Treating Infertility in Polycystic Ovary Syndrome

Peter Kovacs, MD, PhD


August 16, 2010

PCOSMIC: A Multi-Centre Randomized Trial in Women With PolyCystic Ovary Syndrome Evaluating Metformin for Infertility with Clomiphene

Johnson NP, Stewart AW, Falkiner J, et al; on behalf of REACT-NZ (REproduction And Collaborative Trials in New Zealand), a multi-centre fertility trials group
Hum Reprod. 2010 Apr 30. [Epub ahead of print]


Polycystic ovary syndrome (PCOS) occurs in 5%-7% of women and is responsible for at least 80% of ovulatory infertility. The diagnosis is established on the basis of irregular cycles, hyperandrogenism, and the typical polycystic-appearing ovaries, after exclusion of other causes of the clinical picture. The symptoms associated with and the complications caused by the syndrome are heterogeneous. Medical problems that result from the metabolic abnormalities of PCOS (such as diabetes, hypertension, or dyslipidemia) are more common than in the age-matched general population.

The most widely accepted pathomechanism of PCOS explains the connection with insulin resistance. Hyperinsulinemia is responsible for abnormal ovarian hormone production, which leads to the reproductive phenotype. Women of reproductive age with PCOS often seek medical care for infertility. In addition to obesity, infertility is a main consequence of irregular ovarian activity.

Several treatment options are available for PCOS, ranging from lifestyle changes to surgery. Lifestyle changes that lead to weight loss are considered first-line treatment, but additional therapy is often needed to restore regular ovarian activity. Most commonly, this is achieved with ovulation-inducing agents. For a long time, clomiphene citrate was considered the first choice, but in recent years, much was published about the beneficial effect of insulin-sensitizing agents. Initial reports and meta-analyses showed improved cycle regularity and ovulation rates with use of these agents.[1] Recent randomized trials, however, do not support their routine use.[2,3]

This trial evaluated whether the additional use of metformin over standard therapy with clomiphene provides a benefit in the management of PCOS-related anovulatory infertility.

Study Summary

Women with PCOS were invited to participate in this trial. Patients with a body mass index (BMI) greater than 32 kg/m2 were offered either lifestyle intervention or metformin. If the patient remained anovulatory after 3 months, clomiphene citrate was also given. Patients with a BMI of 32 kg/m2 or less received clomiphene citrate (up to 150 mg), metformin (1500 mg/d), or both for 6 months. Baseline characteristics were well matched between the groups. Among women with a higher BMI, no differences in live birth rate were observed with placebo (lifestyle management without drug therapy) vs metformin (16% vs 6%). Among women with a BMI less than 32 kg/m2, live birth rates were similar with metformin, clomiphene, and clomiphene plus metformin (29% vs 36% vs 43%, respectively). In both BMI groups, standard care (no metformin, lifestyle changes with or without clomiphene) was similarly effective to standard care plus metformin in terms of live birth rates (22% vs 30%). Metformin had no effect on miscarriage rates.


Insulin resistance can be diagnosed in most cases of PCOS. The use of insulin-sensitizing agents during the management of these patients seems to be appropriate. Initial studies reported improved cycle regularity and ovulation rate. Because women with PCOS are often infertile as a result of ovulatory problems, the use of insulin-sensitizing agents to increase ovulation should be effective. Metformin is a category B drug; its use is safe during pregnancy. For a long time, other ovulation inducing agents were considered first-line treatment, but after early reports, metformin use became widespread.

Initial small studies were followed by randomized trials that did not find an additional benefit with metformin. At this point, one thing seems certain: Lifestyle changes have to be part of the treatment, especially among overweight women. Clomiphene has a long track record of efficacy. Problems with clomiphene are its negative endometrial effect, multifollicular development, risk for multiple gestation, and safety issues with long-term use.[4]

For women with anovulation but no other fertility issues, mono-ovulation is the desired aim. Insulin-sensitizing agents, if they work, will achieve that. They are not associated with long-term side effects and may have beneficial lasting metabolic effects. In addition, their reproductive effect may improve with extended use (beyond 3 months).[5]The effects of metformin on spontaneous abortion rates (when used during early pregnancy as well), diabetes during pregnancy, and hypertensive complications during pregnancy have not been studied adequately.

On the basis of currently available information, clomiphene citrate seems to be a better choice when short-term success is desired. If it fails to induce ovulation on its own, it should be combined with metformin before moving to gonadotropin injections (which carry a significant risk for multiple gestation) or surgical methods. Future studies will have to evaluate the effect of metformin on medical complications during pregnancy. Miscarriage rates and pregnancy rates should be assessed on the basis of even longer follow-up periods to allow full effect.



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