The Effect of Genetic Polymorphism on Therapeutic Response of Metformin in Women with Polycystic Ovarian Syndrome in Iraqi Population

Abstract

Insulin resistance and compensatory hyperinsulinemia have been proposed as potential mechanisms for the gonadotropin secretory abnormalities characteristic of PCOS. Thus, metformin, an insulin-lowering agents, has been prescribed extensively to regulate insulin level of patients with PCOS. However, there are individual differences in the treatment effectiveness of metformin among PCOS patients. The exact mechanism of insulin resistance remains to be clarified; however, it is supposed that it originates from the post-receptor defects. The insulin receptor substrate-1 (IRS1) is an important intermediate in insulin signaling pathway. Polymorphisms in IRS1 have been associated with insulin resistance. Respectively, in this study, we investigated the effect of the polymorphisms of IRS1 on the treatment effectiveness of metformin in PCOS patients. The study involved 100 women diagnosed with PCOS according to Rotterdam criteria and 100 control healthy women. All patients diagnosed with PCOS received 500 mg twice daily for 12 weeks. Both case and control group were genotyped for the single nucleotide polymorphisms (SNPs) (rs1801123) of IRS.1.Main outcome measures were hormonal parameters, metabolic parameters, and lipid panel parameters. They were measured at baseline for control and PCOS group and 12 weeks post metformin treatment for PCOS patients only.Our study has shown that metformin had differential effects on fasting insulin level, HbA1C, LH, LH/FSH ratio, testosterone (p-value<0.05)among patients based on different genotypes of IRS.1. Patients with mutated IRS.1 were not showing the same response as patients with intact IRS.1 gene. This finding provides data to support future PCOS clinical trials about Iraqi population, but also shows how genetics and polymorphism can play an important role in explaining how the response of PCOS patients might differ according to a specific type of polymorphism.