Introduction: Polymorphisms in the gene for FSH receptor (FSHR) and FSH β subunit (FSHB) might modulate FSH levels and represent genetic markers for a pharmacogenetic approach to male infertility treatment. rs6166 (c.2039 A>G, Asn680Ser) and rs1394205 (c.−29 G>A) in FSHR have been better analysed in women, whereas rs10835638 (−211 G>T) in FSHB seems to have a determinant role especially in men. However, studies considering the combined effect of these three polymorphisms have not been conducted.
Materials and methods: We studied 572 consecutive infertile males (including 93 with azoospermia-cryptozoospermia, 231 with oligozoospermia and 248 with normozoospermia) by means of semen analysis, FSH, LH, and T levels, testicular volume, and rs6166, rs1394205 and rs10835638 genotyping by RFLP and direct sequencing.
Results: The FSHB promoter polymorphism 211 G>T is significantly associated with FSH levels (9.6±7.6, 7.2±5.8 and 2.6±1.9 IU/l respectively in men GG homozygotes, GT heterozygotes and TT homozygotes, P<0.001). The polymorphisms −29 G>A and Asn680Ser in FSHR taken alone were not associated with different FSH concentrations. Combined analysis of the three polymorphisms showed again that the major determinant of FSH levels is the −211 G>T polymorphisms, only slightly modulated by the −29G>A polymorphism, so that men with the genotype −211 GG/−29 GG had the highest levels of FSH and men with the genotype −211 TT/−29 AA the lowest. Polymorphism Asn680Ser in FSHR had no effect neither alone nor in combined analysed. The three polymorphisms had no effect on LH and T levels, and in accordance in these data the total number of sperm and testicular volume are modulated by the genotype. TT homozygotes for the −211 SNP are invariably azoo-oligozoospermic with low testicular volume and FSH levels <8 UI/l.
Conclusions: This is the first study analysing the combined contribution of the most common polymorphisms in FSHR and FSHB genes in influencing male reproductive system and showed that −211 G>T in FSHB has a determinant role, in determining FSH levels, sperm count and testicular volume. This polymorphism alters the transcriptional activity of the gene, and therefore it determines a sort of isolated FSH deficiency with azoo-oligozoospermia and represents the ideal pharmacogenetic marker of FSH treatment.