Association of the (TAAAA)n repeat and Asp327Asn polymorphisms in the sex hormone-binding globulin (SHBG) gene with idiopathic male infertility and relation to serum SHBG concentrations

Sex hormone binding globulin (SHBG) is involved in delivering sex hormones to target tissues. We investigated the association between the (TAAAA)n repeat polymorphism, and Asp327Asn polymorphism in the SHBG gene with semen quality and idiopathic male infertility. We studied 168 men with idiopathic infertility [oligoasthenoteratozoospermia (OAT)] and equal number of age-matched normal controls. The serum levels of SHBG, reproductive and thyroid hormones, and Inhibin B were measured. Semen parameters were also assessed. The genotype assays for the SHBG polymorphism were done using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Baseline SHBG levels tended to be lower in infertile men (21.1 ± 7.2 nmol/l) compared to normal fertile men (24.7 ± 7.9 nmol/l). SHBG levels tended to be higher among the subjects with the Asn/Asn (25.84 ± 3.6 nmol/l) and S/S (24.50 ± 5.4 nmol/l) genotypes compared to subjects with the Asp/Asn (24.38 ± 3.2 nmol/l) and L/L (18.44 ± 4.2 nmol/l) genotypes of the SHBG gene. The genotype frequencies of Asp/Asp were 80.9% in cases and 71.4% in controls (P = 0.001). The variant Asp/Asn genotype was associated with a more than 50% reduced risk of infertility (OR: 0.46, 95% CI: 0.25–0.80, P = 0.001). Genotype analysis demonstrated six SHBG (TAAAA)n alleles with 6–11 repeats. Long SHBG (TAAAA)n alleles (>8 repeats) were at greater frequency in infertile men than fertile subjects (P = 0.001), whereas short SHBG (TAAAA)n alleles (≤8 repeats) tended to be more frequent in fertile men than cases (P = 0.001). Men with the 9/X TAAAA repeat genotype displayed a 2.82-fold increased risk of infertility (95% CI: 1.27–4.79, P = 0.01). There were strong and significant positive correlations between plasma SHBG and sperm count (r = 0.672, P = 0.01), sperm motility (r = 0.721, P = 0.01) and sperm morphology (r = 0.574, P = 0.02). We concluded that the SHBG Asp237Asn and (TAAAA)n polymorphisms may influence SHBG levels and as a result, male infertility. Multicenter large scale studies are warranted to better elucidate the role of SHBG gene polymorphism in male infertility.

Research highlights▶ Sex hormone binding globulin (SHBG) is involved in delivering sex hormones to target tissues. ▶ Polymorphisms in the SHBG gene change either the production or the metabolism of the protein. ▶ Long SHBG (TAAAA)n alleles (>8 repeats) were at greater frequency in infertile men. ▶ The SHBG Asp237Asn and (TAAAA)n polymorphisms influence male infertility.