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

Abstract

Objective: To assess the pharmacogenetic potential of FSH for infertility treatment. Design: Review of the literature and genomic databases. Methods: Single-nucleotide polymorphism (SNP) assessed: rs6166 (c.2039AOG, p.N680S), rs6165 (c.919AOG, p.T307A), rs1394205 (c.K29GOA) in FSHR, and rs10835638 (c.K211GOT) in FSHB. Literature search via PubMed. Blast analysis of genomic information available in the NCBI nucleotide database. Comparison of allele frequency and haplotype distribution using the http://spsmart.cesga.estool. Results: All these SNPs appear first in Homo, result in reduced FSH action, and are present with variable frequencies and combinations worldwide. Stringent clinical studies demonstrate that the FSHR genotype influences serum FSH levels and gonadal response in both sexes. Serum FSH levels depend on the K211GOT SNP, influencing transcriptional activity of the FSHB promoter. Genotypes reducing FSH action are overrepresented in infertile subjects. Conclusions: Although the clinical relevance of the FSHR polymorphisms alone is limited, the combination of FSHR and FSHB genotypes 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 their FSHR-FSHB genotypes improves clinical efficacy of FSH treatment compared with the current, naïve approach. A relative enrichment of less favorable FSHR-FSHB genotypes may be related to changes in human reproductive strategies and be a marker of some health-related advantage at the cost of reduced fertility.

The Common Follicle-Stimulating Hormone Receptor (FSHR) Promoter Polymorphism FSHR −29G > A Affects Androgen Production in Normal Human Small Antral Follicles

“…This frequency distribution compares well to what have been reported from other countries (9, 13, 31). …”

Ala307Thr and Asn680Ser Polymorphisms ofFSHRGene in Human Reproduction Outcomes

“…Allelic variants of FSHR determine different FSHR sensitivity's [20,24,26]. Because of that we expected to find that FSHR 's variants influence in the reproduction outcomes, in our results we observed that the number of MII oocytes and embryos are higher in Ala307Ala women.…”

“…Perez Mayorga et al [20] was the first group that observed differences in Asn680Ser genotypes with dose of rFSH in COH. Other groups observed that the FSHR variants influence the basal FSH and estradiol levels with conflicting results [23,24,25,26,27], for this reason, the FSHR gene and others gene variations may play a role in modulating receptor sensitivity and intracellular second messenger cascades to exogenous hCG and other gonadotrophins [24,28], thus the FSHR SNPs may cause changes in the phosphorylation and glycosylation molecular mechanisms [29,30]. …”

Influence of race and ethnicity on in vitro fertilization outcomes: systematic review

“…Genetic variants in Caucasian and African American women have also been predictive of AMH and FSH levels, with important implications on FSH serum levels, receptor sensitivity to FSH, and response to stimulation (64,67,68). Finally, three studies in this review also found significantly higher peak E2 levels, which may affect implantation, in black women compared with white women, and two reported this finding in Asian women (20, 22, 26, 36, 48).…”