The number of CAG-repeats in the androgen-receptor gene is associated with polycystic ovary syndrome

Objective: Androgenic effects cause the clinical features of PCOS, a common and heterogenic disease with a genetic background. Polymorphisms modulate the phenotype of common diseases. In men, the androgen-receptor (AR) activity is inversely correlated to the CAG-repeat-length in exon 1 of the x-chromosome. In women with PCOS, reported results are contradicting. We conducted this study to analyse the distribution of CAG-repeat-lengths in patients with PCOS compared with healthy women. Material and Methods: Individuals were described by cycle characteristics, endocrine parameters, clinical signs of hyperandrogenemia and sonomorphologic signs of polycystic ovaries. Genomic DNA was isolated from peripheral lymphocytes, PCR was performed using TaqMan technology. CAG-length was determined using PAGE in combination with laser-detection of a marked forward primer. T-Test was applied to compare groups, a P<0.05 was taken as statistically significant. Results: 54 patients met the PCOS-criteria, 57 patients without PCOS were taken as controls. Analyzing all patients the bi-allelic mean of CAG-repeat-length was 21.8 (Range 16.0–28.5, SD±1.96). Comparing both groups, PCOS-patients showed a bi-allelic mean of 21.3 CAG-repeats whereas controls showed a mean of 22.2 CAG-repeats (P=0.017). Analyzing only the shorter CAG allele of each patient showed no difference between groups. However, analyzing only the longer CAG allele, PCOS-patients showed a mean of 22.5 CAG-repeats and controls of 24.0 CAG-repeats (P=0.001). Conclusions: Differences in the length of CAG-repeats of the AR gene are consistent with the hypothesis that AR polymorphisms influence the phenotype of patients with PCOS. Long CAG-repeats may protect against PCOS-phenotype, whereas short CAG-repeats may enhance PCOS-phenotype. These findings could help to better characterize the highly heterogenic syndrome and may explain differences in androgen action in these women. X-chromosome inactivation will be assessed by methylation-assays to evaluate the active allele in heterozygous patients.