Metformin and Ovulation induction in Polycystic Ovary Syndrome (PCOS)

A summarized study by Dr. Christopher Montville- April 2018 

Metformin, a biguanide used in the treatment of type-2 diabetes mellitus, has been utilized as a treatment for women with PCOS desiring pregnancy since the 1990s.  Although the mechanism of action is not entirely understood, Metformin is thought to decrease insulin resistance in women with PCOS, and thereby improve ovulation rates and subsequent pregnancy.  Some of the difficulties associated with studying the effects of Metformin in women with PCOS have been the lack of well-designed randomized controlled trials (RTCs) and the varying heterogeneity of the populations studied.

A guideline on the use of Metformin for women with PCOS desiring pregnancy was recently published in the September 2017 issue of Fertility and Sterility (https://doi.org/10.1016/j.fertnstert.2017.06.026), which provides insight into which patients may benefit from Metformin use.  Important conclusions from the literature review include the following:

Compared to placebo, Metformin improves ovulation rates in women with PCOS.  There is not enough evidence linking Metformin use to higher pregnancy rates or live birth rates, however.  When considering Metformin vs Clomiphene citrate (Clomid) as mono-therapy for ovulation induction, Clomid is superior for improving ovulation, pregnancy rates and live birth rates.  Additionally, the addition of Metformin to Clomid does not improve live birth rates when compared to Clomid alone.  There is no strong data to indicate whether Metformin is more effective in obese vs lean women with PCOS.

Interestingly, the article does cite one RCT that supports the use of Metformin for three months prior to starting Clomid to help improve live birth rates.  Additionally, 1-3 months of pre-treatment with metformin (1500mg/day) prior to Clomid use may be helpful for those women who have previously been resistant to high (150mg/day) doses of Clomid.  There is a lack of strong evidence to suggest that laparoscopic ovarian drilling is better than Clomid-Metformin in women who are Clomid resistant.

In terms of pregnancy, stopping Metformin use at the first indication of pregnancy does not seem to affect miscarriage rate.  Importantly, there is not enough data to suggest that continuation of Metformin in pregnancy will reduce miscarriage rates.

The authors conclude that there is a lack of strong data to support the routine use of Metformin in women with PCOS desiring pregnancy.  As indicated by the Endocrine Society, Metformin use should be reserved for women with documented glucose intolerance.  The authors do concede that many of the studies evaluating the effects of Metformin are inconclusive, given the small sample sizes studied and heterogeneity in the study populations.  Although Metformin may be helpful for women who are resistant to Clomid, there is no strong data indicating that Metformin improves live birth rates in women with PCOS.

Penzias, Alan et al.  Role of metformin for ovulation induction in infertile patients with polycystic ovary syndrome (PCOS): a guideline.  Fertility Sterile 2017;108:426-41.

The authors conclude that there is not sufficient evidence to recommend the use of Metformin alone for ovulation induction in women with PCOS who desire pregnancy.  Although Metformin may be helpful for women who are resistant to Clomid, there is no strong data indicating that Metformin improves live birth rates in this patient population.  The authors do concede that many of the studies evaluating the effects of Metformin are inconclusive, given small samples sizes and heterogeneity in the populations studied, and that individualizing cases over the long term may be of benefit in improving ovulation rates.