Combined Effects of the VariantsFSHB−211G>T andFSHR2039A>G on Male Reproductive Parameters

Context: A polymorphism in the FSHB promoter (211GT, rs10835638) was shown to influence maleserumFSHlevels,whereasapolymorphismintheFSHreceptorgene(FSHR;2039AG,rs6166) was previously shown to be associated with FSH levels in women only. Objective: The objective of the study was to analyze the effects of both FSHB 211GT and FSHR 2039AG on male reproductive parameters. Design and Setting: A total of 1213 German men attending an infertility clinic were genotyped by TaqMan assay. Patients: Patients included male partners in infertile couples without known causes for male infertility. Main Outcome Measures: An association analysis of single and combined single-nucleotide polymorphism genotypes with clinical parameters was performed. Results: The FSHB 211GT T-allele showed significant dosage effects for FSH (0.51 U/liter per T-allele), LH (0.28 U/liter), and bitesticular volume (3.2 ml). Statistical significance was enhanced severalfold after a meta-analysis comprising 3017 men. TT carriers were significantly more prevalent among men with lower sperm counts. The FSHR 2039AG G-allele exhibited nonsignificant trends for associations with higher FSH and reduced testicular volumes. However, in the combined model, FSHR 2039AG significantly modulated the more dominant effect of FSHB 211G To n serum FSH and testicular volume among the T-allele carriers. Conclusions:Byanalyzingbothsingle-nucleotidepolymorphismsforthefirsttime,weconvincingly show that indeed FSHR 2039AG has an effect also in males. In the proposed model of the combined effects, FSHB 211GT acts strongly on male reproductive parameters, whereas the FSHR 2039AG effects were approximately 2–3 times smaller. Clinically this is of importance because oligozoospermicpatientscarryingunfavorablevariantsaffectingFSHactionmaybenefitfromFSH treatment. (J Clin Endocrinol Metab 97: 3639–3647, 2012)