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

• Published in: European journal of endocrinology Vol. 170; no. 3; pp. R91 - R107
• Main Authors: Simoni, Manuela, Casarini, Livio
• Format: Journal Article
• Language: English
• Published: Bristol Bioscientifica Ltd 01.03.2014; BioScientifica
• Subjects: Adult; Animals; Biological and medical sciences; Endocrinopathies; Female; Follicle Stimulating Hormone, beta Subunit - blood; Follicle Stimulating Hormone, beta Subunit - genetics; Follicle Stimulating Hormone, beta Subunit - physiology; Fundamental and applied biological sciences. Psychology; Gene Frequency; Genetics, Population; Humans; Infertility - genetics; Male; Medical sciences; Ovulation Induction - methods; Pharmacogenetics; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Receptors, FSH - genetics; Receptors, FSH - physiology; Reproductive Techniques, Assisted; Review; Vertebrates: endocrinology; Genetics; Gonadotropin; Adenohypophyseal hormone; Endocrinology; Mechanism; Follicle stimulating hormone
• ISSN: 0804-4643; 1479-683X; 1479-683X
• DOI: 10.1530/EJE-13-0624

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) 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.ResultsAll 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.ConclusionsAlthough 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.