Guideline for Metformin Use for Ovulation Induction in PCOS

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There is fair evidence that metformin alone does not increase rates of miscarriage when stopped at the initiation of pregnancy.
There is fair evidence that metformin alone does not increase rates of miscarriage when stopped at the initiation of pregnancy.

The use of metformin in women with polycystic ovary syndrome (PCOS) may increase the ovulation rate when compared with placebo, but should not be considered a first-line therapy drug for anovulation, according to a study published in Fertility and Sterility.

The Practice Committee of the American Society for Reproductive Medicine performed a literature review and compiled guidelines that provide recommendations for clinicians regarding the use of metformin for ovulation induction in women diagnosed with PCOS who desire to become pregnant.

The proposed guidelines were evaluated using a grading system to support the recommendations, either for or against: grade A was considered good evidence, grade B was considered fair evidence, and grade C was considered insufficient evidence.

The following are the proposed guidelines broken down by grade category.

Grade A: Good Evidence

  • Metformin alone vs placebo increases the ovulation rate.
  • Metformin in combination with clomiphene citrate (CC) improves ovulation and clinical pregnancy rates but does not improve live birth rates compared with CC alone.
  • Metformin alone does not increase the rate of multiple pregnancy.

Grade B: Fair Evidence

  • Metformin alone is less effective than CC alone for the achievement of ovulation induction, clinical pregnancy, and live birth.
  • Letrozole is a reasonable first-line agent for ovulation induction.
  • Pretreatment with metformin for at least 3 months followed by the addition of another ovulation-inducing drug increases the live birth rate.
  • CC-metformin improves ovulation and pregnancy rates compared with CC alone in women with CC-resistant PCOS. However, more studies are needed to determine whether there may be subgroups of women with PCOS and CC resistance for which CC-metformin provides the most benefit over CC alone.
  • Overall pregnancy rates are not different with CC-metformin, CC-laparoscopic ovarian drilling (LOD), or LOD alone in women with CC-resistant PCOS.
  • Metformin used while attempting pregnancy and stopped at the initiation of pregnancy does not affect the rate of miscarriage.

Grade C: Insufficient Evidence

  • Metformin alone increases pregnancy rates or live birth rates compared with placebo.
  • Metformin alone increases pregnancy or live birth rates compared with letrozole alone.
  • There is not enough evidence regarding pregnancy rate or live birth rate with the use of metformin alone compared with LOD for ovulation induction in women with CC-resistant PCOS.
  • There is insufficient evidence to compare metformin plus CC with aromatase inhibitors alone or metformin plus aromatase inhibitors for ovulation induction in CC-resistant women.
  • There is conflicting evidence regarding metformin use combined with CC compared with gonadotropins for ovulation induction in women with CC-resistant PCOS.
  • There is not enough evidence to recommend metformin during pregnancy to reduce the chance of miscarriage.
  • Although there is no evidence of an effect (either an increase or a decrease) on multiple pregnancy rates in cycles using combination CC plus metformin vs CC alone, there remains insufficient data on this matter as a result of a lack of adequate power to detect a difference.
  • There is insufficient evidence of a reduced risk for multiple pregnancy with the addition of metformin to follicle-stimulating hormone compared with follicle-stimulating hormone alone.
  • Good-quality evidence to determine whether metformin is more effective in nonobese or obese women with PCOS.

The researchers concluded, "metformin alone should not be used as first-line therapy for ovulation induction in women with PCOS, since ovulation induction agents such as CC or letrozole are more effective." In addition, the evidence found that metformin does not increase miscarriage rates when stopped at the start of pregnancy, and not enough evidence was found to support that metformin in combination with other agents increases the number of live births.

Reference

Penzaias A, Bendikson K, Butts S, et al; Practice Committee of the American Society for Reproductive Medicine. Role of metformin for ovulation induction in infertile patients with polycystic ovary syndrome (PCOS): a guideline. Fertil Steril. 2017;108:426-441. 

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