Is the Co-administration of Metformine and CC as Compared to Placebo and CC Superior to Induce Ovulation in PCOS Patients With a Confirmed insulin-resistant-a Double Blind Randomized Clinical Trial

Introduction:

PCOS is the most common cause of anovulatory infertility which affects 12-21% of the population. This percentage may vary according to the criteria used and population studied.Hyperandrogenism, chronic anovulation, and occasionally obesity are the characteristics of this syndrome. Currently, CC is the first-line infertility treatment in women with the PCOS .However, 20-25% of PCOS women fail to ovulate with incremental doses of CC and and do not respond due to resistance to CC .IR and hyperinsulinemia are considered as important factors in the pathogenesis of PCOS .Hence, lean and obese women with PCOS may have IR.Hyperinsulinism has been shown to play a part in ovarian hyperandrogenism and may directly influence and even prevent ovulation.Metformin, an insulin sensitizing agent, reduces levels of luteinizing hormone, hyperinsulinemia and also decreases ovarian production of androgens .For this reason a number of studies have been performed and evaluated the possible beneficial role of metformin in managing women with PCOS. However, the studies performed evaluate the possible benefit of metformin alone or in combination with CC as first-line treatment for infertility in women with PCOS have reported conflicting results .Recently a meta-analysis concluded that metformin was more burdensome than placebo, hence CC alone and not CC plus metformin should be the drug of choice in these patients.A high-quality Cochrane systematic review has reported on randomized controlled trials(RCTs) comparing metformin with CC in women with PCOS and demonstrated that CC had a significantly higher pregnancy and live birth rate in women with a BMI >30 kg/m2 whereas metformin had better results in women with a BMI <30 kg/m2.Lately, a meta-analysis reported that due to conflicting findings and heterogeneity across the included RCTs, there is insufficient evidence to establish a difference between metformin and CC in terms of ovulation, pregnancy, live birth, miscarriage and multiple pregnancy rates in nonobese women with PCOS. It was proposed that caution should be proceeded when prescribing metformin as first line pharmacological therapy in this group of women until further rigorous trials are done.

These conflicting results from the published studies may be due to the large differences and heterogeneity in study populations, particularly the possible presence or absence of IR. Metformin decreases IR, however there is not a single RCTwith metformin in IR PCOS patients. Therefore, the aim of current study is to compare CC with coadministration of metformin and with CC with coadministration of placebo in IR PCOS patients to induce ovulation.

Methods and materials:

A total of 388 IR women with PCOS will be enrolled in this study from infertility clinic at Amir-Al-Momenin Hospital, Semnan, Iran from november 2015 to april 2020 . All patients will be informed about the study and possible complications of the drugs by a consultant and informed consents will be signed. This study will be supervised and approved by the Research Council and Ethical Committee of Semnan University of Medical Sciences. For randomization random block allocation method was used, in which six blocks with four components will be present: AABB, BBAA, ABAB, BABA, ABBA, and BAAB. A random digit number table or generator to select and sort the blocks will be applied. The allocation sequence will be concealed in sequentially numbered, sealed envelopes.