Abstract
Follicle-Stimulating Hormone Receptor (FSHR) -29G/A polymorphism (rs1394205) was reported to modulate gene expression and reproductive parameters in women, but data in men is limited. We aimed to bring evidence to the effect of FSHR -29G/A variants in men. In Baltic young male cohort (n = 982; Estonians, Latvians, Lithuanians; aged 20.2±2.0 years), the FSHR -29 A-allele was significantly associated with higher serum FSH (linear regression: effect 0.27 IU/L; P = 0.0019, resistant to Bonferroni correction for multiple testing) and showed a non-significant trend for association with higher LH (0.19 IU/L) and total testosterone (0.93 nmol/L), but reduced Inhibin B (−7.84 pg/mL) and total testes volume (effect −1.00 mL). Next, we extended the study and tested the effect of FSHR gene haplotypes determined by the allelic combination of FSHR -29G/A and a well-studied variant c.2039 A/G (Asn680Ser, exon 10). Among the FSHR -29A/2039G haplotype carriers (A-Ser; haplotype-based linear regression), this genetic effect was enhanced for FSH (effect 0.40 IU/L), Inhibin B (−16.57 pg/mL) and total testes volume (−2.34 mL). Finally, we estimated the total contribution of three known FSH-action modulating SNPs (FSHB -211G/T; FSHR -29G/A, c.2039 A/G) to phenotypic variance in reproductive parameters among young men. The major FSH-action modulating SNPs explained together 2.3%, 1.4%, 1.0 and 1.1% of the measured variance in serum FSH, Inhibin B, testosterone and total testes volume, respectively. In contrast to the young male cohort, neither FSHR -29G/A nor FSHR haplotypes appeared to systematically modulate the reproductive physiology of oligozoospermic idiopathic infertile patients (n = 641, Estonians; aged 31.5±6.0 years). In summary, this is the first study showing the significant effect of FSHR -29G/A on male serum FSH level. To account for the genetic effect of known common polymorphisms modulating FSH-action, we suggest haplotype-based analysis of FSHR SNPs (FSHR -29G/A, c.2039 A/G) in combination with FSHB -211G/T testing.
Highlights
Follicle-stimulating hormone (FSH) secreted by anterior pituitary together with other endocrine factors plays a central role in establishing and maintaining human fertility
FSH action in male and female reproductive physiology is modulated by genetic variants determining either serum FSH levels or the functionality of Follicle-Stimulating Hormone Receptor (FSHR) [5]
Few small-scale studies have inconclusively investigated the effect of the FSHR 29G/A alone or in combination with other FSHR genetic variants on male quantitative reproductive parameters [18,19,20,21,22]
Summary
Follicle-stimulating hormone (FSH) secreted by anterior pituitary together with other endocrine factors plays a central role in establishing and maintaining human fertility. Neonatal and pubertal periods, FSH stimulates proliferation of testicular Sertoli cells determining spermatogenic capacity of adult testes, and in adulthood it contributes to normal spermatogenesis and spermatogonial survival and sperm release [1,2]. We have previously shown that the T-allele of the FSHB -211G/T promoter variant (rs10835638) was associated with significantly reduced serum FSH levels and total testes volume in the Baltic cohort of young men [6,7], and these results were confirmed in Estonian, Italian and German infertile male patients [8,9,10]. Recent studies have conclusively shown the association between the Ser680-allele of FSHR 2039A.G (p.Asn680Ser, rs6166) and higher serum FSH, lower total testes volume, Inhibin B and total testosterone levels [11,12]. The FSHR c.2039A.G and the linked variant FSHR c.919A.G (p.Thr307Ala, rs6165) jointly determine the two FSHR isoforms [13]
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