Association of allelic combinations of FSHR gene polymorphisms with ovarian response

Abstract

During an IVF protocol, exogenous FSH is administered to women for ovulation induction. The ovarian response to gonadotrophin stimulation is variable and unpredictable in these women. The FSHR is the most studied gene in relation to ovarian response. The association of a FSHR gene polymorphism at position 680 (p.Asn680Ser) with ovarian response has been well documented. Recently, a polymorphism at position -29 in the 5'-untranslated region of FSHR (g.-29G>A) has been reported to be associated with poor ovarian response and reduced FSHR expression. The present study evaluated the combined effect of the polymorphisms at positions -29 and 680 of FSHR with type of ovarian response and receptor expression. The two FSHR gene polymorphisms together formed four discrete haplotypes and nine allelic combinations. Various clinical parameters revealed that 75% of the subjects with A/A-Asn/Asn genotype were poor ovarian responders (odds ratio 7.92; P=0.009). The relative FSHR mRNA expression in granulosa cells indicated that subjects with A/A-Asn/Asn genotype express significantly lower level of FSHR as compared to the subjects with G/G-Asn/Ser genotype (P=0.029). These results indicate that A/A-Asn/Asn genotype could be used as a potential marker to predict poor ovarian response. The action of FSH is mediated by its receptor (FSHR) present on the granulosa cells in the ovary. Any alterations in the hormone or its receptor are likely to disrupt its normal function, thus causing infertility. Several alterations (mutations/polymorphisms) of the FSHR gene have been reported in women with primary or secondary amenorrhoea. It has also been reported that FSHR gene polymorphisms are associated with variable ovarian response to FSH stimulation during IVF. Women may show poor or normal or hyperovarian response to FSH stimulation. It is well documented that the level of FSHR expression has a great effect on FSH action and is associated with ovarian response. In the present study, we screened normally menstruating women undergoing IVF due to tubal/male factor or unexplained infertility. We analysed two polymorphisms of FSHR, g-29G>A and p.Asn680Ser, in these women. In the subjects studied, 75% women with A/A-Asn/Asn genotype were observed to be poor ovarian responders to FSH stimulation. FSHR expression at the transcript level was observed to be significantly lower in women with A/A-Asn/Asn genotype as compared to women with G/G-Asn/Ser genotype. We also observed that women with A/A-Ser/Ser genotype were not present in the study population. These findings indicate the significance of A/A-Asn/Asn genotype as a predictive marker for poor ovarian response to FSH stimulation.

Keywords: FSH; FSHR; genotype analysis; poor ovarian response.