The long (GGN) n repeat tract in the androgen receptor gene exerts a negative effect on quantitative sperm parameters

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 × 10 6vs 18.2 × 10 6 per ejaculate, P < 0.01). The meta-analysis with the Baltic young men cohort confirmed this association ( n = 1843; linear regression: β = -0.38 × 10 6 [95% confidence interval, 95% CI: -0.75 × 10 6 to -0.01 × 10 6 ] 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 × 10 6 per ejaculate) and concentrations (3.5 × 10 6 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.