Pharmacogenetics of follicle-stimulating hormone action

Abstract

Purpose of review: To review the current knowledge of genetic variants in the two genes affecting the individual responsiveness to follicle-stimulating hormone (FSH) action-the FSH beta-subunit (FSHB) and the FSH receptor (FSHR), as well as the pharmacogenetic ramifications of the findings.

Recent findings: Four common variants in the FSHB and the FSHR genes were shown to exhibit significant effect on FSH action: linked FSHR variants Thr307Ala and Asn680Ser determining common receptor isoforms, and gene expression affecting polymorphisms FSHR -29G/A and FSHB -211G/T. In women, the FSHR Thr307Ala/Asn680Ser polymorphisms show consistent predictive value for estimating the most optimal recombinant FSH dosage in controlled ovarian hyperstimulation (COH). The same variants exhibit a potential for the pharmacogenetic assessment of the treatment of polycystic ovarian syndrome. The FSHR -29G/A variant was also shown to contribute to ovarian response to COH. Pilot studies have suggested the FSHB -211 TT homozygous oligozoospermic men with genetically determined low concentration of FSH, as potentially the best responders to FSH treatment; furthermore, modulation of this response by FSHR polymorphisms is possible.

Summary: Genetic variants in FSHB and FSHR exhibit a potential for pharmacogenetic applications in selecting appropriate treatment options (timing and dosage) in male and female conditions requiring or benefiting from FSH therapy.

Figures

Figure 1

Schematic feedback control of the human hypothalamic-pituitary-gonadal (HPG) axis. In males and females, kisspeptin-triggeredpulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus stimulates the release of pituitary gonadotrophins (FSH and LH). FSH binds to its receptors located in testicular Sertoli and ovarian granulosa cells, and stimulates the secretion of inhibins that suppress FSH production from the pituitary. LH interacts with receptors on testicular Leydig cells and ovarian theca and granulosa cells, thereby stimulating the production of steroid hormones that stimulate their target cells in the reproductive tract.Steroid hormones (androgens, estrogens, progesterone) produced by ovaries and testesexert theirnegative (males) and negativeand positive (females)endocrine feedback to hypothalamic-pituitary levelby regulating thesynthesis and secretion of kisspeptin, GnRH and gonadotrophins.

Figure 2

(A) Genetic variation in the FSHB gene;(B) Phenotypic effects of the carrier status of alternative genotypes of FSHBpromoter polymorphism –211G/T (rs10835638) on male reproductive parameters (A)FSHBtranscribedregions are indicated by boxes and translated sequencesaredenoted by grey areas. Common polymorphisms (minor allele frequency >10%) that form two major gene haplotypes (96.6% of analysed samples[17]) are shown as circle-headed bars and their positionsare denoted relative to the FSHB transcription start-site. The FSHB–211G/T promoter SNP is indicated by an asterisk. FSHB mutations identified in infertile patientsare shown by triangles and their localization in the mature FSH beta peptide is indicated. (B) Effect of the FSHB gene promoter polymorphism –211G/T (rs10835638) on male hormonal and testicular parameters: total testis volume and sperm concentration (left panel), serum FSH and Inhibin B levels (middle panel), serum LH and total testosterone levels (right panel). Individuals are subgrouped according to their FSHB promoter position –211G/T genotype. Median values of reproductive parameters are presented based on Grigorova et al.[20**].

Figure 3

The distribution of currently known functional polymorphisms, and activating and inactivating mutations across the human FSHR gene. The FSHR exon boundaries are marked with short bars striking through the protein sequence. Greycircles depict the activating, greysquares inactivating mutations, and the asterisks the polymorphisms. The two polymorphisms Thr307Ala and Asn680Ser with currently known pharmacogenetic significance and exhibiting linkage disequilibrium in most populations are marked in bold. An additionalpolymorphism that has been indicated to have pharmacogenetic potential is FSHR–29G/A located in 5′-untranslated region and thus, not presented in this figure.