Premature adrenarche: Etiology, clinical findings, and consequences

Journal of Steroid Biochemistry & Molecular Biology 145 (2015) 226–236

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Review

Premature adrenarche: Etiology, clinical findings, and consequences Raimo Voutilainen * , Jarmo Jääskeläinen Department of Pediatrics, Kuopio University Hospital and University of Eastern Finland, P.O. Box 100, Kuopio FI-70029, Finland

A R T I C L E I N F O

A B S T R A C T

Article history: Received 27 February 2014 Received in revised form 16 May 2014 Accepted 5 June 2014 Available online 9 June 2014

Adrenarche means the morphological and functional change of the adrenal cortex leading to increasing production of adrenal androgen precursors (AAPs) in mid childhood, typically at around 5–8 years of age in humans. The AAPs dehydroepiandrosterone (DHEA) and its sulfate conjugate (DHEAS) are the best serum markers of adrenal androgen (AA) secretion and adrenarche. Normal ACTH secretion and action are needed for adrenarche, but additional inherent and exogenous factors regulate AA secretion. Interindividual variation in the timing of adrenarche and serum concentrations of DHEA(S) in adolescence and adulthood are remarkable. Premature adrenarche (PA) is defined as the appearance of clinical signs of androgen action (pubic/axillary hair, adult type body odor, oily skin or hair, comedones, acne, accelerated statural growth) before the age of 8 years in girls or 9 years in boys associated with AAP concentrations high for the prepubertal chronological age. To accept the diagnosis of PA, central puberty, adrenocortical and gonadal sex hormone secreting tumors, congenital adrenal hyperplasia, and exogenous source of androgens need to be excluded. The individually variable peripheral conversion of circulating AAPs to biologically more active androgens (testosterone, dihydrotestosterone) and the androgen receptor activity in the target tissues are as important as the circulating AAP concentrations as determinants of androgen action. PA has gained much attention during the last decades, as it has been associated with small birth size, the metabolic and polycystic ovarian syndrome (PCOS), and thus with an increased risk for type 2 diabetes and cardiovascular diseases in later life. The aim of this review is to describe the known hormonal changes and their possible regulators in on-time and premature adrenarche, and the clinical features and possible later health problems associating with PA. ã 2014 Elsevier Ltd. All rights reserved.

Keywords: Adrenarche DHEA DHEAS PCOS Steroid Birth weight

Contents 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Morphological, functional, and molecular changes in the adrenal cortex during the human life span . . . . . . . . . . . . . . . . . . . . . . Timing and “strength” of adrenarche: on-time, premature, delayed, missing, exaggerated, exacerbated, pronounced adrenarche Clinical and clinical chemistry findings in PA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Childhood statural growth, final adult height, and pubertal timing in PA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The significance of birth size and prematurity in later AA(P) secretion and PA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Association of PA and birth size with ovarian hyperandrogenism and polycystic ovarian syndrome (PCOS) . . . . . . . . . . . . . . . . . Body composition, bone mineral density, cardio-metabolic changes, and chronic inflammation in PA . . . . . . . . . . . . . . . . . . . . . Mutations and genetic polymorphisms associating with PP/PA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction

* Corresponding author. Tel.: +358 17 172391/358 44 7172391; fax: +358 17 172410. E-mail address: raimo.voutilainen@kuh.fi (R. Voutilainen). http://dx.doi.org/10.1016/j.jsbmb.2014.06.004 0960-0760/ ã 2014 Elsevier Ltd. All rights reserved.

The term adrenarche was introduced in the 1940s [1], and it means the morphological and functional change of the adrenal cortex leading to increasing production of adrenal androgen precursors (AAPs) in mid childhood, typically at around 5–8 years of age. This increase in AAP production coincides with the

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Fig. 1. Steroid synthesis pathways in the human adrenal cortex with some peripheral metabolic pathways of adrenal steroids included. CYP11A1, 20,22-desmolase; CYP11B1, 11b-hydroxylase; CYP11B2, aldosterone synthase; CYP17A1, 17a-hydroxylase/17,20-lyase; CYP21A2, 21-hydroxylase; HSD3B, 3b-hydroxysteroid dehydrogenase; HSD11B1, 11b-hydroxysteroid dehydrogenase 1; HSD11B2, 11b-hydroxysteroid dehydrogenase 2; HSD17B, 17b-hydroxysteroid dehydrogenase; STS, sulfatase; SULT2A1, sulfotransferase; PAPSS2, PAPS synthase type 2; H6PDH, hexose-6-phosphate dehydrogenase.

histological development of the zona reticularis, the innermost zone of the adrenal cortex [2]. Dehydroepiandrosterone (DHEA), its sulfate conjugate (DHEAS), and androstenedione are the most important AAPs. Adrenarche occurs only in humans and some other higher primates [3–5], which has limited the clarification of its significance and regulation. The clinical manifestations caused by the increasing secretion of AAPs and their conversion to biologically active androgens appear slightly later than the hormonal changes of adrenarche in serum or urine samples can be detected. Because central puberty may start simultaneously or soon after adrenarche, the clinical signs of adrenarche cannot always be separated from those caused by gonadarche which means the induction of ovarian or testicular sex hormone production in response to the central pubertal activation of the hypothalamo-pituitary-gonadal (HPG) axis. The clinical condition premature (or precocious) adrenarche (PA) is usually defined as the appearance of clinical signs of androgen action before the age of 8 years in girls or 9 years in boys together with serum AAP concentrations (or urinary AAP metabolite excretion) high for prepubertal chronological age but appropriate for normal Tanner pubertal developmental stage II–III. PA offers a possibility to study the influence and significance of adrenal androgens (AAs) and AAPs in childhood. To accept the “diagnosis” of PA, central puberty (leading to gonadarche), adrenocortical and gonadal sex hormone secreting tumors, and congenital adrenal hyperplasia due to enzyme defects in cortisol biosynthesis have to be excluded as causes of excessive androgen production for age. Originally, precocious appearance of “sexual hair” (pubic and/or axillary) named premature pubarche (PP) [6] was considered the main or only clinical manifestation of PA. This is probably at least one reason why PP is still often erroneously described as a synonym for PA (discussed in [7]). Several studies since 1970s have revealed that in addition to PP, other signs of androgen action are quite common in PA. These include adult type body odor, oily hair or skin, comedones, acne, and slightly increased statural growth [8–13]. The aim of this review is to describe briefly the physiological changes occurring in adrenocortical function during adrenarche, and the clinical features and possible later health problems

associating with PA. The readers are advised to see previously published reviews of adrenarche [14–17] and PA [13,18–20] written from different perspectives. 2. Morphological, functional, and molecular changes in the adrenal cortex during the human life span During fetal life, the human adrenal glands are huge (nearly as big as the kidneys) compared to their proportional size in later life. The major part of the human fetal adrenal cortex (about 80% of its total volume) is formed by the innermost fetal zone (FZ) that regresses during the first few months of postnatal life. The outermost zone of the fetal adrenal cortex is called the definitive (or permanent) zone (DZ) and a narrow third layer between the FZ and DZ is called the transitional zone (TZ) (reviewed in [21]). Figs. 1 and 2 outline the steroid synthesis pathways in the human adrenal cortex with some peripheral further metabolic routes of adrenal steroids included (Fig. 1). The fetal adrenal does not express HSD3B (3b-hydroxysteroid dehydrogenase, 3b-HSD) enzyme before

Fig. 2. Regulation of 17,20-lyase activity of CYP17A1. This activity is regulated by P450 oxidoreductase (POR) mediating electrons (e
), and the interaction between POR and CYP17A1 is promoted by the allosteric action of cytochrome b5 (b5). Furthermore, kinase p38a stimulates phosphorylation of CYP17A1, leading to increased 17,20-lyase activity [36].

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about 23 weeks of gestation [22–24], which means that it cannot efficiently synthesize cortisol from cholesterol or pregnenolone in early gestation except during a short period during the first trimester [25] (outlined in Fig. 3). Instead, the fetal adrenal (especially the FZ) produces abundantly DHEAS that serves as an estrogen precursor in the placenta. The FZ can also convert placental progesterone to cortisol [26] as progesterone is beyond the critical HSD3B step (see Fig. 1) and the other enzymes needed for cortisol synthesis are expressed in the fetal adrenal cortex [21,24,27,28]. The fetal zone producing DHEAS regresses during the first few human postnatal months leading to very low AAP production in early childhood (outlined in Fig. 3). Estimation of the activities of the key enzymes involved in AA synthesis in the early 1980s revealed increasing 17,20-lyase and decreasing 3b-HSD activities in adrenarche [29,30], coinciding with the morphological development of the zona reticularis [2] and the increase in adrenal DHEAS secretion [31]. Later immunohistochemical studies have strongly supported the “specialization” of the zona reticularis to DHEA and DHEAS production, thus resembling functionally the fetal zone of the human fetal adrenal gland discussed above. The zona reticularis has very low expression of HSD3B but high expression of CYP17A1 (P450c17), SULT2A1 (DHEA sulfotransferase), P450 oxidoreductase (POR), and cytochrome b5 [32–34]. POR is the obligatory electron donor for CYP17A1 and cytochrome b5 acts as an allosteric factor promoting the interaction of POR and CYP17A1 favoring the 17,20-lyase reaction essential for DHEA and DHEAS production (reviewed in [15]). An additional factor favoring DHEA(S) production in the zona reticularis may be the posttranslational phosphorylation of serine residues on CYP17A1 by a (or several) protein kinase(s) which also increases the 17,20-lyase activity of CYP17A1 [35,36] (outlined in Fig. 2). An alternative or completing mechanism explaining the functional zonation of the human adrenal cortex in respect to the AA(P) secretion was suggested by Anderson in early 1980s. According to his hypothesis, the development of the zona reticularis is explained by a morphological and functional change in the inner cells of the adrenal cortex that is induced by high local cortisol levels [37]. There is experimental evidence in cultured human fetal adrenal cells [38] and in human NCI-H295R adrenocortical cells [39] that corticosterone or cortisol in the high concentrations attainable in the inner layers of human adrenal cortex [40] stimulate DHEA production probably through competitive inhibition of HSD3B2 [39]. High in vivo cortisol or corticosterone concentrations in the inner zones of the normal adrenal cortex [40] are attained by physiological ACTH stimulation. There is also evidence that at least high-dose ACTH treatment of

Fig. 3. Relative secretion of DHEAS and cortisol by the human fetal and postnatal adrenal cortex. The high prenatal production of DHEAS by the fetal zone, its rapid decrease shortly after birth at the time of the involution of the fetal zone, and its increase again during adrenarche are schematically outlined. Note that the vertical axis is logarithmic and the hormone levels are approximate. Modified from Ref. [138].

infants with infantile spasms causes a clear induction of AA(P) production [41]. Whether this ACTH-induced increase in AA(P) production in clearly prepubertal children was mediated by high endogenous intra-adrenal cortisol or corticosterone concentrations or by other ACTH-induced mechanism, can only be speculated. 3. Timing and “strength” of adrenarche: on-time, premature, delayed, missing, exaggerated, exacerbated, pronounced adrenarche Traditionally the adrenarcheal increase in AAP production has been supposed to start at about 6–8 years of age. However, more detailed serum and urinary analyses have shown that the production of AAPs starts gradually already from the age of 3 years onwards [42,43]. The individual variation in serum AA(P) concentrations in each age group and pubertal developmental stage is wide [44], and the same concerns adults [45]. Similarly, a detailed analysis of urinary AA(P) s and their metabolites showed an enormous variation in each age group of 3–18 year-old children and adolescents [43]. These findings demonstrate both the variable timing of adrenarche and the remarkable variation in the amount of AA(P) s produced by children, adolescents and adults of the same age. Fig. 4 demonstrates the high variation of serum DHEA, androstenedione, testosterone, and dihydrotestosterone concentrations in a sample of Finnish children and adolescents, and in 18 girls with PA. As described in the introduction (chapter 1), premature adrenarche is defined as a condition where clinical signs of AAs appear before the age of 8 years in girls and 9 years in boys in the absence of central puberty, androgen producing neoplasms and congenital adrenal hyperplasia. There is no generally accepted definition for delayed adrenarche, because delayed or missing adrenarche does not necessarily cause any clinical signs if adrenal glucocorticoid and mineralocorticoid production are normal. Even in the absence of adrenarche, ovarian androgen secretion in girls and testicular testosterone secretion in boys induce pubic hair growth and other signs of pubertal androgen effects. If both adrenarche and pubertal development (gonadarche) are delayed, sexual hair development, statural growth, and other signs of androgen effects are delayed more than in the adolescents with delayed puberty but on-time adrenarche. Thus delayed adrenarche may emphasize the growth and/or psychosocial problems associating often with delayed puberty especially in boys. Missing or absent adrenarche is seen in subjects with ACTH resistance (familial glucocorticoid deficiency) [46], hypopituitarism (ACTH deficiency) [31,47], and presumably also in children and adolescents with long-term treatment with pharmacological doses of glucocorticoids (causing suppression of ACTH secretion). Even inhaled glucocorticoids used in therapeutic doses for asthma can reduce DHEAS secretion in both children and adults [48,49]. The term exaggerated adrenarche was originally used in reports describing hyperresponsiveness of AA(P)s in ACTH stimulation tests of adult women with polycystic ovarian syndrome (PCOS) [50] or hyperandrogenism with acne and/or hirsutism [51]. Likitmaskul et al. [52] used the term exaggerated adrenarche for those children with PA who had their serum DHEAS concentration above 6 mmol/l (considering that level to be above the normal pubertal range), and Ibanez et al. [53] for asymptomatic 14-yearold girls having been born small for gestational age (SGA) and with their mean serum DHEAS concentrations (7.65 mmol/l) higher than a group of age-matched girls born appropriate for gestational age (AGA) (3.69 mmol/l). Maliqueo et al. [54] used the terms exaggerated and exacerbated adrenarche in parallel for prepubertal and peripubertal girls whose serum DHEAS concentrations exceeded about 1.8 and 2.5 mmol/l, respectively. Recently, Paterson

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Fig. 4. Serum DHEA (DHA in the figure), androstenedione, testosterone, and dihydrotestosterone (DHT) concentrations of 18 girls with premature adrenarche. Open triangles represent dexamethasone-suppressed (0.5 mg/1.7 m2  4 for two days) values. The values connected by lines represent hormone levels of the same girl at different ages. The shaded areas represent the reference values with the same assays [139]. Modified from Ref. [9].

et al. [55] used the term exaggerated adrenarche as a synonym for PA for their group of Scottish prepubertal children with their median serum DHEAS concentrations 2.1 and 4.1 mmol/l in girls and boys, respectively. Additionally, the term pronounced adrenarche has been used practically as a synonym for PA in both girls and boys [56,57] with their prepubertal mean serum DHEAS concentration about 3.3 and 3.0 mmol/l, respectively. Furthermore, Ibanez et al. have used also the term amplified adrenarche for girls with PP due to early adrenarche [58]. Rosenfield defined exaggerated adrenarche in his review article as a clinically extreme type of PA [59]. He suggested serum DHEAS concentrations of about 1.1–3.5 mmol/l for ordinary PA and 3.5–5.0 mmol/l for exaggerated adrenarche (at prepubertal age). Due to the variable and confusing use of the terms exaggerated, exacerbated, pronounced and amplified adrenarche described above, we question the usefulness of these terms in clinical practice and reports. As already mentioned, PA is the most common cause for PP. The term isolated premature pubarche has sometimes been used for PP without a concomitant rise in serum AA(P) concentrations [20,59,60]. Increased androgen receptor (AR) activity due to shorter AR gene CAG repeats [61–63] and/or reduced AR gene methylation pattern [62] could explain PP and other androgenic signs in some prepubertal children with serum DHEAS concentrations below the often used limit levels of 1 mmol/l [7] or 40 mg/ dl [59] for PA. It is evident that serum AAP concentrations do not always correlate with the clinical signs of androgen action. In our prepubertal cohort of “clinical” PA, 9 of 63 girls (14%) had their serum DHEAS concentrations below 1 mmol/l. On the other hand, 36 of the 98 control prepubertal children (37%) without any signs

of androgen action in careful physical examination had their serum DHEAS concentrations 1 mmol/l [7]. Thus, the individually variable peripheral conversion of circulating AAPs to biologically active androgens and the AR activity in the target tissues are as important as the circulating AA(P) concentrations as determinants of the clinical signs of androgen action [64]. For clinical purposes, we would like to accept a prepubertal child with clinical signs of androgen action to have PA when there is any evidence of increased AAP secretion evaluated with a sensitive and specific assay even when the “traditional” threshold levels (for example 1 mmol/l or 40 mg/dl for serum DHEAS) are not reached and the other reasons for the androgen actions are excluded (precocious puberty, sex hormone secreting tumors, defects in cortisol biosynthesis, external exposure to androgens). Actually careful reading of previous PA reports shows that many authors have accepted children with PP or other signs of androgen action to have PA with lower serum DHEAS levels than 1 mmol/l or 40 mg/dl [13,52,55,65]. 4. Clinical and clinical chemistry findings in PA As already mentioned, precocious appearance of “sexual hair” (pubic and/or axillary), premature pubarche (PP), was originally considered the main or only clinical manifestation of PA [6]. Later studies since 1970s have revealed also other clinical signs of androgen action in children with PA. Korth-Schutz et al. [8] described serum androgen levels in 22 girls with PA mentioning the presence of adult type body odor in addition to pubic and axillary hair at the age of 3–7 years. A Finnish group reported in early 1980s clinical and hormonal characteristics of 18 girls with PA. In that series the most common clinical findings at the

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diagnostic stage were precocious pubarche (in 10/18 girls), accelerated statural growth (10/18), acne or comedones (8/18), and adult type body odor (8/18). Precocious pubarche was the only finding in 5/18, accelerated statural growth in 2/18, and adult type body odor in 1/18 of the subjects [9]. In a larger more recent population-based Finnish study, Utriainen et al. analyzed the clinical signs of PA in 73 Caucasian children (63 girls, 10 boys) [7]. Table 1 summarizes their findings confirming the remarkable variability of the clinical signs in PA. Adult type body odor turned out to be the most common clinical sign of androgen action (in 89% of the subjects) at the time of the diagnostic visit when this was recorded carefully (medical history and physical examination of the armpits). Sexual hair (pubic or axillary) was present in “only” 48% of the subjects, and it was usually preceded by other signs of androgen action [7]. Increased androgen action in PA may be detected also in some laboratory parameters. A higher blood erythrocyte count and a tendency toward higher hemoglobin concentration in prepubertal PA children than in age-matched controls [66] may be considered at least partly an androgen effect. It is not known whether the increased serum insulin-like growth factor I (IGF-I) concentrations in PA children [12,67–69] represent increased androgen action, growth hormone effect, or are associated with the often detected overweight and hyperinsulinism in these children (discussed in chapter 8). Higher serum alkaline phosphatase levels in prepubertal PA than control children [70] are probably associated with increased osteoblast activity and accelerated bone growth in PA subjects. 5. Childhood statural growth, final adult height, and pubertal timing in PA Higher childhood height than in the reference population has been reported in many cohorts of PA subjects already since 1950s [6,9–11,71]. Pere et al. analyzed retrospectively the growth charts of 34 children with PA showing an upward bend in the height curves in 82% of the subjects [11]. This bend occurred already at the mean age of 2.3 years and preceded the other signs of adrenarche by on average 3.8 years. The follow-up of these children showed that 50% of the PA subjects had reduced or missing pubertal growth spurt, but the final height did not differ from that expected on the basis of the parental heights. Thus, many children with PA used a greater part of their growth potential before puberty compared to the children with average timing of adrenarche [11]. Ghizzoni and Milani [71] reported later a similar type of pubertal growth pattern and normal adult height in Italian PA subjects. The observed type of statural growth in PA children suggests indirectly that both AAs and gonadal sex hormones contribute to the normal pubertal growth spurt which is more pronounced when both adrenal and Table 1 Clinical signs of androgen action in 73 prepubertal children (63 girls, 10 boys) with premature adrenarche. Clinical sign

Number (%) of subjects

Number (%) of subjects as the only clinical sign

Adult-type body odor Oily hair Comedones/acne Sexual hair (pubic or axillary) Pubic hair Axillary hair Acanthosis nigrigans

65 51 41 35

8 (11)

(89) (70) (56) (48)

1 (1.4)

28 (38) 17 (23) 9 (12)

Premature adrenarche defined as any sign of androgen action before the age of 8/9 years in prepubertal girls/boys with androgen producing tumors and congenital adrenal hyperplasia excluded. Data derived from Ref. [7]. Growth data not included here.

Fig. 5. Growth patterns in length/height (expressed in SD scores) and weight-forheight (expressed as % of the median weight for height). Means and 95% confidence intervals are shown. Modified from Ref. [12].

gonadal sex steroid secretion increases at the same time. Utriainen et al. [12] reported a higher mean length already at the age of 1 year in 54 girls who later developed PA in comparison to 52 agematched control girls, and the length SD score of the “future” PA girls increased significantly already during the first 2 years of life (Fig. 5). Normal adult height has been reported in most PA studies to date [10,11,58,72], although adult height prediction in childhood may forecast reduced adult height in those PA subjects with clearly advanced bone age [72]. Bone age is often somewhat advanced in children with PA [9,10,71,73]. As expected on the basis of the adult heights of SGA-born subjects in general, PA girls born SGA had lower adult heights than those born AGA, but even the SGA-born PA girls reached their midparental heights [58]. The percentage of boys in different PA studies has varied between 3.4 and 25.4% [6,9,11,55,73–77]. Due to the lack or low number of boys in many PA study cohorts, there are not so reliable data available on the growth pattern of PA boys as we have on that of girls. On the basis of the limited growth data on PA boys, it in any case looks that the prepubertal statural growth is often accelerated and normal adult height is reached in boys [11,73], just like in girls. Puberty may start and menarche occur slightly earlier (but usually within normal limits) in girls who have experienced PA compared to the control population. Pere et al. reported the mean age of menarche to be 0.5 years before the estimated population mean in Finnish girls with a history of PA [11]. Ibanez et al. showed earlier menarche in Catalan (Spanish) PA girls compared to the local reference population. In addition, low birth weight among the PA subjects was associated with earlier menarche [58]. 6. The significance of birth size and prematurity in later AA(P) secretion and PA Low birth size has been associated with increased serum DHEAS concentrations in childhood and early adolescence in most studies [53,78–81]. Ong et al. actually reported a continuous inverse

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relationship between birth weight SD scores and serum DHEAS concentrations in both sexes at the age of 8 years in a large British cohort of children [82]. However, it seems that by early adulthood the subjects born SGA do not any more have higher AA(P) secretion than those born AGA [83–86]. Similar normalization of prepubertally enhanced AA(P) production seems to occur postpubertally in PA subjects [11]. Prematurely-born SGA subjects may behave differently, as they have been reported to maintain higher serum DHEAS concentrations than full-term-born controls until 20 years of age [87,88]. In spite of the well documented association of low birth size with increased AAP secretion in childhood, PA children in many studies have not had lower birth weights than controls [12,55,71,89,90]. However, Ibanez et al. have shown lower birth weights in Catalan PP girls than in controls in their retrospective analysis [56], and Neville and Walker [91] showed a high percentage of SGA-born subjects (35%) in a retrospective analysis of an Australian PP cohort where the 10th percentile was used as the birth weight limit for SGA. In the same PP cohort, premature birth was traced in 24% of the PP children, and rapid weight gain and overweight also associated with PP [91]. If we look at the follow-up studies of SGA cohorts, very few SGA-born children have been reported to develop PA [81,92]. Thus, it seems that being born SGA does not play a significant role in the pathogenesis of PA in full-term-born children in most populations, but preterm birth may increase the risk of adrenal hyperandrogenism even until early adulthood. Hyperinsulinism with or without obesity is apparently an important factor contributing to adrenal hyperandrogenism and PA. 7. Association of PA and birth size with ovarian hyperandrogenism and polycystic ovarian syndrome (PCOS) Adrenal hyperresponsiveness to ACTH stimulation has been recognized in adult women with PCOS or hyperandrogenism with acne and/or hirsutism already since 1970s [50,51]. Conversely, Ibanez et al. reported in early 1990s that 16 of their 35 girls (46%) with a history of PP due to PA had functional ovarian hyperandrogenism (FOH) (oligomenorrhea, hirsutism, elevated serum androgen levels) at the mean age of 15.4 years. Eight of the 16hyperandrogenic and three of the 19 regularly menstruating girls with a history of PP had polycystic ovaries on pelvic ultrasonography, but no specific hormonal marker at PP diagnosis predicted the appearance of FOH in adolescence [93]. Later studies on postmenarcheal Catalonian girls showed that the mean birth weight SD score of the PP girls with FOH (n = 23) was significantly lower than that of the PP girls without FOH (n = 25) or of the controls (n = 31) [56]. Another small study (n = 15) on mixed American prepubertal girls with PP due to PA showed no evidence of FOH, although functional adrenal hyperandrogenism was detected [94]. A third study from France did not find polycystic ovarian morphology on pelvic ultrasound examination in any of the 27 Caucasian adolescents (mean age 17.4 years) with a history of PP due to PA [89]. They had slightly higher hirsutism scores, serum androstenedione concentrations, and free androgen index but lower sex hormone binding globulin (SHBG) levels than the 25 age-matched healthy control girls. No significant difference in the birth measures, gestational ages, fasting serum DHEAS, lipid, insulin or plasma glucose levels between the study groups was detected. The same was true for the insulin/glucose ratio during a standard oral glucose tolerance test [89]. Three birth cohort studies in other populations have not found a relationship between low birth weight and PCOS in adult women [95–97]; actually a large birth weight turned out to be associated with PCOS [95,97]. There is no general consensus on the diagnostic criteria of PCOS in adolescence [59,98,99], and the term FOH may often be more

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suitable at this developmental stage. As hyperinsulinism and/or reduced insulin sensitivity are often present in both FOH/PCOS (reviewed in [100,101]) and PA [67,68,90,102], hyperinsulinism is probably a significant factor contributing to hyperandrogenism in both conditions. There is also experimental evidence supporting the view that insulin and insulin-like growth factors (IGFs) stimulate steroidogenesis and cell proliferation in human ovarian and adrenal cells [103–106]. As FOH/PCOS and functional adrenal hyperandrogenism (FAH) often coexist and associate with hyperinsulinism in adult women [59,100], it is logical to hypothesize that the clinical conditions in children with hyperandrogenism and/or hyperisulinism (for example congenital virilizing adrenal hyperplasia, being born SGA or preterm, PA, obesity) could predispose to later FOH/PCOS and/or FAH. Fortunately, only a small percentage of children with small birth size or PA seem to develop significant FOH or FAH in later life in most populations. It may well be that when the physiological hyperinsulinism of puberty [107–109] wanes, the signs of FOH or FAH usually ameliorate or disappear in late adolescence if there is not concomitant obesity. In any case, lifestyle interventions by increasing physical activity and reducing overweight are the most important prevention and treatment modalities for PCOS/FOH in adolescence [98,99] whether there is a history of PA or not. 8. Body composition, bone mineral density, cardio-metabolic changes, and chronic inflammation in PA In one of the earliest reports on the association of overweight with AA(P)s, obese prepubertal girls tended to have higher serum DHEA concentrations than lean ones, suggesting that obesity is associated with the maturation of the D5-pathway of adrenal steroidogenesis [110]. This association has been confirmed in several studies, most recently in a Chilean study on 969 prepubertal children: total and central adiposity indicators associated positively with serum DHEAS concentrations [111]. Most reports indicate that overweight and obesity are more common in children with PA/PP than in controls or general population. In a retrospective Australian analysis of PP children (79 girls, 10 boys), 65% of the subjects were overweight or obese at diagnosis [91]. In a French study on PP children (n = 216), BMI-SD score was  + 2 in 32.5% of the girls aged >4 years and in 46.4% of the boys aged >5 years [77]. Also, in twenty Lithuanian girls with PA (age range 4.9–10.2 years), the mean BMI-SD score was +2.1compared to +0.94 in 13 control girls [112]. Increased prevalence of obesity or high BMI for age was also found in 52 Brazilian PP girls [113] and in Scottish children (42 girls, 8 boys) with PA [55] at diagnosis. In our Finnish cohort of prepubertal PA children (54 girls and 10 boys), the mean BMI SD score was +1.09 compared to +0.26 in the controls [70]. Longitudinal studies have shown that a rise of BMI in both prepubertal and pubertal children is associated with an increase in urinary excretion of DHEAS in healthy subject [114] and that plasma concentrations of AAPs decrease with a weight loss in obese prepubertal and early pubertal boys [115]. Thus, it seems that obesity is a risk factor for PA and changes in adiposity are reflected in AAP secretion. However, there are also reports suggesting no association between body weight and adrenarche. In a recent American study, 35 prepubertal children with PA had their mean BMI Z-score similar to that of 31control children [65], but in this study many of the control children were also overweight or obese (mean BMI Z-score +1.48 in the PA vs. +1.29 in the control group). Also, in a Peruvian cross sectional study on 7–12 year-old children, modified BMI was not associated with AAP levels [116]. A group of Catalan girls with PP were reported to have greater waist circumference, total, truncal and abdominal fat mass (assessed by dual X-ray absorptiometry) than the age- and

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pubertal stage-matched control girls [117]. In our cross-sectional study, fat mass, soft lean mass, and fat percentage were higher but soft lean mass percentage lower in the PA than age-matched control children [70]. Areal bone mineral density has been reported to be increased in prepubertal PA children [70,118], but when adjusted for body size, the difference between the PA and control children was no longer significant in our study [70]. Higher insulin levels (either basal or glucose stimulated) than in controls have been found in several PA cohorts though no significant differences in either basal or stimulated glucose concentrations have been reported. Non-obese Catalan girls with a history of PP due to PA presented with increased early insulin responses to an oral glucose tolerance test, and with decreased SHBG levels at the age of 5.9–18 years, as compared to control girls matched for pubertal stage and bone age [119]. Hyperinsulinemia was strongly related to known cardiovascular risk factors, such as total cholesterol and central adiposity among these mostly adolescent girls with a history of PA [120]. In a recent American study, fasting insulin concentrations were similar in PA and control children, but the area under the curve of the insulin concentrations during a glucose tolerance test was higher in the PA children [65]. This is in good accordance with our study on prepubertal PA girls [90]: the mean weight-for-height-adjusted serum insulin concentrations during a glucose tolerance test were higher in the PA (n = 63) than control group (n = 80), but the fasting insulin levels did not differ significantly between the study groups. However, the PA girls with pubic hair (PP–PA, n = 32) had significantly higher fasting insulin and lower SHBG levels than the non PP–PA (n = 31) and control girls (n = 80), suggesting that prepubertal PA girls without pubic hair have milder metabolic changes than those with it. The prevalence of childhood metabolic syndrome was higher in the PA than control group, explained mainly by overweight and hyperinsulinism in the PA group [90]. Some studies have found no association of insulin concentrations or markers of insulin resistance with serum DHEAS levels in childhood. In a Chilean population-based study on 7-year-old children, metabolic parameters (fasting plasma glucose, insulin, and the insulin resistance index HOMA-IR = homeostasis model assessment for insulin resistance) were similar in high- and normal-DHEAS groups, when the children were analyzed separately in groups with similar BMI-for-age Z-scores [111]. Similarly, in a Brazilian study there was no evidence on hyperinsulinism or insulin resistance in girls with a history of PP due to PA at the mean study age of 12.1 years (range 8.1–21.7) [113]. A few studies have reported dyslipidemia in subjects with PA. Catalan girls (age range 5.9–18 years) with a history of PP due to PA presented with increased serum triglyceride (TG) levels and lowdensity lipoprotein–cholesterol (LDL–C)/high-density lipoprotein– cholesterol (HDL–C) ratios compared to control girls matched for pubertal stage and bone age [119]. In a small Turkish cohort of PA girls (n = 24, age range 5.4–8.6 years), mean total cholesterol (TC), LDL–C, very low-density lipoprotein–cholesterol, TC/HDL–C and LDL–C/HDL–C ratios were significantly higher than in age-matched control girls (n = 13) [121]. Also, in a Brazilian cohort of 53 females with a history of PP, 63.5% of the subjects were interpreted to have abnormal lipid profile at the mean follow-up age of 12.1 years (range 8.1–21.7) [113]. However, in our Finnish study, prepubertal PA girls (n = 63) had similar serum lipid concentrations to the agematched control girls (n = 80) [90]. Blood pressure has not been widely studied in PA subjects. We found no difference in the mean systolic or diastolic blood pressure levels between PA and control girls when adjusted for weight-for height [90]. In a small Turkish study, systolic, diastolic and mean arterial blood pressure of PA girls were higher than in control girls [121], but no adjustment for weight or height was reported in that study.

Insulin resistance and obesity may be associated with chronic inflammation. We found slightly increased serum concentrations of tumor necrosis factor-alpha in prepubertal PA children (n = 69), but interleukin-6 concentrations were similar to those of the agematched controls (n = 95) [122]. Catalan girls with a history of PP (n = 33, age range 6–11 years, birth weight <
1.5 SD scores in 42.4% of the subjects) presented with higher plasminogen activator inhibitor-1 concentrations and activities than the age- and pubertal stage -matched control girls (n = 13, most with short stature) [123]. In another Catalan study, PP girls born SGA (n = 33, mean age 8 years) had their mean blood neutrophil count significantly above the reference range [124]. 9. Mutations and genetic polymorphisms associating with PP/ PA The genetic basis for the inter-individual variation in timing and strength of adrenarche is not known. Though one genome-wide association study (GWAS) on serum DHEAS concentrations in adults and aging individuals has been published [125], no GWAS studies on PA/PP or on the variations of serum DHEAS concentrations in children have yet been reported. Thus all genetic studies on PA subjects have focused on polymorphisms of certain candidate genes in small groups of children. Short androgen receptor (AR) gene CAG trinucleotide repeats (CAG)n have been associated with PA in three separate studies [61–63]. The transcriptional activity of AR is negatively associated with AR (CAG)n and theoretically short repeats could lead to an increased activation of androgen target genes at lower androgen concentrations [126]. In our study, shorter AR CAG repeats were found especially in lean children with PA [63]. Another positive association with PA was found with the ACTH receptor (MC2R)
2 bp T/C diallelic promoter polymorphism; we found that within the PA group, the
2 T > C polymorphism was associated with a more severe phenotype [127]. Polymorphisms of the genes involved in insulin and IGF system have also been detected. The variant GAA1013 ! GAG of the IGF-I receptor (IGF-IR) gene is associated with increased serum concentrations of IGF-I and this SNP was found to be more common in children with PA than in control children [128]. Also, compared to healthy control women, a higher frequency of insulin receptor substrate-1 (IRS-1) gene polymorphism G972R was found in females with a history of PP and hyperinsulinemic ovarian hyperandrogenism [129]. Different forms of congenital adrenal hyperplasia, activating LH receptor (LH/CGR) mutations associated with familial testotoxicosis, and activating GNAS1 mutations may lead to PP and have to be taken into account in the differential diagnosis of PA [19]. The prevalence of non-classical congenital adrenal hyperplasia (NCCAH) varies much in different populations: relatively high percentage of NCCAH among PP or PA subjects has been reported for instance in Italy [76], Greece [130], Australia [52], and some areas of USA [75,131] but much lower in Northern Europe [7,55] and some areas of USA [132]. PP has been associated also with aromatase (CYP19) gene polymorphisms, both within the coding and promoter regions [133]. Furthermore, some other rare disorders in steroid metabolism or action have recently been associated with PP and adrenal hyperandrogenism. These include mutations in the glucocorticoid receptor (GR) gene, leading to generalized glucocorticoid resistance, hypersecretion of ACTH, and adrenal hyperandrogenism [134]. ACTH-driven adrenal hyperandrogenism is present also in apparent cortisone reductase deficiency (ACRD) due to inactivating mutations in the hexose-6-phosphate dehydrogenase (H6PDH) and in “true” cortisone reductase deficiency (CRD) due to inactivating mutations in the 11b-hydroxysteroid dehydrogenase 1 (HSD11B1) genes. Both ACRD and CRD lead to reduced peripheral formation of

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cortisol, and they can be diagnosed by gas chromatography/mass spectrometry (GC/MS) analysis of 24 h urine collections, where cortisone metabolites are elevated [135]. Another rare genetic disorder leading to PP is deficient DHEA sulfotransferase (SULT2A1) activity due to an inactivating mutation in the PAPSS2 gene which encodes for a cofactor for SULT2A1 [136] (Fig. 1). In this disease, DHEA is not converted to DHEAS, thereby fuelling the alternative conversion of DHEA to potent androgens. We did not detect any differences in the genotypic distribution of the common polymorphisms at P450 oxidoreductase (POR), SULT2A1, or HSD11B1 genes between our Caucasian PA (n = 73) and control subjects (n = 98) [137], suggesting that these polymorphic variants do not significantly contribute to PA in the Finnish population. 10. Summary The diagnosis of PA is acceptable when clinical signs of androgen action appear before the age of 8 years in girls or 9 years in boys associated with adrenal AA(P) concentrations high for the prepubertal chronological age and when the androgen effects are not caused by central puberty, adrenocortical or gonadal tumors, congenital adrenal hyperplasia, or exogenous androgens. Quite low serum AAP concentrations are sometimes measured in subjects with typical signs of PA, which suggests that conversion of AAPs to biologically active androgens and AR activity in target tissues are equally important as circulating AA(P)s for the clinical signs of androgen action. Adult type body odor is a very common clinical sign of PA when recorded carefully. Pubic/axillary hair may be present in only about half of the PA children at diagnosis, but the PA subjects with pubic hair may have a higher risk for metabolic disturbances than those without it. Acceleration of statural growth in early childhood even without overweight is often seen in children with later PA suggesting that PA needs to be considered in the differential diagnostics of accelerated statural growth during the first years of life. In addition to androgens, insulin and IGFsystem are involved and possibly interacting in the acceleration of statural growth in PA. The etiology of PA is multifactorial with apparent polygenic contribution, but overweight and obesity are important factors having increased the prevalence of PA during the last decades. In addition to overweight, other conditions with hyperinsulinism (in fasting or postprandial state) increase AA(P) secretion and thus the risk for PA; being born SGA and prematurity belong to these conditions. From the molecular point of view, phosphorylation of CYP17A1 increases its 17,20 lyase activity which favors AA(P) production. It is possible that many of the environmental, nutritional and hormonal factors suggested or known to increase AA(P) production mediate their effects by converging to a common or few pathways leading to increased 17,20-lyase activity of CYP17A1 [36]. In some populations (especially Catalan), the features of PCOS and the metabolic syndrome seem to be common among young women with a history of PA. However, the prevalence of the possible long-term health problems suggested to be associated with a history of PA in other populations is not known indicating why follow-up studies to clarify this issue are needed. In any case, lifestyle interventions by increasing physical activity and reducing overweight are useful in the prevention and treatment of PA and its possible long-term consequences. References [1] F. Albright, Osteoporosis, Ann. Intern. Med. 27 (1947) 861–882. [2] G. Dhom, The prepubertal and pubertal growth of the adrenal (adrenarche), Beitr. Pathol. 150 (1973) 357–377. [3] G.B. Cutler Jr, M. Glenn, M. Bush, G.D. Hodgen, C.E. Graham, D.L. Loriaux, Adrenarche: a survey of rodents, domestic animals, and primates, Endocrinology 103 (1978) 2112–2118.

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[4] P.J. Smail, C. Faiman, W.C. Hobson, G.B. Fuller, J.S. Winter, Further studies on adrenarche in nonhuman primates, Endocrinology 111 (1982) 844–848. [5] A.J. Conley, R.M. Bernstein, A.D. Nguyen, Adrenarche in nonhuman primates: the evidence for it and the need to redefine it, J. Endocrinol. 214 (2012) 121– 131. [6] S. Silverman, C. Migeon, E. Rosemberg, L. Wilkins, Precocious growth of sexual hair without other secondary sexual development: “premature pubarche” a constitutional variation of adolescence, Pediatrics 10 (1952) 426–432. [7] P. Utriainen, R. Voutilainen, J. Jääskeläinen, Continuum of phenotypes and sympathoadrenal function in premature adrenarche, Eur. J. Endocrinol. 160 (2009) 657–665. [8] S. Korth-Schutz, L.S. Levine, M.I. New, Serum androgens in normal prepubertal and pubertal children and in children with precocious adrenarche, J. Clin. Endocrinol. Metab. 42 (1976) 117–124. [9] R. Voutilainen, J. Perheentupa, D. Apter, Benign premature adrenarche: clinical features and serum steroid levels, Acta Paediatr. Scand. 72 (1983) 707–711. [10] L. Ibanez, R. Virdis, N. Potau, M. Zampolli, L. Ghizzoni, M.A. Albisu, A. Carrascosa, S. Bernasconi, E. Vicens-Calvet, Natural history of premature pubarche: an auxological study, J. Clin. Endocrinol. Metab. 74 (1992) 254– 257. [11] A. Pere, J. Perheentupa, M. Peter, R. Voutilainen, Follow up of growth and steroids in premature adrenarche, Eur. J. Pediatr. 154 (1995) 346–352. [12] P. Utriainen, R. Voutilainen, J. Jääskeläinen, Girls with premature adrenarche have accelerated early childhood growth, J. Pediatr. 154 (2009) 882–887. [13] R.M. Williams, C.E. Ward, I.A. Hughes, Premature adrenarche, Arch. Dis. Child. 97 (2012) 250–254. [14] R.J. Auchus, W.E. Rainey, Adrenarche – physiology, biochemistry and human disease, Clin. Endocrinol. 60 (2004) 288–296. [15] W.L. Miller, Androgen synthesis in adrenarche, Rev. Endocr. Metab. Disord. 10 (2009) 3–17. [16] P.J. Hornsby, Adrenarche a cell biological perspective, J. Endocrinol. 214 (2012) 113–119. [17] J. Rege, W.E. Rainey, The steroid metabolome of adrenarche, J. Endocrinol. 214 (2012) 133–143. [18] L. Ibanez, J. Dimartino-Nardi, N. Potau, P. Saenger, Premature adrenarche – normal variant or forerunner of adult disease? Endocr. Rev. 21 (2000) 671– 696. [19] J. Idkowiak, G.G. Lavery, V. Dhir, T.G. Barrett, P.M. Stewart, N. Krone, W. Arlt, Premature adrenarche: novel lessons from early onset androgen excess, Eur. J. Endocrinol. 165 (2011) 189–207. [20] S.E. Oberfield, A.B. Sopher, A.T. Gerken, Approach to the girl with early onset of pubic hair, J. Clin. Endocrinol. Metab. 96 (2011) 1610–1622. [21] S. Mesiano, R.B. Jaffe, Developmental and functional biology of the primate fetal adrenal cortex, Endocr. Rev. 18 (1997) 378–403. [22] K.M. Doody, B.R. Carr, W.E. Rainey, W. Byrd, B.A. Murry, R.C. Strickler, J.L. Thomas, J.I. Mason, 3 Beta-hydroxysteroid dehydrogenase/isomerase in the fetal zone and neocortex of the human fetal adrenal gland, Endocrinology 126 (1990) 2487–2492. [23] R. Voutilainen, V. Ilvesmäki, P.J. Miettinen, Low expression of 3 beta-hydroxy5-ene steroid dehydrogenase in human fetal adrenals in vivo; adrenocorticotropin and protein kinase C-dependent regulation in adrenocortical cultures, J. Clin. Endocrinol. Metab. 72 (1991) 761–767. [24] T. Narasaka, T. Suzuki, T. Moriya, H. Sasano, Temporal and spatial distribution of corticosteroidogenic enzyme immunoreactivity in developing human adrenal, Mol. Cell. Endocrinol. 174 (2001) 111–120. [25] M. Goto, K. Piper Hanley, J. Marcos, P.J. Wood, S. Wright, A.D. Postle, I.T. Cameron, J.I. Mason, D.I. Wilson, N.A. Hanley, In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development, J. Clin. Invest. 116 (2006) 953–960. [26] R. Voutilainen, A.I. Kahri, M. Salmenperä, The effects of progesterone, pregnenolone, estriol, ACTH and HCG on steroid secretion of cultured human fetal adrenals, J. Steroid Biochem. 10 (1979) 695–700. [27] R. Voutilainen, W.L. Miller, Developmental expression of genes for the steroidogenic enzymes P450scc (20,22 desmolase), P450c17 (17-hydroxylase/17,20 lyase) and P450c21 (21-hydroxylase) in the human fetus, J. Clin. Endocrinol. Metab. 63 (1986) 1145–1150. [28] V. Ilvesmäki, R. Voutilainen, Interaction of phorbol ester and adrenocorticotropin in the regulation of steroidogenic P450 genes in human fetal and adult adrenal cell cultures, Endocrinology 128 (1991) 1450–1458. [29] R.J. Schiebinger, B.D. Albertson, F.G. Cassorla, D.W. Bowyer, G.W. Geelhoed, G. B. Cutler Jr, D.L. Loriaux, The developmental changes in plasma adrenal androgens during infancy and adrenarche are associated with changing activities of adrenal microsomal 17-hydroxylase and 17,20-desmolase, J. Clin. Invest. 67 (1981) 1177–1182. [30] B.H. Rich, R.L. Rosenfield, A.W. Lucky, J.C. Helke, P. Otto, Adrenarche: changing response to adrenocorticotropin, J. Clin. Endocrinol. Metab. 52 (1981) 1129– 1136. [31] E.O. Reiter, V.G. Fuldauer, A.W. Root, Secretion of the adrenal androgen, dehydroepiandrosterone sulfate, during normal infancy, childhood, and adolescence, in sick infants, and in children with endocrinologic abnormalities, J. Pediatr. 90 (1977) 766–770. [32] J.S. Gell, B.R. Carr, H. Sasano, B. Atkins, L. Margraf, J.I. Mason, W.E. Rainey, Adrenarche results from development of a 3beta-hydroxysteroid dehydrogenase-deficient adrenal reticularis, J. Clin. Endocrinol. Metab. 83 (1998) 3695–3701.

234

R. Voutilainen, J. Jääskeläinen / Journal of Steroid Biochemistry & Molecular Biology 145 (2015) 226–236

[33] S. Mapes, C.J. Corbin, A. Tarantal, A. Conley, The primate adrenal zona reticularis is defined by expression of cytochrome b5, 17alpha-hydroxylase/ 17,20-lyase cytochrome P450 (P450c17) and NADPH-cytochrome P450 reductase (reductase) but not 3beta-hydroxysteroid dehydrogenase/delta5-4 isomerase (3beta-HSD), J. Clin. Endocrinol. Metab. 84 (1999) 3382–3385. [34] T. Suzuki, H. Sasano, J. Takeyama, C. Kaneko, W.A. Freije, B.R. Carr, W.E. Rainey, Developmental changes in steroidogenic enzymes in human postnatal adrenal cortex: immunohistochemical studies, Clin. Endocrinol. 53 (2000) 739–747. [35] L.H. Zhang, H. Rodriguez, S. Ohno, W.L. Miller, Serine phosphorylation of human P450c17 increases 17,20-lyase activity: implications for adrenarche and the polycystic ovary syndrome, Proc. Natl. Acad. Sci. U. S. A. 92 (1995) 10619–10623. [36] M.K. Tee, W.L. Miller, Phosphorylation of human cytochrome P450c17 by p38a selectively increases 17,20 lyase activity and androgen biosynthesis, J. Biol. Chem. 288 (2013) 23903–29313. [37] D.C. Anderson, The adrenal androgen-stimulating hormone does not exist, Lancet 2 (8192) (1980) 454–456. [38] A.I. Kahri, R. Voutilainen, M. Salmenperä, Different biological action of corticosteroids, corticosterone and cortisol, as a base of zonal function of adrenal cortex, Acta Endocrinol. (Copenh.) 91 (1979) 329–337. [39] L.S. Topor, M. Asai, J. Dunn, J.A. Majzoub, Cortisol stimulates secretion of dehydroepiandrosterone in human adrenocortical cells through inhibition of 3betaHSD2, J. Clin. Endocrinol. Metab. 96 (2011) E31–E39. [40] Z. Dickerman, D.R. Grant, C. Faiman, J.S. Winter, Intraadrenal steroid concentrations in man: zonal differences and developmental changes, J. Clin. Endocrinol. Metab. 59 (1984) 1031–1036. [41] R. Voutilainen, R. Riikonen, O. Simell, J. Perheentupa, The effect of ACTH therapy on serum dehydroepiandrosterone, androstenedione, testosterone and 5adihydrotestosterone in infants, J. Steroid Biochem. 28 (1987) 193–196. [42] M.R. Palmert, D.L. Hayden, M.J. Mansfield, J.F. Crigler Jr, W.F. Crowley Jr, D.W. Chandler, P.A. Boepple, The longitudinal study of adrenal maturation during gonadal suppression: evidence that adrenarche is a gradual process, J. Clin. Endocrinol. Metab. 86 (2001) 4536–4542. [43] T. Remer, K.R. Boye, M.F. Hartmann, S.A. Wudy, Urinary markers of adrenarche: reference values in healthy subjects, aged 3–18 years, J. Clin. Endocrinol. Metab. 90 (2005) 2015–2021. [44] G. Lashansky, P. Saenger, K. Fishman, T. Gautier, D. Mayes, G. Berg, J. Di Martino-Nardi, E. Reiter, Normative data for adrenal steroidogenesis in a healthy pediatric population: age- and sex-related changes after adrenocorticotropin stimulation, J. Clin. Endocrinol. Metab. 73 (1991) 674–686. [45] N. Orentreich, J.L. Brind, R.L. Rizer, J.H. Vogelman, Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood, J. Clin. Endocrinol. Metab. 59 (1984) 551–555. [46] A. Weber, A.J.L. Clark, L.A. Perry, J.W. Honour, M.O. Savage, Diminished adrenal androgen secretion in familial glucocorticoid deficiency implicates a significant role for ACTH in the induction of adrenarche, Clin. Endocrinol. 46 (1997) 431–437. [47] C. Boettcher, M.F. Hartman, J. de Laffolie, K.P. Zimmer, S.A. Wudy, Absent adrenarche in children with hypopituitarism: a study based on urinary steroid metabolomics, Horm. Res. Paediatr. 79 (2013) 356–360. [48] S. Kannisto, M. Korppi, K. Remes, R. Voutilainen, Serum dehydroepiandrosterone sulfate concentration as an indicator of adrenocortical suppression in asthmatic children treated with inhaled steroids, J. Clin. Endocrinol. Metab. 86 (2001) 4908–4912. [49] S. Kannisto, A. Laatikainen, A. Taivainen, K. Savolainen, H. Tukiainen, R. Voutilainen, Serum dehydroepiandrosterone sulfate concentration as an indicator of adrenocortical suppression during inhaled steroid therapy in adult asthmatic patients, Eur. J. Endocrinol. 150 (2004) 687–690. [50] G.C. Lachelin, M. Barnett, B.R. Hopper, G. Brink, S.S. Yen, Adrenal function in normal women and women with the polycystic ovary syndrome, J. Clin. Endocrinol. Metab. 49 (1979) 892–898. [51] A.W. Lucky, R.J. Rosenfield, J. McGuire, S. Rudy, J. Helke, Adrenal androgen hyperresponsiveness to adrenocorticotropin in women with acne and/or hirsutism: adrenal enzyme defects and exaggerated adrenarche, J. Clin. Endocrinol. Metab. 62 (1986) 840–848. [52] S. Likitmaskul, C.T. Cowell, K. Donaghue, D.J. Kreutzmann, N.J. Howard, B. Blades, M. Silink, ‘Exaggerated adrenarche' in children presenting with premature adrenarche, Clin. Endocrinol. 42 (1995) 265–272. [53] L. Ibanez, N. Potau, M.V. Marcos, F. de Zegher, Exaggerated adrenarche and hyperinsulinism in adolescent girls born small for gestational age, J. Clin. Endocrinol. Metab. 84 (1999) 4739–4741. [54] M. Maliqueo, T. Sir-Petermann, V. Perez, B. Echiburu, A.L. de Guevara, C. Galvez, N. Crisosto, R. Azziz, Adrenal function during childhood and puberty in daughters of women with polycystic ovary syndrome, J. Clin. Endocrinol. Metab. 94 (2009) 3282–3288. [55] W.F. Paterson, S.F. Ahmed, L. Bath, M.D. Donaldson, R. Fleming, S.A. Greene, I. Hunter, C.J. Kelnar, A. Mayo, J.S. Schulga, D. Shapiro, P.J. Smail, A.M. Wallace, Exaggerated adrenarche in a cohort of Scottish children: clinical features and biochemistry, Clin. Endocrinol. 72 (2010) 496–501. [56] L. Ibanez, N. Potau, I. Francois, F. de Zegher, Precocious pubarche, hyperinsulinism, and ovarian hyperandrogenism in girls: relation to reduced fetal growth, J. Clin. Endocrinol. Metab. 83 (1998) 3558–3562. [57] N. Potau, L. Ibanez, S. Rique, C. Sanchez-Ufarte, F. de Zegher, Pronounced adrenarche and precocious pubarche in boys, Horm. Res. 51 (1999) 238–241.

[58] L. Ibanez, R. Jimenez, F. de Zegher, Early puberty-menarche after precocious pubarche: relation to prenatal growth, Pediatrics 117 (2006) 117–121. [59] R.L. Rosenfield, Identifying children at risk for polycystic ovary syndrome, J. Clin. Endocrinol. Metab. 92 (2007) 787–796. [60] L. Ghizzoni, V. Gasco, Premature pubarche, Horm. Res. Paediatr. 73 (2010) 420–422. [61] L. Ibanez, K.K. Ong, N. Mongan, J. Jääskeläinen, M.V. Marcos, I.A. Hughes, F. De Zegher, D.B. Dunger, Androgen receptor gene CAG repeat polymorphism in the development of ovarian hyperandrogenism, J. Clin. Endocrinol. Metab. 88 (2003) 3333–3338. [62] A. Vottero, M. Capelletti, S. Giuliodori, I. Viani, M. Ziveri, T.M. Neri, S. Bernasconi, L. Ghizzoni, Decreased androgen receptor gene methylation in premature pubarche: a novel pathogenetic mechanism? J. Clin. Endocrinol. Metab. 91 (2006) 968–972. [63] S. Lappalainen, P. Utriainen, T. Kuulasmaa, R. Voutilainen, J. Jääskeläinen, Androgen receptor gene CAG repeat polymorphism and X-chromosome inactivation in children with premature adrenarche, J. Clini. Endocrinol. Metab. 93 (2008) 1304–1309. [64] J. Liimatta, S. Laakso, P. Utriainen, R. Voutilainen, J.J. Palvimo, T. Jääskeläinen, J. Jääskeläinen, Serum androgen bioactivity is low in children with premature adrenarche, Pediatr. Res. 75 (2014) 645–650. [65] A.B. Sopher, A.M. Jean, S.K. Zwany, D.M. Winston, C.B. Pomeranz, J.J. Bell, D.J. McMahon, A. Hassoun, I. Fennoy, S.E. Oberfield, Bone age advancement in prepubertal children with obesity and premature adrenarche: possible potentiating factors, Obesity 19 (2011) 1259–1264. [66] P. Utriainen, J. Jääskeläinen, R. Voutilainen, Blood erythrocyte and hemoglobin concentrations in premature adrenarche, J. Clin. Endocrinol. Metab. 98 (2013) E87–E91. [67] L. Ibanez, N. Potau, M. Zampolli, S. Rique, P. Saenger, A. Carrascosa, Hyperinsulinemia and decreased insulin-like growth factor-binding protein-1 are common features in prepubertal and pubertal girls with a history of premature pubarche, J. Clin. Endocrinol. Metab. 82 (1997) 2283–2288. [68] M.R. Denburg, M.E. Silfen, A.M. Manibo, D. Chin, L.S. Levine, M. Ferin, D.J. McMahon, C. Go, S.E. Oberfield, Insulin sensitivity and the insulin-like growth factor system in prepubertal boys with premature adrenarche, J. Clin. Endocrinol. Metab. 87 (2002) 5604–5609. [69] M.E. Silfen, A.M. Manibo, M. Ferin, D.J. McMahon, L.S. Levine, S.E. Oberfield, Elevated free IGF-I levels in prepubertal Hispanic girls with premature adrenarche: relationship with hyperandrogenism and insulin sensitivity, J. Clin. Endocrinol. Metab. 87 (2002) 398–403. [70] P. Utriainen, J. Jääskeläinen, A. Saarinen, E. Vanninen, O. Mäkitie, R. Voutilainen, Body composition and bone mineral density in children with premature adrenarche and the association of LRP5 gene polymorphisms with bone mineral density, J. Clin. Endocrinol. Metab. 94 (2009) 4144–4151. [71] L. Ghizzoni, S. Milani, The natural history of premature adrenarche, J. Pediatr. Endocrinol. Metab. 13 (Suppl. 5) (2000) 1247–1251. [72] T. Oron, Y. Lebenthal, L. de Vries, M. Yackobovitch-Gavan, M. Phillip, L. Lazar, Interrelationship of extent of precocious adrenarche in appropriate for gestational age girls with clinical outcome, J. Pediatr. 160 (2012) 308–313. [73] J. von Oettingen, J. Sola Pou, L.L. Levitsky, M. Misra, Clinical presentation of children with premature adrenarche, Clin. Pediatr. (Phila.) 51 (2012) 1140– 1149. [74] S.E. Oberfield, D.M. Mayes, L.S. Levine, Adrenal steroidogenic function in a black and hispanic population with precocious pubarche, J. Clin. Endocrinol. Metab. 70 (1990) 76–82. [75] S.F. Siegel, D.N. Finegold, M.D. Urban, R. McVie, P.A. Lee, Premature pubarche: etiological heterogeneity, J. Clin. Endocrinol. Metab. 74 (1992) 239–247. [76] R. Balducci, B. Boscherini, A. Mangiantini, M. Morellini, V. Toscano, Isolated precocious pubarche: an approach, J. Clin. Endocrinol. Metab. 79 (1994) 582– 589. [77] M.-L. Charkaluk, C. Trivin, R. Brauner, Premature pubarche as an indicator of how body weight influences the onset of adrenarche, Eur. J. Pediatr. 163 (2004) 89–93. [78] I. Francois, F. de Zegher, Adrenarche and fetal growth, Pediatr. Res. 41 (1997) 440–442. [79] J. Dahlgren, M. Boguszewski, S. Rosberg, K. Albertsson-Wikland, Adrenal steroid hormones in short children born small for gestational age, Clin. Endocrinol. 49 (1998) 353–361. [80] P. Ghirri, M. Bernardini, M. Vuerich, A.M. Cuttano, L. Coccoli, I. Merusi, C. Ciulli, L. D’Accavio, U. Bottone, A. Boldrini, Adrenarche, pubertal development, age at menarche and final height of full-term, born small for gestational age (SGA) girls, Gynecol. Endocrinol. 15 (2001) 91–97. [81] S. Tenhola, A. Martikainen, E. Rahiala, M. Parviainen, P. Halonen, R. Voutilainen, Increased adrenocortical and adrenomedullary hormonal activity in 12-year-old children born small for gestational age, J. Pediatr. 141 (2002) 477–482. [82] K.K. Ong, N. Potau, C.J. Petry, R. Jones, A.R. Ness, J.W. Honour, F. de Zegher, L. Ibanez, D.B. Dunger, Avon longitudinal study of parents and children study team. Opposing influences of prenatal and postnatal weight gain on adrenarche in normal boys and girls, J. Clin. Endocrinol. Metab. 89 (2004) 2647–2651. [83] D. Jaquet, J. Leger, D. Chevenne, P. Czernichow, C. Levy-Marchal, Intrauterine growth retardation predisposes to insulin resistance but not to hyperandrogenism in young women, J. Clin. Endocrinol. Metab. 84 (1999) 3945– 3949.

R. Voutilainen, J. Jääskeläinen / Journal of Steroid Biochemistry & Molecular Biology 145 (2015) 226–236 [84] K. Allvin, C. Ankarberg-Lindgren, H. Fors, J. Dahlgren, Elevated serum levels of estradiol, dihydrotestosterone, and inhibin B in adult males born small for gestational age, J. Clin. Endocrinol. Metab. 93 (2008) 1464–1469. [85] R.B. Jensen, S. Vielwerth, T. Larsen, L. Hilsted, A. Cohen, D.M. Hougaard, L.T. Jensen, G. Greisen, A. Juul, Influence of fetal growth velocity and smallness at birth on adrenal function in adolescence, Horm. Res. Paediatr. 75 (2011) 2–7. [86] B. Todorova, M. Salonen, J. Jääskeläinen, A. Tapio, T. Jääskeläinen, J. Palvimo, U. Turpeinen, E. Hämäläinen, M. Räsänen, S. Tenhola, R. Voutilainen, Adrenocortical hormonal activity in 20-year-old subjects born small or appropriate for gestational age, Horm. Res. Paediatr. 77 (2012) 298–304. [87] M. Szathmari, B. Vasarhelyi, T. Tulassay, Effect of low birth weight on adrenal steroids and carbohydrate metabolism in early adulthood, Horm. Res. 55 (2001) 172–178. [88] C.L. Meuwese, A.M. Euser, B.E. Ballieux, H.A. van Vliet, M.J. Finken, F.J. Walther, F.W. Dekker, J.M. Wit, Growth-restricted preterm newborns are predisposed to functional adrenal hyperandrogenism in adult life, Eur. J. Endocrinol. 163 (2010) 681–689. [89] T. Meas, D. Chevenne, E. Thibaud, J. Leger, S. Cabrol, P. Czernichow, C. LevyMarchal, Endocrine consequences of premature pubarche in post-pubertal Caucasian girls, Clin. Endocrinol. 57 (2002) 101–106. [90] P. Utriainen, J. Jääskeläinen, J. Romppanen, R. Voutilainen, Childhood metabolic syndrome and its components in premature adrenarche, J. Clin. Endocrinol. Metab. 92 (2007) 4282–4285. [91] K.A. Neville, J.L. Walker, Precocious pubarche is associated with SGA, prematurity, weight gain, and obesity, Arch. Dis. Child. 90 (2005) 258–261. [92] V.H. Boonstra, P.G. Mulder, F.H. de Jong, A.C. Hokken-Koelega, Serum dehydroepiandrosterone sulfate levels and pubarche in short children born small for gestational age before and during growth hormone treatment, J. Clin. Endocrinol. Metab. 89 (2004) 712–717. [93] L. Ibanez, N. Potau, R. Virdis, M. Zampolli, C. Terzi, M. Gussinye, A. Carrascosa, E. Vicens-Calvet, Postpubertal outcome in girls diagnosed of premature pubarche during childhood: increased frequency of functional ovarian hyperandrogenism, J. Clin. Endocrinol. Metab. 76 (1993) 1599–1603. [94] R.P. Mathew, J.L. Najjar, R.A. Lorenz, D.E. Mayes, W.E. Russell, Premature pubarche in girls is associated with functional adrenal but not ovarian hyperandrogenism, J. Pediatr. 141 (2002) 91–98. [95] J.L. Cresswell, D.J. Barker, C. Osmond, P. Egger, D.I. Phillips, R.B. Fraser, Fetal growth, length of gestation, and polycystic ovaries in adult life, Lancet 350 (1997) 1131–1135. [96] J. Laitinen, S. Taponen, H. Martikainen, A. Pouta, I. Millwood, A.L. Hartikainen, A. Ruokonen, U. Sovio, M.I. McCarthy, S. Franks, M.R. Jarvelin, Body size from birth to adulthood as a predictor of self-reported polycystic ovary syndrome symptoms, Int. J. Obes. Relat. Metab. Disord. 27 (2003) 710–715. [97] H. Mumm, M. Kamper-Jørgensen, A.M. Nybo Andersen, D. Glintborg, M. Andersen, Birth weight and polycystic ovary syndrome in adult life: a register-based study on 523,757 Danish women born 1973-1991, Fertil. Steril. 99 (2013) 777–782. [98] A.A. Bremer, Polycystic ovary syndrome in the pediatric population, Metab. Syndr. Relat. Disord. 8 (2010) 375–394. [99] L.S. Vilmann, E. Thisted, J.L. Baker, J.C. Holm, Development of obesity and polycystic ovary syndrome in adolescents, Horm. Res. Paediatr. 78 (2012) 269–278. [100] D.A. Ehrmann, R.B. Barnes, R.L. Rosenfield, Polycystic ovary syndrome as a form of functional ovarian hyperandrogenism due to dysregulation of androgen secretion, Endocr. Rev. 16 (1995) 322–353. [101] E. Diamanti-Kandarakis, A. Dunaif, Insulin resistance and the polycyctic ovary syndrome revisited: an update on mechanisms and implications, Endocr. Rev. 33 (2012) 981–1030. [102] E. Oppenheimer, B. Linder, J. DiMartino-Nardi, Decreased insulin sensitivity in prepubertal girls with premature adrenarche and acanthosis nigricans, J. Clin. Endocrinol. Metab. 80 (1995) 614–618. [103] R.L. Barbieri, A. Makris, K.J. Ryan, Insulin stimulates androgen accumulation in incubations of human ovarian stroma and theca, Obstet. Gynecol. 64 (1984) 73S–80S. [104] R. Voutilainen, W.L. Miller, Coordinate tropic hormone regulation of mRNAs for insulin-like growth factor II and the cholesterol side-chain-cleavage enzyme, P450scc, in human steroidogenic tissues, Proc. Natl. Acad. Sci. U. S. A. 84 (1987) 1590–1594. [105] D. l'Allemand, A. Penhoat, M.-C. Lebrethon, R. Ardevol, V. Baehr, W. Oelkers, J. M. Saez, Insulin-like growth factors enhance steroidogenic enzyme and corticotrophin receptor messenger ribonucleic acid levels and corticotropin steroidogenic responsiveness in cultured human adrenocortical cells, J. Clin. Endocrinol. Metab. 81 (1996) 3892–3897. [106] S. Mesiano, S.L. Katz, J.Y. Lee, R.B. Jaffe, Insulin-like growth factors augment steroid production and expression of steroidogenic enzymes in human fetal adrenal cortical cells: implications for adrenal androgen regulation, J. Clin. Endocrinol. Metab. 82 (1997) 1390–1396. [107] S.A. Amiel, S. Caprio, R.S. Sherwin, G. Plewe, M.W. Haymond, W.V. Tamborlane, Insulin resistance of puberty: a defect restricted to peripheral glucose metabolism, J. Clin. Endocrinol. Metab. 72 (1991) 277–282. [108] A. Moran, D.R. Jacobs Jr, J. Steinberger, C.P. Hong, R. Prineas, R. Luepker, A.R. Sinaiko, Insulin resistance during puberty: results from clamp studies in 357 children, Diabetes 48 (1999) 2039–2044. [109] A. Moran, D.R. Jacobs Jr, J. Steinberger, P. Cohen, C.P. Hong, R. Prineas, A.R. Sinaiko, Association between the insulin resistance of puberty and the

[110]

[111]

[112]

[113]

[114] [115]

[116]

[117]

[118]

[119]

[120]

[121] [122]

[123]

[124]

[125]

[126]

[127]

[128]

[129]

[130]

[131] [132]

[133]

235

insulin-like growth factor-I/growth hormone axis, J. Clin. Endocrinol. Metab. 87 (2002) 4817–4820. A.R. Genazzani, C. Pintor, R. Corda, Plasma levels of gonadotropins, prolactin, thyroxine, and adrenal and gonadal steroids in obese prepubertal girls, J. Clin. Endocrinol. Metab. 47 (1978) 974–979. C. Corvalan, R. Uauy, V. Mericq, Obesity is positively associated with dehydroepiandrosterone sulfate concentrations at 7 year in Chilean children of normal birth weight, Am. J. Clin. Nutr. 97 (2013) 318–325. S. Zukauskaite, A. Seibokaite, L. Lasas, D. Lasiene, B. Urbonaite, J. Kiesylyte, Serum hormone levels and anthropometric characteristics in girls with hyperandrogenism, Medicina (Kaunas) 41 (2005) 305–312. K. de Ferran, I.A. Paiva, S. Garcia Ldos, P. Gama Mde, M.M. Guimarães, Isolated premature pubarche: report of anthropometric and metabolic profile of a Brazilian cohort of girls, Horm. Res. Paediatr. 75 (2011) 367–373. T. Remer, F. Manz, Role of nutritional status in the regulation of adrenarche, J. Clin. Endocrinol. Metab. 84 (1999) 3936–3944. C. Pintor, S. Loche, A. Faedda, V. Fanni, A.M. Nurchi, R. Corda, Adrenal androgens in obese boys before and after weight loss, Horm. Metab. Res. 16 (1984) 544–548. G.F. Gonzales, A. Villena, C. Gonez, M. Zevallos, Relationship between body mass index, age, and serum adrenal androgen levels in Peruvian children living at high altitude and at sea level, Hum. Biol. 66 (1994) 145–153. L. Ibanez, K. Ong, F. de Zegher, M.V. Marcos, L. del Rio, D.B. Dunger, Fat distribution in non-obese girls with and without precocious pubarche: central adiposity related to insulinaemia and androgenaemia from prepuberty to postmenarche, Clin. Endocrinol. 58 (2003) 372–379. A.B. Sopher, J.C. Thornton, M.E. Silfen, A. Manibo, S.E. Oberfield, J. Wang, R.N. Pierson Jr, L.S. Levine, M. Horlick, Prepubertal girls with premature adrenarche have greater bone mineral content and density than controls, J. Clin. Endocrinol. Metab. 86 (2001) 5269–5272. L. Ibanez, N. Potau, P. Chacon, C. Pascual, A. Carrascosa, Hyperinsulinaemia, dyslipaemia and cardiovascular risk in girls with a history of premature pubarche, Diabetologia 41 (1998) 1057–1063. N. Potau, R. Williams, K. Ong, C. Sanchez-Ufarte, F. de Zegher, L. Ibanez, D. Dunger, Fasting insulin sensitivity and post-oral glucose hyperinsulinaemia related to cardiovascular risk factors in adolescents with precocious pubarche, Clin. Endocrinol. 59 (2003) 756–762. A. Güven, P. Cinaz, A. Bideci, Is premature adrenarche a risk factor for atherogenesis? Pediatr. Int. 47 (2005) 20–25. P. Utriainen, J. Jääskeläinen, O. Gröhn, J. Kuusisto, K. Pulkki, R. Voutilainen, Circulating TNF-alpha and IL-6 concentrations and TNF-alpha -308 G > A polymorphism in children with premature adrenarche, Front. Endocrinol. (Lausanne) 1 (2010) 6. L. Ibanez, C. Aulesa, N. Potau, K. Ong, D.B. Dunger, F. de Zegher, Plasminogen activator inhibitor-1 in girls with precocious pubarche: a premenarcheal marker for polycystic ovary syndrome? Pediatr. Res. 51 (2002) 244–248. L. Ibanez, A. Fucci, C. Valls, K. Ong, D. Dunger, F. de Zegher, Neutrophil count in small-for-gestational age children: contrasting effects of metformin and growth hormone therapy, J. Clin. Endocrinol. Metab. 90 (2005) 3435–3439. G. Zhai, A. Teumer, L. Stolk, J.R. Perry, L. Vandenput, A.D. Coviello, A. Koster, J.T. Bell, S. Bhasin, J. Eriksson, A. Eriksson, F. Ernst, L. Ferrucci, T.M. Frayling, D. Glass, E. Grundberg, R. Haring, A.K. Hedman, A. Hofman, D.P. Kiel, H.K. Kroemer, Y. Liu, K.L. Lunetta, M. Maggio, M. Lorentzon, M. Mangino, D. Melzer, I. Miljkovic, Muther Consortium, A. Nica, B.W. Penninx, R.S. Vasan, F. Rivadeneira, K.S. Small, N. Soranzo, A.G. Uitterlinden, H. Völzke, S.G. Wilson, L. Xi, W.V. Zhuang, T.B. Harris, J.M. Murabito, C. Ohlsson, A. Murray, F.H. de Jong, T.D. Spector, H. Wallaschofski, Eight common genetic variants associated with serum DHEAS levels suggest a key role in ageing mechanisms, PLoS Genet. 7 (2011) e1002025. N. Chaberlain, E. Driver, R. Miesfeld, The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function, Nucleic Acids Res. 22 (1994) 3181–3186. S. Lappalainen, P. Utriainen, T. Kuulasmaa, R. Voutilainen, J. Jääskeläinen, ACTH receptor promoter polymorphism associates with severity of premature adrenarche and modulates hypothalamo-pituitary-adrenal axis in children, Pediatr. Res. 63 (2008) 410–414. M.B. Roldan, C. White, S.F. Witchel, Association of the GAA1013 ! GAG polymorphism of the insulin-like growth factor-1 receptor (IGF1R) gene with premature pubarche, Fertil. Steril. 88 (2007) 410–417. L. Ibanez, M.V. Marcos, N. Potau, C. White, C.E. Aston, S.F. Witchel, Increased frequency of the G972R variant of the insulin receptor substrate-1 (irs-1) gene among girls with a history of precocious pubarche, Fertil. Steril. 78 (2002) 1288–1293. C. Dacou-Voutetakis, M. Dracopoulou, High incidence of molecular defects of the CYP21 gene in patients with premature adrenarche, J. Clin. Endocrinol. Metab. 84 (1999) 1570–1574. J.W. Temeck, S. Pang, C. Nelson, M. New, Genetic defects of steroidogenesis in premature pubarche, J. Clin. Endocrinol. Metab. 64 (1987) 609–617. A.H. Morris, E.O. Reiter, M.E. Geffner, B.M. Lippe, R.M. Itami, D.M. Mayes, Absence of nonclassical congenital adrenal hyperplasia in patients with precocious adrenarche, J. Clin. Endocrinol. Metab. 69 (1989) 709–715. C.J. Petry, K.K. Ong, K.F. Michelmore, S. Artigas, D.L. Wingate, A.H. Balen, F. de Zegher, L. Ibanez, D.B. Dunger, Association of aromatase (CYP 19) gene variation with features of hyperandrogenism in two populations of young women, Hum. Reprod. 20 (2005) 1837–1843.

236

R. Voutilainen, J. Jääskeläinen / Journal of Steroid Biochemistry & Molecular Biology 145 (2015) 226–236

[134] N. Nader, B.E. Bachrach, D.E. Hurt, S. Gajula, A. Pittman, R. Lescher, T. Kino, A novel point mutation in helix 10 of the human glucocorticoid receptor causes generalized glucocorticoid resistance by disrupting the structure of the ligand-binding domain, J. Clin. Endocrinol. Metab. 95 (2010) 2281–2285. [135] G.G. Lavery, J. Idkowiak, M. Sherlock, I. Bujalska, J.P. Ride, K. Saqib, M.F. Hartmann, B. Hughes, S.A. Wudy, J. De Schepper, W. Arlt, N. Krone, C.H. Shackleton, E.A. Walker, P.M. Stewart, Novel H6PDH mutations in two girls with premature adrenarche: ‘apparent’ and ‘true’ CRD can be differentiated by urinary steroid profiling, Eur. J. Endocrinol. 168 (2013) K19–K26. [136] C. Noordam, V. Dhir, J.C. McNelis, F. Schlereth, N.A. Hanley, N. Krone, J.A. Smeitink, R. Smeets, F.C. Sweep, H.L. Claahsen-van der Grinten, W. Arlt,

Inactivating PAPSS2 mutations in a patient with premature pubarche, N. Engl. J. Med. 360 (2009) 2310–2318. [137] P. Utriainen, S. Laakso, J. Jääskeläinen, R. Voutilainen, Polymorphism of POR, SULT2A1 and HSD11B1 in children with premature adrenarche, Metabolism 61 (2012) 1215–1219. [138] P.C. White, Ontogeny of adrenal steroid biosynthesis: why girls will be girls, J. Clin. Invest. 116 (2006) 872–874. [139] D. Apter, Serum steroids and pituitary hormones in female puberty: a partly longitudinal stydy, Clin. Endocrinol. 12 (1980) 107–120.