Mechanisms in endocrinology: Genetics of FSH action: a 2014-and-beyond view

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.2039A>G,
p.N680S), rs6165 (c.919A>G, p.T307A), rs1394205 (c.-29G>A) in FSHR, and
rs10835638 (c.-211G>T) 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 -211G>T 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.