The Role of Metformin in PCOS-Related Infertility

Peter Kovacs, MD, PhD


November 07, 2017

Polycystic Ovary Syndrome: The Role of Metformin

Polycystic ovary syndrome (PCOS) affects 3%-8% of reproductive-age women. It is characterized by clinical and laboratory hyperandrogenism; polycystic, enlarged ovaries; and irregular menstrual cycles. Various diagnostic criteria are in use, but the most widely applied are the Rotterdam criteria, which require two of three features to be present.[1,2] PCOS may present with various clinical problems, such as hyperandrogenism, oligo- or amenorrhea, obesity, the metabolic syndrome, or infertility.

Metabolic problems mediated through insulin resistance (IR) are a common feature of PCOS. Women with PCOS produce more insulin to maintain normal glucose levels. The degree of IR varies in different tissues; it is present in the liver and skeletal muscles, but the ovaries show less IR.

The benefits of insulin sensitizers have long been studied in women with PCOS. Metformin is an insulin-sensitizing agent that reduces glucose absorption and hepatic glucose synthesis and increases glucose uptake in skeletal muscles. Furthermore, through gastrointestinal side effects, it often results in weight loss. It has long been studied alone or in combination with other agents to restore ovulation.

A new guideline from the practice committee of the American Society for Reproductive Medicine[3] reviews the evidence for the use of metformin for ovulation induction.

Guideline Summary

Studies evaluating the use of metformin for PCOS are heterogeneous; different diagnostic criteria have been used, some have evaluated lean women and others obese women, some screened for IR whereas others did not, insulin sensitivity was measured by different tests, and outcome parameters have varied. This heterogeneity limits the strength of the associations found.

The following key findings are reported:

  • Metformin versus placebo: The ovulation rate was higher with metformin; clinical pregnancy rate showed a modest improvement with metformin.

  • Metformin versus clomiphene citrate: Metformin is less effective than clomiphene citrate for induction of ovulation; for clinical pregnancy rate and live births, a meta-analysis of 14 trials found a lower live birth rate with metformin versus clomiphene citrate (odds ratio, 0.48; 95% confidence interval, 0.31-0.73).[4]

  • Metformin plus clomiphene citrate versus metformin: With the combination, ovulation, clinical pregnancy rates, and live birth rates were all higher.

  • Metformin plus clomiphene citrate versus clomiphene citrate in clomiphene citrate-resistant women: Ovulation and pregnancy rates improved with combination therapy.

  • Metformin plus clomiphene citrate versus laparoscopic ovarian drilling in clomiphene-citrate resistant women: No significant difference was observed in pregnancy rates with the two interventions.

  • Clomiphene citrate plus metformin versus gonadotropins in clomiphene-citrate-resistant women: Reports on ovulation and pregnancy rates with the two approaches are conflicting.

  • Metformin is a category B drug; no fetal risks have been shown when used during pregnancy. Data on an effect on miscarriage rates are insufficient to draw conclusions.

The guideline concludes that currently, evidence is lacking to suggest improved live birth rates with metformin in women with PCOS, although there is some evidence that it improves ovulation and pregnancy rates.


Irregular ovulation is typical of PCOS, and women with PCOS are often infertile. For women with patent fallopian tubes whose partners have normal semen parameters, restoration of ovulation could restore fertility. In addition, more than 50% of women with PCOS are overweight or obese. In those cases, lifestyle changes resulting in weight loss may be sufficient to restore more regular ovarian function.[5] Women who remain oligo-ovulatory will require further treatment.

The goal in these cases is to restore monofollicular development, but the so-called therapeutic window is narrow. Too little medication will not induce ovulation, and higher doses may induce multifollicular development (resulting in multiple pregnancies) or ovarian hyperstimulation. The dose of the stimulating agent must be slowly titrated until the therapeutic effect is achieved.

According to the new guideline,[3] metformin alone offers little advantage and is therefore not recommended as a first-line agent. Metformin could prove to be useful in combination therapy for women with clomiphene citrate-resistant anovulation, before using gonadotropin or surgical intervention. Metformin has also been shown to reduce the risk for hyperstimulation during in vitro fertilization.[6]


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