Association Between Follicle-Stimulating Hormone Receptor (FSHR) rs6166 and Estrogen Receptor 1 (ESR1) rs2234693 Polymorphisms and Polycystic Ovary Syndrome Risk, Phenotype, and Reproductive Outcomes in an Infertile Portuguese Population.

Introduction: Polycystic ovary syndrome (PCOS) is a common endocrine disorder often leading to anovulatory infertility. PCOS pathophysiology is still unclear and several potential genetic susceptibility factors have been proposed. The effect of polymorphisms in two genesrelated to follicular recruitment and development, the follicle-stimulating hormone receptor () and the estrogen receptor 1 (), have been studied in different populations with contradictory results.

Aims: To evaluate the influence of rs6166 (c.2039A>G) and of rs2234693 (Pvull c.453-397 T > C) polymorphisms on PCOS risk, phenotype, and response to controlled ovarian stimulation (COS).

Materials And Methods: Genotyping of the rs6166 and the rs2234693 polymorphisms was performed in PCOS women and a control group undergoing in vitro fertilization (IVF). Demographic, clinical, and biochemical data, genotype frequency, and IVF outcomes were compared between groups.

Results: We evaluated 88 PCOS women and 80 controls. There was no significant difference in the genotype distribution of rs6166 polymorphism between PCOS women and controls (AA 31.8%/AS 48.9%/SS 19.3% in PCOS women vs AA 37.5%/AS 40.0%/SS 22.5% in controls; p = 0.522). The same was true for the rs2234693 (CC 24.1%/CT 46.0%/TT 29.9% in PCOS women vs CC 18.8%/CT 48.8%/TT 32.5% in controls; p = 0.697). In PCOS women, we found higher follicle-stimulating hormone (FSH) levels on the third day of the menstrual cycle associated with the SS variant of the polymorphism (9.2 vs6.2 ± 1.6 and 5.6 ± 1.6 mUI/mL; p = 0.011). We did not find other associations between the baseline hormonal parameters, antral follicle count, and response measures to COS with or genotypes. We found, however, a need for higher cumulative doses of FSH for COS in patients with the SS variant of the rs6166 polymorphism (1860.5 ± 627.8 IU for SSvs1498.1 ± 359.3 for AA and 1425.4 ± 474.8 for SA; p = 0.046 and p = 0.046).

Conclusion: Our data suggest that in the population,  rs6166and polymorphisms do not influence the risk of developing PCOS nor do they influence the patient's phenotype and IVF success. However, the SS variant of the rs6166 polymorphism may be associated with FSH resistance requiring higher FSH doses for COS.