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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.

Reproductive Physiology in Young Men Is Cumulatively Affected by FSH-Action Modulating Genetic Variants: FSHR -29G/A and c.2039 A/G, FSHB -211G/T