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Androgen Receptor Gene CAG Repeat Polymorphism in the Development of Ovarian Hyperandrogenism

Endocrine Unit (L.I.), Hospital Sant Joan de Déu, University of Barcelona, E-08950 Barcelona, Spain; Department of Paediatrics (K.K.O., N.M., J.J., I.A.H., D.B.D.), University of Cambridge CB2 2QQ, United Kingdom; Endocrine Unit (M.V.M.), Consorci Hospitalari de Terrassa, Barcelona, Spain; and Department of Paediatrics (F.D.Z.), University of Leuven, B-3000 Leuven, Belgium

Address all correspondence and requests for reprints to: Professor David B. Dunger, Department of Pediatrics, University of Cambridge, Addenbrooke’s Hospital, Level 8, Box 116, Cambridge CB2 2QQ, United Kingdom. E-mail: dbd25{at}cam.ac.uk.

	Abstract

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Ovarian hyperandrogenism, a key feature of polycystic ovary syndrome, is preceded by precocious pubarche (PP) (pubic hair < 8 yr) in some populations. We hypothesized that this earlier presentation may relate to increased androgen sensitivity, indicated by androgen receptor gene CAG repeat length. This polymorphism was genotyped in 181 Barcelona girls (age, 10.9 yr; range, 4–19 yr) who had presented with PP, and in 124 Barcelona control girls. PP girls had shorter mean CAG number than Barcelona controls (PP vs. controls: mean, range: 21.3, 7–31 repeats vs. 22.0, 15–32, P = 0.003) and greater proportion of short alleles 20 repeats or less (37.0% vs. 24.6%, P = 0.002). Among post-menarcheal PP girls (n = 69), shorter CAG number (biallelic mean 20) was associated with higher 17-hydroxy-progesterone levels post leuprolide (P = 0.009), indicative of ovarian hyperandrogenism, higher testosterone levels (P = 0.02), acne (P = 0.03) and hirsutism scores (P = 0.01), and more menstrual cycle irregularities (P = 0.04). In multiple regression, ovarian hyperandrogenism risk was related to both low birth weight (SD <-1.5: odds ratio = 17.0; 95% confidence interval: 4.2–69.2) and shorter mean CAG number (20 or less repeats: odds ratio = 7.3; 1.3–42.0).

In summary, shorter androgen receptor gene CAG number, indicative of increased androgen sensitivity, increases risks for PP and subsequent ovarian hyperandrogenism. Shorter CAG repeat alleles in Barcelona compared with United Kingdom women could lead to higher prevalences of these conditions.

	Introduction

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OVARIAN HYPERANDROGENISM IN women is a key feature of the polycystic ovary syndrome (PCOS) and commonly presents with excessive virilization, menstrual irregularity, or infertility. It is associated with excess weight gain, but may occur in relatively lean women with increased central adiposity and it is often linked with dyslipidemia and later risks for cardiovascular disease and type 2 diabetes (1).

In some populations, it has been observed that women who develop ovarian hyperandrogenism post menarche may present earlier with exaggerated adrenarche and precocious pubarche (PP) (i.e. appearance of pubic hair before 8 yr) (2, 3). PP, once considered to be a benign condition, has recently been shown to be associated with dyslipidemia, insulin resistance, and hyperinsulinemia, particularly in girls with a history of low birth weight (2, 4). The original longitudinal studies were carried out in Barcelona-Spanish girls, and similar observations have been made in African-American girls (5). Androgen receptor blockade therapy improves the clinical and biochemical features of ovarian hyperandrogenism in girls who first presented with PP (6).

We hypothesized that risk for the development of PP and subsequent features of ovarian hyperandrogenism might relate to genetic variation in androgen receptor sensitivity. Shorter androgen receptor (AR) gene CAG repeat number is linked to increased receptor sensitivity in vitro (7, 8) and has been associated with clinical variations in androgen activity in both females (9, 10, 11) and males (12, 13, 14, 15, 16, 17, 18). We compared CAG repeat number in Barcelona-Spanish girls who presented with PP against Spanish controls, and examined the relationship between CAG number and clinical-metabolic phenotypes of ovarian hyperandrogenism post menarche.

	Subjects and Methods

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Study population

One-hundred eighty-one girls who had presented with PP and were followed in the Endocrine Unit of Hospital Sant Joan de Déu (Barcelona, Spain) were enrolled. Girls with PP were only eligible for the study if the entity was attributable to pronounced adrenarche, as suggested by elevated dehydroepiandrosterone-sulfate (DHEAS) levels at PP diagnosis and corroborated by an ACTH test to exclude nonclassic adrenal hyperplasia (2). None of the girls had acanthosis nigricans, thyroid dysfunction, Cushing’s syndrome, hyperprolactinemia, a family or personal history of diabetes mellitus, or was receiving oral contraceptive medication or any drug known to affect carbohydrate or lipid metabolism.

Birth weight and gestational age data in PP girls were obtained from hospital records. Birth weight was transformed into gestational age-adjusted SD scores, and body mass index was also transformed into SD scores by comparison to published normative data (4).

Genotype frequencies were contrasted with 124 healthy control Barcelona-Spanish girls, selected from short normal children (heights between the 10th and 25th percentiles) referred to the Endocrine Unit, and from subjects undergoing minor surgical procedures or routine gynecological analysis at the Pediatric or Gynecology Departments at the Barcelona hospital. None of the subjects had a history of PP or showed clinical signs and/or symptoms of androgen excess.

The study protocol was approved by the Institutional Review Board of Barcelona University Hospital of Sant Joan de Déu. Informed consent was obtained from parents and/or study subjects, assent being obtained from minors, including collection and genotyping of DNA samples.

Genotyping

DNA was extracted from blood samples from Barcelona-Spanish PP and control girls using standard methods. The AR exon A region encoding the polyglutamine repeat was amplified using two rounds of PCR. Each PCR contained (per microliter): 0.4 ng of each oligonucleotide, 10 ng genomic DNA, 2.5 x 10^-2 U Taq DNA polymerase, and accompanying 1x buffer (Invitrogen, Paisley, UK), 1.5 mM MgCl₂, 0.2 mM deoxynucleotide triphosphates. The first round PCR (forward primer 5'-gag gag ctt tcc aga atc tgt t-3'; reverse primer 5'-cag gat gtc ttt aag gtc agc gg-3') was diluted 1 in 100 for the second round of PCR. Thermal cycling was performed as follows: 95 C for 5 min; followed by 35 cycles of 94C for 30 sec; 56 C for 30 sec (oligonucleotide annealing), 72 C for 90 sec (DNA synthesis). The second, nested PCR used primers (forward primer: 5'-cca gag cgt gcg cga agt gat cca gaa ccc gg-3', and reverse primer: 5'-acc agg tag cct gtg ggg cct cta cga tgg gc-3') and protocols as described by Dunning et al. (19). The reverse primer was labeled with FAM for patients and HEX for control DNA amplifications. The PCR products were mixed with GS-350-TAMRA or GS-350-TAMRA size markers (Applied BioSystems, Warrington, UK) and loading buffer, were heat denatured and electrophoresed on an ABI 377 or ABI 3700 sequencer. To control for discrepancies between each run, DNA samples from PP and control girls were analyzed together, and selected samples, including a 20 repeat allele verified by DNA sequencing, were electrophoresed on multiple occasions. The band sizes were analyzed using Genescan (Applied Biosystems) software.

Endocrine and metabolic assessments

The following endocrine and metabolic assessments were performed on all Spanish PP girls (n = 181). After 3 d on a high carbohydrate diet (300 g/day) and an overnight fast, a standard 1.75 g/kg (maximum, 75 g) 2-h oral glucose tolerance test was performed, starting at 0800 h. Blood was sampled 0, 30, 60, and 120 min after oral glucose administration for glucose and insulin measurements. All subjects had normal glucose tolerance, according to the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus criteria (20). Serum lipids, lipoproteins, and SHBG levels were measured from the baseline fasting blood samples.

Spanish PP girls who had reached postmenarche (n = 69) were studied in the follicular phase (d 3–8) of the menstrual cycle, and these girls had additional assessments for biochemical and clinical features of ovarian hyperandrogenism, including hirsutism by Ferriman and Gallwey score (21), and the presence and severity of acne lesions (22). We also measured 17-hydroxy-progesterone (OHP) levels in response to leuprolide acetate, a GnRH agonist (Procrin, 500 µg sc; Abbott, Madrid, Spain), and biochemical ovarian hyperandrogenism was defined as a peak 17-OHP value greater than 160 ng/dl (23).

Part of the Barcelona cohort (50 control subjects and 35 PP girls) had been previously genotyped for the variable number of tandem repeats of the insulin gene; glucose, insulin, and androgen levels of the 35 PP girls had also been reported (24).

Hormonal assays

Serum glucose was measured by the glucose oxidase method. Immunoreactive insulin was assayed by IMX (Abbott Diagnostics, Santa Clara, CA). The mean intraassay and interassays coefficients of variation were 4.7% and 7.2%, respectively. Serum total cholesterol, high-density lipoprotein cholesterol, and triglycerides were measured by the CHOD-PAP and GPO-PAP-based methods, as described (20); low-density lipoprotein cholesterol was calculated by the Friedewald formula. Serum 17-OHP and testosterone were determined using a commercially available RIA kit (4), and serum DHEAS and SHBG were measured by enzymo-immuno-chemiluminescence (6). Serum samples were stored at -20 C until assay.

Analyses

Areas under the curve for insulin during the oral glucose tolerance test (mean serum insulin) were calculated according to the trapezoidal rule. Individual mean serum insulin levels were transformed into SD scores by comparison with normative data (20). Estimates of insulin sensitivity were derived from fasting serum insulin and glucose levels by the homeostasis model (25).

The AR CAG repeat length was compared between Spanish PP and Spanish control girls using t tests. In post-menarcheal PP girls, relationship between CAG repeat length and phenotypic features of ovarian hyperandrogenism were analyzed using ANOVA for continuous outcomes and ² tests for discreet outcomes. 17-OHP, testosterone, insulin sensitivity, and hirsutism score showed positively skewed distributions and were transformed to normal distributions by calculation of natural logarithms to allow use of parametric tests. All reported significant comparisons remained significant using nonparametric Mann-Whitney U tests.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Population differences in CAG repeat length

Mean androgen receptor CAG number was shorter in PP girls (mean: 21.3, range: 7–31 repeats, n = 362 alleles) than in Barcelona control girls (22.0, 15–32, n = 248 alleles, P = 0.003). Examination of the allele distributions revealed that this difference was due to an excess of alleles with 20 repeats or less in the PP group (PP: 37.0% of all alleles were 20 repeats or less, vs. Barcelona controls: 24.6%, ² test: P = 0.002, Fig. 1, A and B), whereas the proportion of alleles longer than 23 repeats was identical in both groups (PP: 34.8% of alleles had 23 or more repeats, vs. Barcelona controls: 34.3%, P = 1.0). Furthermore eight PP girls compared with none of the Barcelona control girls had extremely short androgen receptor alleles less than 15 repeats (Fisher’s exact test, P = 0.02).

View larger version (32K): [in this window] [in a new window]   FIG. 1. A, Bar, and B, cumulative distributions of AR CAG repeat alleles in Barcelona PP girls (A, solid bars; B, thick line), Barcelona control girls (A, striped bars; B, thin line).

Among post-menarcheal PP girls, those with average of both androgen receptor alleles 20 repeats or less were significantly more likely to have functional ovarian hyperandrogenism compared with PP girls with longer alleles, as indicated by higher 17-OHP levels in response to GnRH agonist (P = 0.009), higher serum testosterone levels (P = 0.02), higher hirsutism scores (P = 0.01), higher rates of moderate or severe acne (P = 0.03), and higher rates of irregular or absent menstrual cycles (P = 0.04, Table 1). Girls with shorter biallelic mean CAG number also had greater hyperinsulinemia in response to oral glucose than girls with longer repeat lengths (P = 0.01) but no difference in fasting insulin sensitivity (P = 0.5).

We have previously reported that risk of functional ovarian hyperandrogenism post menarche is related to low birth weight (SD <-1.5) (4, 26). Using multiple logistic regression we observed that risk of ovarian hyperandrogenism in these post-menarcheal PP girls was independently related to both low birth weight (SD <-1.5: odds ratio = 17.0; 95% confidence interval: 4.1–69.2) and shorter CAG number (biallelic mean 20 repeats or less: odds ratio = 7.3; 1.3–42.0) (Fig. 2A). Both lower birth weight and shorter CAG number were also independently related to hyperinsulinemia (Fig. 2B).

View larger version (17K): [in this window] [in a new window]   FIG. 2. Independent effects of low birth weight and lower AR CAG repeat length (average 20 repeats or less: broken line, vs. more than 20 repeats, solid line) in post-menarcheal Barcelona PP girls on: A, 17-OHP levels post leuprorelin (multivariate model: birth weight P < 0.0005, CAG length P = 0.02); and B, mean serum insulin levels post oral glucose (birth weight, P = 0.01; CAG length, P = 0.01).

	Discussion

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Exon 1 of AR on the X chromosome encodes the transactivation domain and contains a large variable length CAG repeat polymorphism that encodes glutamine residues in the amino terminal of the androgen receptor. CAG repeat number normally ranges between 11 and 35 and, except for very long alleles more than 36 repeats, shows stable inheritance. Decreasing CAG repeat number has been shown to increase transcriptional response to androgens (7, 8), and the resulting variation in androgen activity has been related to a number of clinical consequences. In females who have two copies of the AR gene, associations have been reported with breast cancer risk (28) and serum testosterone levels (9, 10, 11), but these findings have been variable (11, 19). One study analyzed X inactivation and reported preferential expression of longer CAG alleles in women with ultrasound-proven PCOS (11); however, that finding was opposite to the authors’ original hypothesis and to previous results (29), and studies on peripheral lymphocytes may not reflect tissue androgen receptor inactivation. We, therefore, examined associations with the mean, lower, and higher of the two CAG repeat alleles in each subject. Features of ovarian hyperandrogenism appeared to be most closely related to subject’s mean CAG repeat number, which in the absence of nonrandom X inactivation should represent their average tissue androgen receptor activity. Our findings do not rule out a possible influence of this polymorphism on X inactivation, and future studies may need to consider tissue variation in such an effect.

We found that both androgen levels and clinical hyperandrogenism were increased in women with shorter AR CAG repeat alleles. From this, we infer that increased androgen activity in women has a stimulatory effect on ovarian androgen production, and this positive feedback on serum androgen levels may exacerbate the severity of hyperandrogenism in women. Importantly, in our Spanish PP girls, the major source of raised androgen levels was ovarian production as indicated by high 17-OHP levels post-GnRH agonist (23). Androgen receptors are present in the ovary (30), and short-term androgen administration promotes follicular growth (31). Our findings and interpretation are strongly supported by the observation that in these young girls androgen receptor inhibition with low-dose flutamide markedly reduces serum testosterone levels as well as clinical features of virilization (6). Insulin resistance with compensatory hyperinsulinemia is another key pathogenic factor in the ovarian hyperandrogenism that follows low birth weight, probably by stimulating ovarian androgen production (4, 20), and insulin sensitization therapy effectively reduces circulating testosterone levels and clinical hyperandrogenism (20). We found that low birth weight and shorter CAG repeats are independently related to both ovarian hyperandrogenism and hyperinsulinemia and their effects appear to be additive. In PP girls, levels of hyperinsulinemia are strongly related to central adiposity (27). Increased androgen activity related to shorter AR CAG repeat alleles could promote a central, or android, distribution of body fat (32), and thus further stimulate insulin and androgen secretion, and also accelerate the development of other risk markers for cardiovascular disease. These closely interlinked mechanisms could explain the greater efficacy of low-dose combination therapy with insulin sensitization and androgen receptor blockade compared with their use as monotherapies (33).

Wide population differences in AR CAG repeat distributions have been reported (34) and could relate to ethnic differences in body habitus and cancer risk. In our study, both Barcelona PP and control girls had shorter CAG number compared with published United Kingdom control women (19) (23.5, 10–39 repeats, n = 852 alleles, P < 0.0005). Whereas low birth weight associations with insulin resistance have been reported in diverse populations (35), the progression to PP and later ovarian hyperandrogenism has been largely confined to Mediterranean or African-American girls (2, 5, 36, 37). Preliminary biochemical data from a large United Kingdom birth cohort confirm the presence of a link between low birth weight and higher childhood androgen levels (38); however, relatively lower androgen sensitivity related to longer AR CAG repeat lengths could explain our clinical perception that presentation with PP and ovarian hyperandrogenism is less common in United Kingdom, or Northern France (39), than in Catalunya.

We postulate that variation in the AR CAG repeat length could contribute to population differences in central adiposity inherent in adulthood disease risk. Shorter AR CAG repeat alleles could represent thrifty genotypes, as increased androgen activity and central fat deposition could confer a survival advantage during periods of poor nutrition but may increase disease risk in more affluent contemporary society (40).

	Acknowledgments

 
We are extremely grateful to all the girls who took part in this study and to their families. We also thank Jennifer Masters and Chris Lowe for assistance in genotyping.

	Footnotes

 
L.I. was supported by a Visiting Fellowship from the European Society for Pediatric Endocrinology (ESPE). J.J. was supported by ESPE Research Fellowship, sponsored by Novo Nordisk. F.d.Z. is a Clinical Research Investigator of the Fund for Scientific Research (Flanders, Belgium). D.B.D. is supported by the Juvenile Diabetes Research Foundation and the Wellcome Trust.

Abbreviations: AR, Androgen receptor gene; DHEAS, dehydroepiandrosterone-sulfate; 17-OHP, 17-hydroxy-progesterone; PCOS, polycystic ovary syndrome; PP, precocious pubarche.

Received November 14, 2002.

Accepted March 31, 2003.

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