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Androgen Receptor-Mediated Hypersensitivity to Androgens in Women with Nonhyperandrogenic Hirsutism: Skewing of X-Chromosome Inactivation¹

Section on Pediatric Endocrinology, DEB, NICHD, NIH, (A.V., C.A.S., C.A.L., M.K., G.P.C.) Bethesda, Maryland 20892; Department of Pediatrics (C.A.S.), Georgetown University, Washington, DC 20007; and Department of Pediatrics (L.G.), University of Parma, Italy

Address all correspondence and requests for reprints to: Alessandra Vottero, M.D., DEB, NICHD, NIH, Building 10, Room 10N262, 10 Center Drive, MSC 1862, Bethesda, Maryland 20892-1862. E-mail: votteroa{at}cc1.nichd.nih.gov

	Abstract

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Idiopathic hirsutism may result from an increase in the androgen receptor (AR)-mediated sensitivity of the hair follicle. The AR gene is located on the X-chromosome and contains a highly polymorphic trinucleotide repeat (CAGn) in its first exon, whose length and methylation pattern affect both AR expression and function. We analyzed these CAG repeats in the genomic DNA from 16 nonhyperandrogenic hirsute patients (Ferriman score: 16 ± 4.7, mean ± SD) and 10 normal controls (Ferriman score: 3 ± 1.4), who were similar in their hormonal profiles. We found no difference in the number of CAG repeats between hirsute patients and controls, and no correlation between number of repeats and the Ferriman score or hormonal values. However, after DNA digestion with methylation-sensitive HpaII and measurement of the optical density, we found a marked decrease in the hirsute group (P < 0.0001), which was greater than in the control group (P = 0.0003). In addition, in the hirsute patients, the shorter of the two alleles was preferentially less methylated (P = 0.007), suggesting skewing of X-chromosome inactivation in the patients but not in the controls. When the mean optical density of both alleles was correlated with the Ferriman score, we observed a significant negative correlation (P = 0.02, r = -0.45), which became stronger when the shorter alleles were analyzed separately (P = 0.01; r = -0.48). We conclude that nonhyperandrogenic hirsutism is associated with skewing of X-chromosome inactivation in peripheral blood lymphocytes. This leads to the longer of the two AR alleles being preferentially methylated, allowing for the shorter (and presumably, more functional) allele to be expressed on the active X-chromosome. Further studies need to be performed to investigate whether this phenomenon is present in androgen-sensitive tissues in these patients.

	Introduction

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THE ANDROGEN receptor (AR), encoded by the AR gene on the X-chromosome, is a member of the steroid receptor superfamily (1). This gene contains a polymorphic CAG microsatellite repeat within exon 1, which codes for a variable length of polyglutamine chain in the aminoterminal, the transactivation domain of the AR protein. Triplet-repeat DNA sequences can be sites of genetic instability, and indeed, their expansion in a variety of genes has been associated with human genetic diseases, such as fragile X-syndrome (2, 3) and myotonic dystrophy (4). In the case of the AR gene, an inverse correlation of the number of CAG repeats with the risk for prostate cancer was described (5, 6, 7, 8), and its expansion was documented in Kennedy’s disease (spinal and bulbar muscular atrophy), a disorder associated with primary hypogonadism (9). In vitro studies showed that progressive expansion of the repeat length in the AR was associated with a linear decrease in its transactivation function (10).

Methylation of deoxycytosine residues is another factor involved in the modulation of gene expression. Belmont et al. (11) found that the methylation of HpaII and HhaI sites near the polymorphic CAG repeats in the first exon of the human AR (HUMARA) locus correlated with X-inactivation. Most women with idiopathic hirsutism have normal circulating adrenal and gonadal androgens; thus, increased target tissue sensitivity to androgens has been considered as a potential mechanism for this condition. To examine this hypothesis, we analyzed the polymorphic CAG microsatellite and evaluated X-chromosome inactivation in patients with significant hirsutism but normal levels of circulating androgens.

	Subjects and Methods

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Patients and control subjects

Sixteen patients with nonhyperandrogenic hirsutism and 10 age-matched normal controls (hirsute group: age 21.7 yr ± 6.5; control group: age 25.7 yr ± 5.1; mean ± SD) were studied. All women were Caucasian, of Italian ethnicity. The Ferriman score for hirsutism was 16 ± 4.7 (mean ± SD) in the patients and 3 ± 1.4 in the control group (12, 13). There were no differences between the hormonal profiles (including measurements of plasma LH, FSH, testosterone, free-testosterone, androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone-sulfate) of the two groups (Table 1). Late onset congenital adrenal hyperplasia, caused by 21-hydroxylase deficiency, was ruled out by measuring plasma 17-hydroxyprogesterone response to ACTH 1–24.

Genomic DNA was extracted from peripheral blood samples obtained from a total of 26 individuals, using a rapid extraction protocol (QIAamp Blood kit, Qiagen, Chatsworth, CA), according to the instructions provided by the manufacturer, or by the standard phenol/chloroform method (14). PCR amplification of the AR CAG repeat was carried out using primers designed to flank the repeat region of interest (8). The sense (5'-AGAGGCCGCGAGCGCAGCACCTC-3') and the antisense (5'- GCTGTGAAGGTTGCTGTTCCTCAT-3') primers correspond, respectively, to nucleotides 204–226 and 404–427 of the AR sequence (15). After labeling the antisense primer by [³³P]-dATP (Amersham, Arlington Heights, IL) through the use of T4 polinucleotide kinase (New England Biolabs, Inc., Beverly, MA), about 100 ng of DNA was amplified through 30 cycles in a 10-µl vol. Amplification conditions consisted of an initial denaturating step at 95 C for 5 min, followed by 30 cycles at 95 C for 1 min, at 57 C for 1 min, and at 72 C for 1 min. Extension was carried out at 72 C for 5 min. The PCR final products were denatured at 95 C for 5 min and then analyzed by electrophoresis on a 6% sequencing gel. The gels were subsequently subjected to autoradiography, and the number of CAG repeats was calculated from the size of the PCR products, in relation to a series of previously determined (by direct sequencing of PCR products) CAG repeat size standards (8).

X-chromosome inactivation analysis

Assessment of clonality at the human AR (HUMARA) locus was performed by PCR amplification, according to the procedure of Allen et al. (11), with minor modifications. Human genomic DNA, isolated from peripheral blood by standard procedures (see Microsatellite Size Determination: CAG repeat), was employed.

For each DNA sample, two parallel reactions were set: in the first, 2 µg DNA was digested with 20 U HpaII; in the second, 2 µg DNA was incubated with the enzyme digestion buffer containing no enzyme. All the reactions were allowed to take place in 20 µl total vol at 37 C overnight. After digestion, the mixture was incubated at 95 C for 5 min to terminate the enzymatic reaction and to denature the DNA. An aliquot of 2 µl was then amplified by PCR, using the primers 5'-TCCAGAATCTGTTCCAGAGCGTGC-3' and 5'-GCTGTGAAGGTTGCTGTTCCTCAT-3' labeled with [-³³P]-dATP. An initial denaturation at 95 C for 5 min was followed by 30 PCR cycles (1 min at 95 C, 1 min at 57 C, and 1 min at 72 C). PCR products were then run in a 6% acrylamide gel; autoradiography was performed, and the DNA bands corresponding to the different alleles were measured by optical densitometry (NIH 1.611 program). HpaII digests only the unmethylated DNA, allowing thus PCR amplification of only the remaining methylated DNA.

Statistical analyses

The Software SigmaStat for Windows Version 1.0 (Jandel Scientific Co., San Rafael, CA) and Statistica for Windows Release 4.5 (StatSoft Inc., Tulsa, OK) were used to perform the statistical analyses. After performing a normality test, Student’s t test was employed to compare the same variable between the two groups. Variables without normal distribution were analyzed by the Mann-Whitney rank sum test. When data from the same individual were analyzed before and after HpaII digestion, a paired Student’s t test was employed. The z-test was used to compare the proportion of patients and controls presenting a mean decrease in OD greater or less than 0.4. The correlation between different variables was tested by the Pearson product moment correlation. The level of significance throughout was set at 0.05.

	Results

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CAG microsatellite analysis

The number of repeats ranged from 10–20 in the control group and from 8–19 in the hirsute group (Table 2). There was no difference between hirsute patients (mean ± SE: 13.66 ± 0.60) and controls (13.85 ± 0.64). Also, there was no correlation between the number of repeats and Ferriman score or hormonal values. It is noteworthy, however, that the shortest alleles (less than 10 repeats) were recorded only in hirsute patients.

Before digestion with HpaII, no difference was found in the OD of the DNA bands between the hirsute and control groups (P = 0.4) (Fig. 1, Table 2). After digestion, however, a significant decrease in the OD of the DNA bands (corresponding to a lower degree of methylation) was observed in the hirsute group (P < 0.0001), whereas there was a smaller decrease in the control group (P = 0.0003) (Fig. 2A). When the two groups were compared after digestion, the OD of the bands was significantly lower in hirsute patients than in controls (P = 0.005). The percentage of decrease in the OD after digestion (representing the unmethylated DNA) was significantly higher in patients than in controls (P = 0.003) (Fig. 2B).

View larger version (56K): [in this window] [in a new window]   Figure 1. Analysis of methylation of HpaII sites at the human AR locus in normal controls (A) and hirsute patients (B). Each allele is represented by two major bands and several additional bands of lesser intensity. This is because both strands of DNA are detected and each single-stranded DNA migrates slightly differently in the gel, because of complementary base composition. The bands of each subject before (-) and after digestion (+) are shown. The arrows show the position of the smallest and greatest alleles. Each band is separated from the following one by three bases.

View larger version (17K): [in this window] [in a new window]   Figure 2. Decrease in the OD of DNA bands, after digestion with HpaII, in normals and patients, shown as absolute values (A) and as a percentage of baseline (B) (Student’s t test; mean ± SE).

View larger version (15K): [in this window] [in a new window]   Figure 3. Correlation between Ferriman score and unmethylated genomic DNA in both control and IH groups. Solid circles represent hirsute patients; open circles represent normals. Patients had a Ferriman score higher than 8 (horizontal line). The 90th percentile for the difference in OD before and after digestion with HpaII is represented by the vertical line, at 4 x 10-1.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Hirsutism, characterized by an excessive growth of terminal hairs in androgen-dependent regions of the body, is a common disorder affecting approximately 5 to 10% of women (16). In most women with hirsutism, the condition is idiopathic, or caused by hyperandrogenism attributable to the polycystic ovary syndrome or late onset congenital adrenal hyperplasia. Most women with idiopathic hirsutism have normal circulating androgen concentrations, suggesting that some of these patients may have increased hair follicle sensitivity to androgens, possibly because of an alteration(s) in the androgen signal transduction system at the target tissue level.

Agonist-activated ARs stimulate the expression of androgen target genes, including those related to the growth and function of the hair follicle and sebaceous glands. Part of the transactivation activity of the AR resides in the N-terminal domain of the protein, which is encoded by exon 1 and contains a polyglutamine chain of variable length. Differences in the size of triplet repeat regions have clinical consequences in several diseases (2, 3, 4, 9, 17, 18, 19, 20) and alter the biological function of the AR in transactivation assays in vitro (10). Recently, the size of the CAG-repeat/polyglutamine chain was inversely correlated with the incidence of prostate cancer, suggesting that men prone to develop this neoplasm have androgen hypersensitivity (21). These observations support the idea that there is an optimal repeat length, which varies in the population (average size: 21 ± 2; range: 11–31) (5).

In our study, we found no differences in the number of repeats between hirsute patients and normal controls. Interestingly, however, the shortest (and hence, most active) alleles were recorded only in hirsute patients. This tendency of smaller size alleles to be more frequent in IH patients than in controls may contribute to hirsutism in some patients and may become significant in a larger study.

More interesting were our findings from the X-chromosome inactivation analysis of the peripheral lymphocyte DNA. Because methylation can silence gene expression and can be replicated during mitosis, DNA methylation has long been considered an important mechanism in the inactivation of the X-chromosome (22). In the present study, hirsute patients had skewing of their X-chromosome inactivation, as shown by the methylation status of the HUMARA locus. Specifically, and in contrast to Lyon’s hypothesis of random X-chromosome inactivation (23), patients with hirsutism, but not normal controls, had preferential methylation of their longer AR allele and, thus, inactivation of the functionally weaker gene. This skewing could have allowed the shorter, more active AR allele (6, 10) to be expressed in patients with hirsutism, and this might explain their peripheral hypersensitivity to androgens. In this study, we selected patients whose main complaint was hirsutism; we believe that similar findings may be obtained in patients whose predominant manifestations are postadolescent cystic acne or male pattern baldness, depending on the genetics and constitution of the specific end-organ (24, 25).

Although skewing of the X-chromosome inactivation is a novel finding for hirsute patients, this phenomenon, favoring the expression of specific alleles of various X-linked genes, has been shown before (23, 26). It was hypothesized that hemizygous selection of favorable genes was influenced by X-chromosome loci and that this was the mechanism behind skewing of the X-chromosome inactivation process in peripheral blood (27). We speculate that similar skewing of X-chromosome inactivation exists in patients with hirsutism, which results in an increase of tissue sensitivity to androgens. Although skewing of X-chromosome may occur because deleterious genes are present in one of the X-chromosomes, other potential mechanisms may also be present (28, 29, 30). It is thus possible that somatic, epigenetic changes create conditions that render certain lymphocytic cell lines more fit for survival than others. We speculate that decreased methylation of the AR may lead to increased presence of its messenger RNA and protein, which in turn may be in favor of the survival of certain cell clones. It is also possible that other modifier genes may be differentially expressed in women with idiopathic hirsutism that favor the expansion of clones that have the less methylated AR allele.

Direct studies on androgen target tissues need to be performed to confirm our hypothesis that skewing of X-chromosome inactivation may lead to higher expression of more potent AR molecules, conferring hypersensitivity to the skin of hirsute women. Increased 5-reductase-mediated conversion of testosterone to dihydrotestosterone in the skin has also been considered as a potential pathophysiologic mechanism of tissue hypersensitivity to androgens (31). One may additionally speculate that increased AR activity in the skin may also lead to tissue hypersensitivity to androgens.

	Acknowledgments

 
We thank Mr. Keith Zachman (DEB NICHD, NIH) for his excellent technical support.

	Footnotes

 
¹ Presented, in part, at the 80th Annual Meeting of The Endocrine Society, New Orleans, LA. This work was supported, in part, by a European Society for Pediatric Endocrinology Research Fellowship (to A.V.), sponsored by Novo Nordisk A/S.

Received July 30, 1998.

Revised November 11, 1998.

Accepted December 7, 1998.

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