• Polycystic Ovary Disorder
• Infertility

• Polycystic Ovary Disorder
• Obstetrics & Gynecology
• Infertility

Metformin is a commonly used treatment in polycystic ovary syndrome (PCOS), and it is widely believed that metformin improves reproductive outcomes in patients with PCOS. Richard S. Legro, MD, Milton S. Hershey Medical Center, Hershey Pennsylvania, USA, discussed the pathophysiology of PCOS as well as management of PCOS-associated infertility.

Approximately 80% of women with anovulatory infertility also have PCOS. The original characterization of PCOS noted amenorrhea, hirsutism, hyperandrogenemia, sterility, and large pale polycystic ovaries. Decades later, the previous characteristics are still applicable when making a diagnosis of PCOS, regardless of which criteria is used.

PCOS can be associated with several risk factors for cardiovascular disease, including elevated body mass index, insulin resistance, and elevated lipids, as well as an increase in carotid intimal medial thickness [Talbot EO et al. Arterio Thromb Vase Biol 2000].

There is evidence that treatment of insulin resistance in patients with PCOS can improve symptoms, including infertility. Although treatment with D-chiro-inositol and troglitazone increased the rate of ovulation, they have substantial side effects that prohibit their use [Nestler JE et al. N Engl J Med 1999; Azziz R et al. Clin Endocrinol Metab 2001]. However, open-label treatment of 26 women with PCOS with metformin was demonstrated to reduce hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, as well as improved menstruation and rate of pregnancy [Velazquez EM et al. Metabolism 1994].

Increasingly, women with PCOS who wish to conceive are referred for in vitro fertilization (IVF) therapy, which in turn has resulted in a high rate of multiple pregnancies. Dr. Legro discussed other methods of increasing fertility in women with PCOS. In a highly cited study, metformin plus clomiphene improved the ovulation rate to 90% compared with 8% in patients who received placebo [Nestler JE et al. N Engl J Med 1998]. In addition, a randomized study demonstrated that continued therapy with metformin reduced PCOS-related pregnancy complications [Vanky E et al. Hum Reprod 2004]. In a more recent study, women with PCOS treated with clomiphene alone had significantly increased rates of live birth compared with patients who received metformin alone (p<0.001) and was not significantly different from a combination therapy with both [Legro RS et al. N Engl J Med 2007]. In addition, fecundity per ovulation was greater in patients who received clomiphene compared with metformin. Despite these finding, a meta-analysis found that metformin and clomiphene, as monotherapy or in combination, did not improve the number of live births [Tang T et al. Cochrane Database Syst Rev 2012], suggesting that metformin has a limited effect on reproductive outcomes in women with PCOS (Table 1).

Dr. Legro concluded by highlighting several reasons why metformin continues to be used in women with PCOS to improve reproductive outcomes, despite a lack of evidence supporting its use for that indication. He noted that most of the positive studies using metformin used surrogate variables such as ovulation rate, and the initial randomized trials were small and irreproducible. In addition, a safety bias occurs because metformin has a good risk-benefit ratio.

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