Making a case for metformin

By Thomas S. Kosasa, MD

While metformin is certainly no miracle cure for polycystic ovary disease, a wide range of studies support its role in lowering serum androgens, restoring normal menstrual cycles and ovulation, and—perhaps—even improving pregnancy rates.

The realization that insulin resistance is a pivotal defect in polycystic ovary syndrome (PCOS) probably counts as one of the most important advances in the battle to control the disorder. This metabolic "mishap" leads to a compensatory increase in circulating insulin, and evidence suggests that this elevated insulin level directly stimulates the ovary to produce excess androgens.^1,2 Since both obese and lean women with PCOS have insulin resistance, it's safe to assume that women with PCOS are insulin resistant.^3,4

If, as the research strongly suggests, insulin resistance turns out to be one of the primary causes of PCOS, we would expect drugs that reverse insulin resistance to also relieve hyperandrogenism, restore normal menses, and help eliminate the infertility associated with PCOS. At the top of that list of pharmaceutical agents is metformin, which was developed in 1957 to treat type 2 diabetes. Metformin reduces insulin resistance of peripheral tissue and allows muscle and adipose cells to take in glucose at normal insulin levels. The drug also reduces intestinal absorption of glucose and decreases the production of glucose by the liver, without causing hypoglycemia.⁵

The first published experiment that used metformin to treat PCOS patients administered 500 mg three times a day after meals to 26 moderately obese women for 8 weeks.⁶ The drug significantly reduced serum luteinizing hormone (LH) and increased follicle stimulating hormone (FSH) and sex hormone binding globulin (SHBG). It also reduced free testosterone levels by 49% and total testosterone by 52%. None of the women had a normal menstrual cycle before entering the study, but after taking metformin, three became pregnant, and seven out of seven women who took the drug for more than 8 weeks resumed normal menstrual cycles. In a subsequent study, 21 out of 22 women treated with metformin for 6 months resumed normal menstrual cycles and four became pregnant.⁷

The first placebo-controlled clinical trial that looked at metformin for the treatment of PCOS used 500 mg three times daily for 4 to 8 weeks in 24 obese women. The drug caused insulin levels to drop and caused decreases in GnRH-stimulated LH release and free testosterone; it also increased SHBG levels. These improvements occurred in the absence of any change in body weight. An independent placebo-controlled study using metformin 500 mg three times daily in lean women with PCOS yielded similar results: Metformin decreased fasting- and glucose-stimulated insulin levels, decreased basal and GnRH-stimulated LH release, decreased free and total testosterone, and increased SHBG.⁴

Unfortunately, not all the evidence on metformin is so positive. In a placebo-controlled 16-week trial, French investigators concluded that metformin had no additional benefit over diet in improving hyperinsulinemia and hyperandrogenism. This study, however, used 850 mg of metformin twice daily in very obese women (averaging 35.2 kg/m²).⁸ Similarly, a 1997 investigation using 850 mg three times daily in markedly obese women (averaging 39 kg/m²) found that metformin did not significantly reduce hyperinsulinemia or hyperandrogenism.⁹ These studies suggest that the drug will not benefit PCOS patients suffering from morbid obesity. Finally, Turkish researchers conducted a single-blind study using 850 mg of metformin twice daily in 16 patients for 10 weeks and were also unable to detect any improvement in insulin resistance.¹⁰