SYNERGIC ACTION OF FSHB AND FSHR POLYMORPHISMS ON GONADAL FUNCTION IN MEN

Introduction. The -211G/T SNP in the FSHB gene promoter decreases its transcriptional activity, the FSH production rate limiting step, resulting in lower serum FSH levels. A very recent study showed that the reduced FSHR expression in presence of the FSHR -29 G/A SNP influences serum FSH level in normal men. The FSHR A2039G SNP influences the FSHR sensitivity to FSH, but its role on male infertility is still debated. Aim. This study was undertaken to evaluate the effects of FSHB -211G/T, FSHR -29G/A and A2039G SNPs on gonadal function in men. Patients and methods. We genotyped these SNPs in 90 men with azoospermia or oligozoospermia (group 1) and 108 normozoospermic men (group 2) by TaqMan assay specific for each SNP. Following statistical analysis, significance was accepted when the p value was <0.05. Results. FSH showed a significant downward gradient along the 3 FSHB -211G/T genotypes: GG (6.9±6.3 IU/L), GT (3.7±2.3 IU/L) and TT (2.27±0.7 IU/L) (p=0.002, Median test). The FSHB SNP was also associated with significant serum LH decrease and with a non-significant trend towards lower testosterone levels, sperm concentration, total sperm count and total testicular volume. The frequency of T allele-carrying genotypes was significantly higher (34.4%) in men of group 1 compared to those of group 2 (20.7%) (p=0.027, z-test). We also found a significant upward serum FSH levels among the 3 FSHR -29 G/A genotypes: GG (5.7±6.3 IU/L), GA (5.9±4.8 IU/L) and AA (8.04±4.1 IU/L) (p=0.008, Median test). This SNP showed a non-significant trend towards higher LH and testosterone levels and lower total testicular volume. No significant association was found between FSHR A2039G genotype and gonadal function. The 9 combinations between FSHB and FSHR -29 G/A SNPs showed significant different serum FSH levels (p=0.003, Median test). Overall 21.5% of the men had “less favorable” FSHB/FSHR genotype combinations in terms of serum FSH levels and FSHR expression. Conclusions. This study showed that serum FSH levels are significantly influenced by both FSHB -211 G/T and FSHR -29G/A SNPs. The former had also an important role on serum LH and, though non-significantly, on testosterone levels. The association between the FSHB SNP and spermatogenesis is underlined by the higher frequency of T allele carriers in patients with azoospermia/ oligozoospermia. The synergic action of FSHB and FSHR -29 G/A polymorphisms is highlighted by the different FSH levels observed in the various genotype combinations including those “less favorable” which were found in 21.5% of the men studied.