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Serum Androgen Bioactivity Is Low in Children with Premature Adrenarche

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Serum Androgen Bioactivity Is Low in Children with Premature Adrenarche nature publishing group Clinical Investigation Articles Serum androgen bioactivity is low in children with premature adrenarche Jani Liimatta1, Saila Laakso1, Pauliina Utriainen1, Raimo Voutilainen1, Jorma J. Palvimo2, Tiina Jääskeläinen2,3 and Jarmo Jääskeläinen1 BACKGROUND: Clinical findings in children with premature DHEA, DHEAS, or androstenedione (A4) (2,3). In peripheral adrenarche (PA) correlate only partly with circulating levels of tissues such as the skin, DHEA and DHEAS interconvert via adrenal androgens. It is not known whether the prepubertal hydroxysteroid sulfotransferase and steroid sulfatase (4), but low circulating concentrations of testosterone (T) and dihy- DHEAS desulfonation in the liver is controversial (5). DHEAS drotestosterone, together with those of adrenal androgens, are is biologically inactive, and DHEA is only a weak androgen capable of activating the androgen receptor. receptor (AR) agonist (6), but they are present in the serum of METHODS: This cross-sectional study was performed at a PA subjects in excess concentrations. university hospital. Circulating androgen bioactivity was mea- The effects of androgens are mediated via the AR, resulting sured in 67 prepubertal children with clinical signs of PA and 94 in the activation of target gene transcription (7). Whereas tes- control children using a novel androgen bioassay. tosterone (T) and dihydrotestosterone (DHT) are potent AR RESULTS: Circulating androgen bioactivity was low in the PA agonists, the affinity of adrenal androgen precursors to AR is and control children. In the subgroup of children (n = 28) with weak (6,8), and prereceptor level conversion to more potent serum T concentration over the assay sensitivity (0.35 nmol/l) androgens is needed for the full activation of AR. In periph- and a signal in the androgen bioassay, we found a positive cor- eral tissues, DHEA is converted to the most potent androgen, relation between androgen bioactivity and serum T (r = 0.50; P DHT, through A4 and T. The main enzymes responsible for < 0.01) and the free androgen index (r = 0.61; P < 0.01) and a this intracrine conversion are 3β-hydroxysteroid dehydro- negative correlation with serum sex hormone–binding globu- genase 1 (HSD3B1), 17β-hydroxysteroid dehydrogenase 5 lin concentration (r = −0.41; P < 0.05). (HSD17B5), and 5α-reductase. Expression of these convert- CONCLUSION: Peripheral metabolism of adrenal androgen ing enzymes has been discovered in many peripheral tissues, precursors may be required for any androgenic effects in including the skin epidermis, hair follicles, and dermal exo- PA. However, the limitations in the sensitivity of the bioassay crine gland cells (4,9,10), and the level of conversion varies in developed herein may hide some differences between the PA different cells (11). However, it is not known to what extent and control children. adrenal androgens are converted to T and DHT in the liver, or whether the androgens found in the circulation of PA subjects are able to induce further AR activation. he reticular zone (zona reticularis (ZR)) of the adrenal Peripheral intracrine prereceptor modulation of androgens Tcortex starts to develop from small focal islets in early and AR activity may be key points in explaining the variability childhood (1). Later on, continuous ZR begins to produce of androgenic activity in PA. Recent studies have demonstrated weak androgen precursors, mostly dehydroepiandrosterone that a shorter CAG repeat polymorphism in the AR gene lead- (DHEA) and its sulfate (DHEAS), and this phenomenon is ing to increased transactivation efficacy of the receptor is asso- referred to as adrenarche. During adrenarche, increasing ciated with PA, especially among lean children (12,13). On androgenic activity leads to greasiness of the skin and hair, the other hand, factors regulating peripheral conversion and comedones/acne, adult-type body odor, and finally to the its efficiency, e.g., polymorphisms of peripheral steroidogenic development of axillary and pubic hair. Though not uniformly enzymes, have been poorly studied to date. Polymorphisms in used, adrenarche may be defined as premature (premature genes encoding HSD17B5 and aromatase have been studied adrenarche (PA)) if these clinical signs are evident together by Petry et al. (14,15) showing no significant association with with elevated serum levels of adrenal androgens before the age premature pubarche. Variations in genes encoding steroid sul- of 8 y in girls or 9 y in boys (2). fatase, HSD3B1, and 5α-reductase have not been studied in In both normal-timed and PA, the clinical signs of andro- PA. However, Wang et al. (16) found significant differences in gen activity do not correlate well with the circulating levels of the gene encoding HSD3B1 in four different ethnic groups of 1Department of Pediatrics, University of Eastern Finland, Kuopio University Hospital, Kuopio, Finland; 2Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland; 3Institute of Dentistry, University of Eastern Finland, Kuopio, Finland. Correspondence: Jarmo Jääskeläinen ([email protected]) Received 5 June 2013; accepted 23 October 2013; advance online publication 5 March 2014. doi:10.1038/pr.2014.21 Copyright © 2014 International Pediatric Research Foundation, Inc. Volume 75 | Number 5 | May 2014 Pediatric RESEarch 645 Articles Liimatta et al. adults. They also found decreased enzyme activity with com- 1.2 mon polymorphisms of the HSD3B1 in an in vitro luciferase (LUC) reporter gene assay (16). Thus, genetic variation in the 1 peripheral metabolism of steroid hormones may be one factor explaining the phenotypic variability in children with PA from different ethnic backgrounds. 0.8 Furthermore, a recent study has shown HSD17B5 to be expressed in the human adrenal ZR from the age of 9 y, ation 0.6 enabling the production of T (17), and it has been speculated that more potent adrenal androgens in addition to DHEA and AR activ DHEAS could increase circulating androgen activity during 0.4 adrenarche (18). Circulating androgen bioactivity can be studied using 0.2 androgen bioassays that measure bioactivity directly from a small amount of human serum. The developed assays are based on cell lines transfected transiently or stably with the 0 AR and different androgen-responsive promoters that drive 0.1 110 100 1,000 the expression of an easily measurable enzyme, usually LUC Steroid concentration (nmol/l) (19,20). However, these assays have not yet been used to study Figure 1. Androgen receptor (AR) activation by different androgens as androgen bioactivity in children with PA. In this study, we assessed by luciferase (LUC) reporter gene assays in COS-1 cells. Results measured circulating androgen bioactivity in children with PA are shown relative to the LUC activity of pPB(−285/+32)-LUC in the pres- using a novel androgen bioassay. Our goal was to investigate ence of 1 µmol/l testosterone (T) set as 1. Each line represents a differ- whether potent androgens are produced or converted to the ent experiment. T was studied thrice and the other steroids twice. Filled diamond, T; open square, dihydrotestosterone; filled triangle, androstene- circulation in children with PA, and therefore, our choice for dione; capital x, dehydroepiandrosterone; open circle, dehydroepiandros- the cell line was COS-1 (CV-1 in origin, carrying the SV40 terone sulfate. genetic material), in which the converting enzymes (including 5α-reductase) are not expressed (19,21). T concentration (r = 0.50; P < 0.01) and free androgen index (r = 0.61; P < 0.01) and a negative correlation between androgen RESULTS bioactivity and serum SHBG concentration (r = −0.41; P < 0.05). Androgenic Activity of Different Steroids There was also a significant correlation between androgen bio- Different androgens were studied for their ability to activate activity and serum T (but not SHBG; r = 0.59; P < 0.01) and free the AR-dependent reporter gene in COS-1 cells. All steroids at androgen index (r = 0.61; P < 0.01) in all girls selected using the each concentration were compared with T at the concentration same criteria (n =25). Because only three boys met these criteria, of 1 µmol/l (=1), and the experiments were performed two to we were unable to calculate any correlations in this subgroup. Of three times. The results are presented in Figure 1. DHEA and the PA children selected using the same criteria (n = 17), 13 chil- DHEAS did not activate AR at the tested concentrations. dren (76%) had pubarche, whereas of the remaining 52 children, only 19 (37%) had pubarche (P < 0.05). We did not find any Androgenic Activity of the Sera in the Studied Subjects correlations between androgen bioactivity and serum DHEAS, The serum androgen bioactivity of the control and PA children, DHEA, or A4 concentrations. In all children, T concentrations adult females, and males is presented in Figure 2. Circulating correlated negatively with SHBG (r = −0.23; P < 0.01) and posi- androgen bioactivity in the PA children was low, and there tively with DHEA (r = 0.47; P < 0.001), DHEAS (r = 0.42; P < was no difference in the mean bioactivity between the PA and 0.001), and A4 (r = 0.53; P < 0.001) concentrations. control children (0.33 vs. 0.33 nmol/l T equivalents; not sig- nificant; Figure 2a). We found significant differences in the DISCUSSION mean bioactivity between all children and adult females (0.33 Our study supports the hypothesis that peripheral conversion vs. 0.73 nmol/l T equivalents; P = 0.01), as well as between the of weak adrenal androgens is essential for the clinical andro- adult females and males (0.73 vs. 5.45 nmol/l T equivalents; P genic effects in PA. Measured circulating androgen bioactiv- < 0.001; Figure 2b). ity in children with PA was low without differing significantly Mean serum androgen bioactivity levels, androgen, and sex from that of the control children, albeit the sensitivity of our hormone–binding globulin (SHBG) concentrations as well as assay was not optimal for any definite conclusions.
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