Metformin or Clomiphene for Infertility Due to PCOS?

Nancy Hope Goodbar, PharmD

Disclosures

July 26, 2012

Question

How does metformin compare to clomiphene for treating infertility in women?

Response from Nancy Hope Goodbar, PharmD
Assistant Professor of Pharmacy Practice, Presbyterian College School of Pharmacy, Clinton, South Carolina

Metformin plays a role in managing infertility caused by polycystic ovary syndrome (PCOS), an endocrine abnormality that, through numerous proposed mechanisms, leads to anovulation.[1] Mechanisms related to the beneficial effect of metformin use in patients with PCOS include hyperinsulinemia and hyperandrogenism, which cause a decrease in sex hormone-binding globulin and, ultimately, anovulation.[2] Metformin is an insulin sensitizer that corrects hyperinsulinemia and secondarily corrects hyperandrogenism, possibly leading to ovulation.

Over the years, clomiphene has been the first-line agent for management of PCOS-induced infertility, but more recent studies and meta-analyses of the literature have shown promise with the use of metformin, either as monotherapy in certain characteristic populations or as an add-on treatment option. Although the comparative results of clomiphene vs metformin have differed, a 2009 meta-analysis[3] showed no difference between the 2 treatments in terms of ovulation rate, pregnancy rate, or live birth rate, although it should be noted that there was significant heterogeneity between the populations in the 2 groups. When clomiphene plus metformin was compared with monotherapy with each agent, combination therapy was not found to be superior to monotherapy.[3] The results of this study left lingering questions about the place of metformin vs clomiphene as a fertility agent.

A meta-analysis published in 2011[4] focused on clomiphene compared with metformin in subgroups of nonobese women, defined in international studies as a body mass index (BMI) of ≤ 32 kg/m2. The findings of the pooled data analyses showed that in this patient population, clomiphene and metformin did not differ in terms of pregnancy rate, live birth rate, or ovulation induction.

On the basis of compilation of the literature since 2009, metformin has become a reasonable first-line agent for fertility therapy in women of reproductive age who have PCOS, keeping in mind that it does not have US Food and Drug Administration approval for this indication. Other documented advantages of metformin over clomiphene include no known adverse effects on the endometrium, no known increase in the rate of multiple pregnancies, and no known ovarian risk in the long term.[4] Recent literature has also shown that metformin therapy continued through the first 12 weeks of pregnancy significantly improves live birth rates compared with placebo, which could be another niche for the use of metformin.[1]

Patients who are candidates for metformin therapy must be made aware that this therapy induces ovulation indirectly, taking up to 6 months to improve ovulation.[3] Clomiphene, in contrast, acts directly by producing a surge of luteinizing hormone and could cause ovulation within days.[3]

All patient-specific factors should be taken into account when determining the most appropriate regimen for treating infertility in a woman with PCOS. It is prudent to determine previous attempts at pharmacologic induction of ovulation, because this may lead to either enhanced sensitization to therapy or treatment resistance.

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