Insulin Sensitizers Because hyperinsulinemia appears to play a role in PCOS-associated anovulation, treatment with insulin sensitizers may shift the endocrine balance toward ovulation and pregnancy, either alone or in combination with other treatment modalities.
Metformin (Glucophage) is an oral biguanide antihyperglycemic drug used extensively for non– insulin-dependent diabetes. Metformin is pregnancy category B drug with no known human teratogenic effect. It lowers blood glucose mainly by inhibiting hepatic glucose production and by enhancing peripheral glucose uptake. Metformin enhances insulin sensitivity at the postreceptor level and stimulates insulin-mediated glucose disposal (144).
Metformin has been used extensively to treat oligo-ovulatory infertility, insulin resistance, and hyperandrogenism in PCOS patients. Metformin is used to treat PCOS oligo-ovulatory infertility either alone or in combination with dietary restriction, clomiphene, or gonadotropins. In randomized control studies, metformin improves the odds of ovulation in women with PCOS when compared with placebo (145,146). A large multicenter, randomized control trial in women with PCOS concluded that clomiphene is superior to metformin in achieving live births in infertile women with PCOS. When ovulation was used as the outcome, the combination of metformin and clomiphene was superior to either clomiphene alone or metformin alone (147). Multiple births are a complication of clomiphene therapy.
The most common side effects are gastrointestinal, including nausea, vomiting, diarrhea, bloating, and ﬂatulence. Because the drug caused fatal lactic acidosis in men with diabetes who have renal insufficiency, baseline renal function testing is suggested (148). The drug should not be given to women with elevated serum creatinine levels (144).
Concepts regarding the role of obesity and insulin resistance or hyperinsulinemia in PCOS suggest that the primary intervention should be recommending and assisting with weight loss (5% to 10% of body weight). In those with an elevated BMI, orlistat proved helpful in initiating and maintaining weight loss. A percentage of PCOS patients will respond to weight loss alone with spontaneous ovulation. In those who do not respond to weight loss alone or who are unable to lose weight, the sequential addition of clomiphene citrate followed by an insulin sensitizer, followed by the combination of these agents may promote ovulation without resorting to injectable gonadotropins.
A prevailing concern over the increased incidence of spontaneous abortions in women with PCOS and the potential reduction afforded by insulin sensitizers suggests that insulin sensitizers may be beneficial in combination with gonadotropin therapy for ovulation induction or in vitro fertilization (149). Women with early pregnancy loss have a low level of insulin-like growth factor (IGF) binding protein-1 (IGFBP-1), and of circulating glycodelin, which has immunomodulatory effects protecting the developing fetus. Use of metformin increased levels of both factors, which might explain early findings suggesting that metformin use may reduce the high spontaneous abortion rates seen among women with PCOS (150).
A number of observational studies suggested that metformin reduces the risk of pregnancy loss (151,152). However, there are no adequately designed and sufficiently powered randomized control trials to address this issue. In the prospective randomized pregnancy and PCOS (PPCOS) trial, there was a concerning nonsignificant trend toward a greater rate of miscarriages in the metformin only group (151). This trend was not noted in other trials.
There are no conclusive data to support a beneficial effect of metformin on pregnancy loss, and the trend toward a higher miscarriage rate in the PPCOS trial, which used extended release metformin, is of some concern (145,147).