Genetically Determined Dosage of Follicle-Stimulating Hormone (FSH) Affects Male Reproductive Parameters

Context: The detailed role of FSH in contributing to male testicular function and fertility has been debated. Wehave previously identified the association between the T-allele of the FSHB promoter polymorphism (rs10835638; G/T, -211 bp from the mRNA start) and significantly reduced male serum FSH. Objective: In the current study, the T-allele carriers of the FSHB -211 G/T single nucleotide polymorphism represented a natural model for documenting downstream phenotypic consequences of insufficient FSH action. Design and Subjects: We genotyped rs10835638 in the population-based Baltic cohort of young men(n = 1054; GGcarriers, n = 796; GT carriers, n = 244; TT carriers, n = 14) recruited by Andrology Centres in Tartu, Estonia; Riga, Latvia; and Kaunas, Lithuania. Marker-trait association testing was performed using linear regression (additive, recessive models) adjusted by age, body mass index, smoking, and recruitment center. Results: Serum hormones directly correlated with the T-allele dosage of rs10835638 included FSH (additive model, P = 1.11 x 10(-6); T-allele effect, -0.41IU/liter), inhibin-B (P = 2.16 x 10(-3); T-allele effect, -14.67 pg/ml), and total testosterone (P = 9.30 x 10(-3); T-allele effect, -1.46 nmol/liter). Parameters altered only among TT homozygotes were reduced testicular volume (recessive model, P = 1.19 x 10(-4); TT genotype effect, -9.47 ml) and increased serum LH (P = 2.25 x 10(-2); TT genotype effect, 1.07 IU/liter). The carrier status of rs10835638 alternative genotypes did not affect sperm motility and morphology, calculated free testosterone, serum SHBG, and estradiol concentrations. Conclusion: We showed for the first time that genetically determined low FSH may have wider downstream effects on the male reproductive system, including impaired testes development, altered testicular hormone levels (inhibin-B, total testosterone, LH), and affected male reproductive potential. (J Clin Endocrinol Metab 96: E1534-E1541, 2011)