MECHANISMS IN ENDOCRINOLOGY: Genetics of FSH action: a 2014-and-beyond view

Abstract

ObjectiveTo assess the pharmacogenetic potential of FSH for infertility treatment.DesignReview of the literature and genomic databases.MethodsSingle-nucleotide polymorphism (SNP) assessed: rs6166 (c.2039A>G, p.N680S), rs6165 (c.919A>G, p.T307A), rs1394205 (c.−29G>A) inFSHR, and rs10835638 (c.−211G>T) inFSHB. Literature search via PubMed. Blast analysis of genomic information available in the NCBI nucleotide database. Comparison of allele frequency and haplotype distribution using thehttp://spsmart.cesga.estool.ResultsAll these SNPs appear first inHomo, result in reduced FSH action, and are present with variable frequencies and combinations worldwide. Stringent clinical studies demonstrate that theFSHRgenotype influences serum FSH levels and gonadal response in both sexes. Serum FSH levels depend on the −211G>T SNP, influencing transcriptional activity of theFSHBpromoter. Genotypes reducing FSH action are overrepresented in infertile subjects.ConclusionsAlthough the clinical relevance of theFSHRpolymorphisms alone is limited, the combination ofFSHRandFSHBgenotypes has a much stronger impact than either one alone in both sexes. About 20% of people are carriers of the alleles associated with lower serum FSH levels/reduced FSHR expression or activity, possibly less favorable for reproduction. Prospective studies need to investigate whether stratification of infertile patients according to theirFSHR–FSHBgenotypes improves clinical efficacy of FSH treatment compared with the current, naïve approach. A relative enrichment of less favorableFSHR–FSHBgenotypes may be related to changes in human reproductive strategies and be a marker of some health-related advantage at the cost of reduced fertility.