relative lack of HSD3B2 expression/activity facilitates increased DHEAS synthesis because HSD3B2 competes with CYP17A1 for pregnenolone Figure 3 DHEAS and expansion of the adrenal reticularis. and 17OHPreg (Conley & Bird 1997, Rainey et al. 2002). (A) The relationship between the development of the ZR Thus, HSD3B2 expression in the expanding ZR coincides and plasma DHEAS levels (Dhom 1973, Reiter et al. 1977). (B) The morphological development of the adrenal zona reticularis with elevated adrenal DHEAS synthesis through the postnatal depicting the appearance of focal islands of reticular tissue and a period to adult life and is one of the driving forces of continuous ‘functional’ ZR (Dhom 1973). adrenarche (Gell et al. 1996, 1998, Suzuki et al. 2000, Hui et al.2009). The phenomenon of increased androgen gestation (Rainey et al. 2002, Dharia et al. 2004, Nguyen et al. production as a result of decreased HSD3B2 activity was also 2008). Immunohistochemical studies indicated that CYB5A demonstrated by McCartin et al. (2000) when they reported is weakly synthesized in all the adrenal zones of pre- the presence of premature adrenarche (PA) in an 11-year-old adrenarchal children (Suzuki, et al. 2000). However, subject with a profound loss of HSD3B2 activity owing to a CYB5A expression markedly rises in the ZR after age 5 compound heterozygotic mutation in the HSD3B2 gene years and plateaus at age 13 years, whereas the levels remain (McCartin et al. 2000). However, it should be noted that there extremely low in the ZG and ZF at all ages (Suzuki, et al. are cortical cells located at the border between the ZF and 2000). A reduction in the proportion of the adrenal cortex ZR in normal adult adrenal glands that co-express HSD3B2 that expresses CYB5A and DHEA levels was also detected and CYB5A, suggesting that these cells have the potential with aging (Parker 1999, Parker et al. 2000, Dharia et al. for direct production of androstenedione (Nakamura et al. 2005). These finding shed light on the significance of CYB5A 2011). Human ovarian theca cells also co-express HSD3B2, in adrenarche. CYP17A1, and CYB5A and similarly have potential for The sulfoconjugation of steroids occurs extensively in the androstenedione biosynthesis (Dharia et al. 2004, Simard et al. adrenal cortex and is primarily carried out by the enzyme 2005). Nevertheless, these results await further investigations SULT2A1, of the human hydroxysteroid sulfotransferase to clarify the regulatory mechanisms of co-expression of the family (Luu-The et al. 1996, Strott 2002, Shi et al. 2009). two enzymes in this population of cortical cells. SULT2A1 has a broad substrate specificity, which includes DHEA, pregnenolone, and 17OHPreg. Sulfonation of pregnenolone and 17OHPreg precludes metabolism by Control of adrenarche HSD3B2 and CYP17A1 and thereby their utilization as precursors for the , , and The precise mechanisms that control adrenal androgen androgen biosynthetic pathways. Also, conversion of DHEA biosynthesis have not been clearly defined. ACTH has been into its sulfate ester, i.e. DHEAS, prevents the transformation considered as the accepted primary mediator of adrenarche www.endocrinology-journals.org Journal of Endocrinology (2012) 214, 133–143

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Figure 4 (A) Steroid pathways for biosynthesis of adrenocortical steroids. StAR, steroidogenic acute regulatory protein; CYP11A1, cytochrome P450 cholesterol side-chain cleavage; CYP17A1, 17a-hydroxylase/17,20-lyase; HSD3B2, 3b-hydroxysteroid dehydrogenase type 2; CYB5A, cytochrome b5; HSD17B5, 17b-hydroxysteroid dehydrogenase type 5; SULT2A1, steroid sulfotransferase type 2A1; CYP11B1, 11b-hydroxylase. (B) Immunohistochemical examination of HSD3B2 expression in the human adrenal cortex from a 4-year-old child (pre-adrenarche) and a 9-year-old child (post-adrenarche). As observed in these micrographs, the post-adrenarche adrenal is characterized by the expansion of a HSD3B3-deficient ZR.

for the past few decades (Rosenfeld et al. 1971a,b, Reiter et al. several studies have demonstrated that ACTH and cortisol 1977). Clearly, dexamethasone suppression of adrenal levels both remain constant even during adrenarche’s rise in androgens suggests a regulatory role for ACTH (Abraham adrenal androgens (Mellon et al. 1991, Parker 1991, Penhoat 1974, Kim et al. 1974, Rich et al. 1981). Moreover, children et al. 1991, Auchus & Rainey 2004). This is partly due to the with an ACTH receptor defect fail to experience adrenarche tight regulatory feedback system between ACTH and (Weber et al. 1997), thereby supporting the postulate that cortisol, which keeps their levels within the physiologic ACTH plays an essential role in this phenomenon. However, range throughout life (Reader et al. 1982, 1983) as opposed to

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DHEA and other C19 steroids that have no clear feedback intermediates in cortisol and androgen metabolism, respect- system. Thus, although ACTH affects both cortisol and ively, thereby making them the most analyzed C21 steroids in adrenal androgen secretion, there is a divergence in cortisol adrenarche. Abraham et al. (1973) demonstrated by RIA that and androgen production at adrenarche. A related hypothesis the concentration of 17OHPreg was higher in neonates than proposing that the proximal 18-amino acid hinge region in preadolescents, adult males, and nonpregnant women, (amino acids 79–96) of pro-opiomelanocortin (POMC) was a presumably due to the low activity of HSD3B2 in neonatal stimulator for adrenal androgen synthesis, was not supported adrenal cortex as compared with the adult cortex. Hughes & by in vitro studies (Parker et al. 1989, Mellon et al. 1991, Winter (1976) also observed age-related changes in serum Penhoat et al. 1991). However, there have been numerous concentrations of 17OHProg. However, a detailed age- studies indicating that plasma levels of POMC-related peptides dependent analysis of 17OHPreg and 17OHProg was like b-lipotropin and b-endorphin correlate to the increasing described by Shimozawa et al. (1988). They examined the levels of DHEAS during adrenarche (Genazzani et al. 1983a,b, levels of 17OHPreg and 17OHProg by RIA in 11 umbilical O’Connell et al. 1996). Several studies also indicated no cord blood specimens and sera from 82 normal children of positive correlation between other potential endocrine various ages and 20 normal adults (Shimozawa et al. 1988). regulatory candidates including prolactin, insulin, and According to this study, the levels of these steroids are the insulin-like growth factor 1 with the DHEAS levels seen highest in the cord blood owing to their metabolism by the during adrenarche (Aubert et al. 1974, Parker et al. 1978, Smith feto-placental unit; and after birth they start declining to reach et al. 1989, Guercio et al. 2002). Thus, determination of the a nadir at 1–2 years age, followed by a gradual increase from controlling factor of adrenarche still needs more investigation. ages 3 to 6 years till adulthood. This is in agreement with the Anderson (1980) postulated that adrenarche is triggered observation that CYP17A1 expression in the ZF and ZR through an unknown mechanism involving the increased increases during adrenarche (Suzuki et al. 2000). intra-adrenal levels of cortisol associated with the growth of The pattern of some of the unconjugated C21 steroids the gland. Recent in vitro studies by Topor et al. (2011) also has been traced in humans from birth to adulthood. Toscano established that cortisol inhibits HSD3B2 and stimulates the et al. (1989) examined the levels of serum pregnenolone biosynthesis of DHEA at concentrations above 50 mM. (50G7 ng/dl), cortisol (13G1.8 mg/dl), and 11-deoxy- Dickerman et al. (1984) and Byrne et al. (1985, 1986) cortisol (52G3.6 ng/dl) in 20 children between ages 5.5 confirmed that there were age-dependent increases in intra- and 9 years. Several studies carried out in large cohorts of adrenal concentrations of several C and C steroids and 19 21 children between 2 and 12 years of age have established that proposed that these concentrations were in the range of serum cortisol levels do not increase in adrenarche (Parker the Michaelis–Menten constant (K ) for HSD3B2 and m et al. 1978, Franckson et al. 1980). Thus, it is clear that the might therefore inhibit the enzyme and promote 17OHPreg serum levels of most of the adrenal unconjugated C steroids metabolism to DHEA at adrenarche. However, the same study 21 are not grossly affected during the course of adrenarche. demonstrated that 1 mM cortisol did not inhibit HSD3B2 (Byrne et al. 1986). Also, DHEAS levels appear to be high in The robust expression of the adrenal-related sulfo- adrenarchal children with untreated classic congenital transferase enzyme, namely SULT2A1 (Strott 2002), and its adrenal hyperplasia where intra-adrenal cortisol levels should broad substrate specificity has also encouraged researchers to be low (Brunelli et al. 1995). Thus, the exact role for the examine the sulfonated derivatives of various C21 steroids. modulation of HSD3B2 enzymatic activity by intra-adrenal de Peretti & Mappus (1983) traced the levels of pregnenolone steroid inhibitors remains unclear, while decreased expression sulfate (Preg-S) from birth to adulthood and observed that of HSD3B2 in the post-adrenarche ZR appears clear. Preg-S levels were high in cord plasma as a consequence of residual fetal zone activity. The levels started declining during the first year after birth and remained low thereafter. Steroid production in adrenarche Also, there was no detectable rise in Preg-S during the adrenarchal period as is seen for the classical markers of The difference in expression and activity of the various adrenarche, namely DHEA and DHEAS (de Peretti & adrenal steroidogenic enzymes from infancy to adulthood Mappus 1983). Shimozawa et al. (1988) demonstrated that suggest that there should also be age-related changes in serum 17OHPreg sulfate (17OHPreg-S) exhibited an age-related concentrations of several D5- and D4-steroids that would change, wherein the 17OHPreg-S concentration was highest underlie the physiologic processes of adrenarche. in cord blood and decreased to a minimum at 3–6 years, followed by a gradual increase from 7 years till adulthood as opposed to its nonsulfated form that showed a nadir Serum C21 steroids in adrenarche at 1–2 years. These observations agree with what we now As described earlier, it has been established that adrenarche is know regarding the adrenarchal expansion of the ZR that associated with the expansion of the ZR having deficient has high CYP17A1 and SULT2A1 and low HSD3B2 expression of HSD3B2 along with increasing expression of expression. This would explain the ability of 17OHPreg-S CYP17A1. Also, 17OHProg and 17OHPreg are the key to act as an additional steroid marker of adrenarche. www.endocrinology-journals.org Journal of Endocrinology (2012) 214, 133–143

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Serum C19 steroids in adrenarche levels of the enzyme 17b-hydroxysteroid dehydrogenase type 5 (HSD17B5 or AKR1C3) than the adjacent ZF and The weak C steroids DHEA and DHEAS are the 19 its expression increases across adrenarche (Hui et al. 2009, characteristic markers of adrenarche (Fig. 1). Extensive RIA Nakamura et al.2009b). This enzyme has numerous studies tracing these steroids from birth to adolescence activities, including the ability to convert androstenedione demonstrated that plasma DHEA levels rapidly declined in to testosterone (Fig. 4A). Thus, while it is clear that the first 2 years of life, stayed low for the next few years, and DHEA/DHEAS represent the most consistent markers of then dramatically increased after 6 years of age, corresponding adrenarche, the production of more potent androgens needs to ‘adrenarche’ (Ducharme et al. 1976, Korth-Schutz et al. further study and the analysis of these androgens may require 1976c, de Peretti & Forest 1976, 1978, Parker et al. 1978, consideration of adrenal circadian secretion as well. de Peretti & Mappus 1983). DHEAS has been the most Studies carried out in the 1970s and 80s (Mauvais-Jarvis extensively studied steroid across adrenarche. A number of et al. 1973, Moghissi et al. 1984) indicating that the conjugated research groups traced the age-related changes in plasma androgen, androstane-3a,17b-diol glucuronide (Adiol-G) DHEAS concentration and demonstrated that DHEAS would be a good measure of testosterone transformation, decreased slowly during the first years of life, remained low led to further investigations that established the change in till age 5 years and then abruptly started to rise (Korth-Schutz plasma steroid glucuronide levels at different ages (Belanger et al. 1976a, Parker et al. 1978, de Peretti & Forest 1978, Rich et al. 1986, Brochu & Belanger 1987). Brochu et al. et al. 1981, Tung et al. 2004). Recent liquid chromatography– determined the levels of glucuronide and tandem mass spectrometry (LC–MS/MS) studies in a large Adiol-G across various age groups in males and concluded cohort of children confirmed the same age-related pattern of that, since these 5a-reduced and conjugated steroids increase serum DHEA levels (Kushnir et al. 2010). The patterns seen significantly before , the adrenal C19 steroids like for both DHEA and DHEAS correlate well with intra-adrenal androstenedione and androstanedione must be getting changes occurring during this period. Specifically, the high converted into androsterone glucuronide and potentially neonatal levels relate to the residual fetal zone that regresses into testosterone, which in turn is transformed into Adiol-G over the first year leading to a nadir of DHEA/DHEAS, during prepubertal development (Brochu & Belanger 1987). and their rise in the circulation correlates well with the Their findings support the premise that androgenic mani- expansion of the reticularis. festations like appearance of pubic and axillary hair are The age-related patterns of secretion of several other C19 induced by the conversion of adrenal C19 steroids to active products have also been investigated but with varying results. androgens that are further metabolized into their conjugated While some immunoassay studies suggest no adrenarchal rise inactive products. in androstenedione (Korth-Schutz et al. 1976c, Parker et al. 1978), others show significant adrenarche-related increases in serum levels of androstenedione (Ducharme et al. 1976, Urinary C19 steroids in adrenarche Franckson et al. 1980, Likitmaskul et al. 1995, Tung et al. Nathanson et al. (1941) was one of the first groups of 2004). Recent LC–MS/MS analysis also showed a similar researchers to report the presence of androgen metabolites in age-related rise in concentration of androstenedione (Kulle the urine of a large cohort of children. The results of their et al. 2010). Parker et al. (1978) did not find a relationship study demonstrated that from ages 3 to 7 years, constant between serum 11b-hydroxyandrostenedione (11OHA) amounts of androgens are excreted; however, at about 7 years, concentration and age, whereas Franckson et al. (1980) the rate of excretion of these steroids begins to progressively found that serum 11OHA increased with bone age increase. Several studies were carried out to confirm the age- throughout prepubertal childhood. The major difference related changes in androgen excretion. It was also demon- between the studies was data analysis. Because of the circadian strated that urinary total DHEA and DHEAS levels are association of 11OHA with cortisol, Franckson et al. utilized a elevated from ages 8 to 12 years (Tanner & Gupta 1968, 11OHA/cortisol ratio to make steroid comparisons. Gupta 1970, Kelnar & Brook 1983). In 1991, the normal Some immunoassay studies of testosterone in a large ranges for urinary steroid excretion were determined for population of children established that this androgen did not the first time by gas chromatography (GC), and it was rise demonstrably during the early stages of adrenarche demonstrated that urinary steroid excretion rates in childhood (Ducharme et al. 1976, Korth-Schutz et al. 1976c). Later positively correlate with growth and activity of the adrenal studies using LC–MS/MS confirmed that the plasma levels cortex (Honour et al. 1991). With the advent of better of testosterone do not rise at adrenarche, but that its levels techniques and availability of commercial assays, Remer et al. do rise as puberty approaches in boys (Kulle et al. 2010). The (1994a,b) demonstrated that urinary total 17-ketosteroid exact role of direct adrenal secretion of testosterone remains sulfate and DHEAS concentrations in 8-year-old normal unclear. Previous studies in adult women exhibiting signs of children is significantly higher than preadrenarchal children androgen excess demonstrated that the adrenal could secrete (aged 4 years). Extensive studies by GC–MS to determine the testosterone under pathologic conditions (Stahl et al. 1973a,b, urinary markers of adrenarche were carried out in a large Greenblatt et al. 1976). In addition, the ZR expresses higher population of healthy children and adolescents between 3 and

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18 years (Remer et al. 2005), which established that DHEA 11beta-hydroxylation testosterone by the adrenal-specific and its metabolites, like 16a-hydroxy DHEA, 3b,16a,17a- enzyme CYP11B1 in a reaction similar to that of the androstenetriol, and , show a continuous rise conversion of androstenedione to 11OHA (Schloms et al. from ages 3–4 years to 17–18 years, thereby suggesting 2012, Kley et al. 1984, Schlaghecke et al. 1986). Because the that adrenarche is a gradual process starting at an early age. adrenal produces large amounts of DHEA, DHEAS, The gradual nature of increasing steroids would appear to androstenedione, and 11OHA, it is likely that agree with Dhom’s histologic studies showing a gradual these androgen precursors will feed into both the classical expansion of the adrenal ZR (Fig. 3). Recent studies by Shi and alternative peripheral metabolic pathways that can lead et al. (2009) also confirmed the use of the C19 steroids as to active androgens. urinary markers of adrenarche.

Premature adrenarche Future directions toward understanding the adrenarche steroid metabolome PA can be defined as the early rise in adrenal androgen production that usually results in the appearance of pubic or Hui et al. (2009) suggested that the process of adrenarche axillary hair before age 8 years in girls and 9 years in boys, was associated with ZR increased expression of HSD17B5, without the appearance of other secondary sex characteristics an enzyme able to convert androstenedione to testosterone. (Talbot et al. 1943, Silverman et al. 1952). Girls with PA They demonstrated the presence of HSD17B5 in the ZR of are susceptible to the development of polycystic ovary human adrenals around age 9 years, which tracks well with syndrome with , irregular menses, and hyperan- the onset of pubarche (Hui et al. 2009). drogenism (Ibanez et al. 1993). PA is also an early onset Testosterone derived from the testes as well as the adrenals is predictor of hyperinsulinemia (Oppenheimer et al. 1995, converted to a more potent androgen, 5a-dihydrotetosterone Ibanez et al. 2000). Children with PA have been shown to (DHT) by the enzyme 5a-reductases type I and II (SRD5A) exhibit higher serum levels of DHEA, DHEAS, androstene- in androgen target tissues like genital skin and prostate dione, and testosterone as well as their urinary metabolites (Wilson et al. 1993, Chang et al. 2011). Recent studies (Doberne et al. 1975, Korth-Schutz et al. 1976b,c, Rosenfield suggest that there are likely several pathways leading to et al. 1982, Voutilainen et al. 1983, Rosenfield & Lucky 1993, DHT biosynthesis (Wilson 1999, Wilson et al. 2003, Likitmaskul et al. 1995, Ibanez et al. 2000). Recently studied Auchus 2004, Ghayee & Auchus 2007, Fluck et al. 2011). LC–MS/MS steroid profiles of infants with fine genital hair The peculiarity about these pathways is the synthesis showed a mild elevation of DHEAS as compared with healthy of 5a-androstane-3a,17b-diol (androstanediol) involving pre-adrenarchal children, thus indicating that pubic hair in 5a-pregnane-3a,17a-diol-20-one as a key intermediate. infancy may represent a mild and early-onset variant of Androstanediol, in turn, acts as precursor for DHT, thereby PA (Kaplowitz & Soldin 2007). Toscano et al. observed bypassing the need for testosterone, which is the ‘classical’ increases in plasma levels of C21 steroids like pregnenolone precursor for DHT production. Recently, Fluck et al. and 17OHPreg along with the C19 steroids like DHEA, (2011) confirmed that both the classical and alternative DHEAS, and androstenedione but with no change in cortisol pathways of testicular androgen production are involved or 11-deoxycortisol in PA children as compared with in the formation of normal human male sexual differen- controls. They interpreted these steroid changes to suggest tiation, whereas another group suggested that synthesis that the PA adrenal had decreased HSD3B2 activity and of DHT in castration-resistant requires increased CYP17A1 activity (Toscano et al. 1989). They also 5a-androstenedione and not testosterone as an obligate indicated that PA might not be exclusively dependent on precursor (Chang et al. 2011). ACTH regulation (Toscano et al. 1989). The levels of Two derivatives of testosterone, 11b-hydroxytestosterone Adiol-G also increased in children with PA and showed a (11OHT) and 11-ketotestosterone (11KT), may represent strong correlation with DHEA, DHEAS, and androstene- unique adrenal-derived androgens. While testosterone and dione (Montalto et al. 1990, Riddick et al. 1991, Balducci DHT are the primary human androgens, 11OHT and 11KT et al. 1992, 1993, Ibanez et al. 2000). Thus, it is clear that are the major androgens found in a variety of fish (Rosenblum numerous adrenal-derived steroids can be used as markers in et al. 1985, Brantley et al. 1993, Yazawa et al. 2008). These C19 the diagnosis of PA. steroids are also produced in small quantities by mouse gonads (Yazawa et al. 2008). The physiologic role of these steroids in humans has not been studied, but circulating levels of Conclusions these androgens have been examined in human blood (Kley et al. 1984, Schlaghecke et al. 1986). 11OHT could Adrenarche is characterized by rising levels of C19 steroids be speculated to be an adrenal-derived androgen as it like DHEA and DHEAS due to the expanding adrenal ZR, might require the activity of 11b-hydroxylation via the and in humans this occurs at ages 6–8 years. The phenotypic adrenal-specific enzyme CYP11B1 can be derived by the hallmark of adrenarche is the appearance of axillary and pubic www.endocrinology-journals.org Journal of Endocrinology (2012) 214, 133–143

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hair. This phenomenon is driven by the concerted actions Balducci R, Finocchi G, Mangiantini A, Maggi C, Bianchi P, Guglielmi R & of the enzymes CYP17A1, SULT2A1, and the cofactor Toscano V 1992 Lack of correlation between binding globulin, adrenal and peripheral androgens in precocious adrenarche. CYB5A, which are highly expressed in the expanding Journal of Endocrinological Investigation 15 501–505. population of ZR cells seen during adrenarche. The low Balducci R, Finocchi G, Mangiantini A, Bianchi P,Guglielmi R & Toscano V expression of HSD3B2 in the ZR also enables the 1993 Plasma 3 a-androstanediol glucuronide in precocious adrenarche. increased production of androgens by the adrenal cortex. Journal of Endocrinological Investigation 16 117–121. 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