Androgens act through the androgen receptor (AR), which regulates nearly a thousand genes. The human AR gene contains polymorphic repeats, including (CAG)n and (GGN)n, which affect AR transactivation. This study investigated their independent and combined effects on reproductive and general health. The study included 866 patients with male factor infertility (mean age: 32.8 years, and standard deviation: 6.8 years). Standard protocols were followed for semen analysis, phenotyping, and laboratory data collection. Repeat numbers of (CAG)n and (GGN)n polymorphisms were detected simultaneously using an established genotyping assay. Significantly lower sperm counts were observed in carriers of the AR gene with ≥24 compared to ≤22 GGN repeats (median: 13.5 × 106 vs 18.2 × 106 per ejaculate, P < 0.01). The meta-analysis with the Baltic young men cohort confirmed this association (n = 1843; linear regression: β = −0.38 × 106 [95% confidence interval, 95% CI: −0.75 × 106 to −0.01 × 106] per ejaculate, P = 0.044). The effect was further enhanced by long AR (CAG)n tract (≥25 repeats). The lowest sperm counts (median: 13.6 × 106 per ejaculate) and concentrations (3.5 × 106 ml−1) were detected in carriers of the AR haplotype combining ≥24 GGN and ≥25 CAG repeats (6.8% of patients). For AR (CAG)n repeats, a positive association was observed only with body mass index (BMI; P = 0.02). Neither AR repeat stretch affected semen volume, serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, glucose, lipids, uric acid, or C-reactive protein (CRP) levels. In conclusion, an increased AR (GGN)n repeat number exerts a pronounced negative modulatory effect on sperm parameters. To date, only a limited number of common genetic variants have been reported to be associated with quantitative sperm parameters.

Keywords: androgen receptor; combined genetic effect; GGN and CAG repeats; sperm counts and concentration