Functional genetic polymorphisms and female reproductive disorders: Part I: Polycystic ovary syndrome and ovarian response

Abstract

Background: The identification of polymorphisms associated with a disease can help to elucidate its pathogenesis, and this knowledge can be used to improve prognosis for women with a particular disorder, such as polycystic ovary syndrome (PCOS). Since an altered response to ovarian stimulation is also a characteristic of the disease, further knowledge about its aetiology could help in defining the parameters that determine the response of an individual to ovarian stimulation.

Methods: PubMed and EMBASE databases were systematically searched for gene association studies published until the end of August 2007, using search criteria relevant to PCOS and ovarian response to stimulation. Data from additional papers identified through hand searches were also included; 139 publications were reviewed.

Results: Several genes involved in ovarian function and metabolism are associated with increased susceptibility to PCOS, but none is strong enough to correlate alone with susceptibility to the disease, or response to therapy. A single-nucleotide polymorphism in exon 10 of the FSH receptor (FSHR) gene, FSHR p.N680S, was consistently identified as having a significant association with ovarian response to FSH.

Conclusions: No consistent association between gene polymorphism and PCOS could be identified. The FSHR gene may play a significant role in the success of ovarian stimulation, and can be used as a marker to predict differences in FSHR function and ovarian response to FSH. Genotyping the FSHR p.N680S polymorphism may provide a means of identifying a population of poor responders before in vitro fertilization procedures are initiated.

Figure 1:

Graphic representation of types of genetic variants, showing insertion/deletion (ins/del) polymorphisms, both coding and non-coding SNPs, and repeat polymorphisms such as tandem repeats or VNTR. Variants are shown occurring within a gene (in this example the INS gene), but can also occur outside of genes. Other types of genetic variations that affect larger regions, such as copy number variations, are not shown. SNP, single-nucleotide polymorphism; VNTR, variable number of tandem repeats.

Figure 2:

Principles of genetic association, and possible explanations for an observed association.

Figure 3:

LD plot of the genomic region on chromosome 2 harbouring the FSHR gene, obtained from the HapMap website (www.hapmap.org). More than 900 SNPs are currently listed in the National Centre for Biotechnology Information SNP database. These SNPs are grouped into two major LD blocks (red triangles). FSHR, follicle-stimulating hormone receptor; LD, linkage disequilibrium.

Figure 4:

Menstrual cycle-dependent serum levels of LH (A), FSH (B), estradiol (C), progesterone (D), inhibin A (E), and inhibin B (F) referenced to the day of the LH surge (0) in women with the Asn680/Asn680 (n=12) and the Ser680/Ser680 (n=9) genotype from the luteo-follicular transition phase (LH -25) until ovulation (LH +2). Means are displayed as bars, and error bars show SEM; *P<0.05; **P<0.005. Serum hormone concentrations during the menstrual cycle in women carrying either N⁶⁸⁰/N⁶⁸⁰ or S⁶⁸⁰/S⁶⁸⁰ allele variants of the N680S polymorphism in the FSH receptor gene [Reproduced with permission from Greb et al. (2005), © 2005 The Endocrine Society].

Figure 5:

Serum levels of oestradiol before ovulation induction were significantly lower in women with the Ser/Ser allele variant (group I, n=24) compared to the Asn/Asn allele variant (group III, n=44) of the FSH receptor (lower panel: *significant difference between group I and III). This difference in ovarian response could be overcome by increasing the daily FSH dose from 150U/day to 225U/day (upper panel:*significant higher total FSH dose) in women with the Ser/Ser allele variant (group II, n=25); lower panel: no significant difference between group II and III. Total FSH dose required (upper) and serum estradiol concentration (lower) in normo-ovulatory women undergoing controlled ovarian hyperstimulation, grouped according to N680S genotype for the FSH receptor gene [Reproduced with permission from Behre et al. (2005), ©2005 Lippincott Williams & Wilkins].