What is the role of Metformin (metformin hydrochloride) in the treatment of female infertility?

From the Guidelines

Metformin is not the first-line treatment for female infertility, particularly in women with polycystic ovary syndrome (PCOS), as its effects on early pregnancy are not well established, and clomiphene citrate is recommended as the initial treatment due to its effectiveness 1.

Treatment Overview

The typical treatment for women with PCOS who wish to conceive starts with weight control and a regular exercise program, followed by medication if needed.

• The American College of Obstetricians and Gynecologists (ACOG) recommends treatment with clomiphene citrate because of its effectiveness in inducing ovulation in women with PCOS, with approximately 80% of women ovulating and half of them conceiving 1.
• Metformin may be considered for women with PCOS who have insulin resistance, as it improves insulin sensitivity, reduces androgen levels, and normalizes menstrual cycles, leading to improved ovulation rates 1.

Metformin Usage

• The medication is typically started at a dose of 500 mg once daily, gradually increasing to 1500-2000 mg daily in divided doses to minimize gastrointestinal side effects.
• Treatment duration varies, but it often continues for 3-6 months before evaluating effectiveness, and may be maintained throughout pregnancy attempts.
• Metformin can be used alone or combined with clomiphene citrate when metformin monotherapy fails.

Recent Findings

• A recent systematic review and meta-analysis found that GLP-1 RAs (exenatide, liraglutide, and semaglutide) have variable weight reduction efficacy and may have metabolic and reproductive benefits in PCOS, but the evidence on fertility outcomes is limited 1.
• The review also found that metformin consistently resulted in greater adverse events than controls, including gastrointestinal disturbances.

Recommendations

• Metformin should not be used as the first-line treatment for female infertility, particularly in women with PCOS, due to the lack of established effects on early pregnancy and the availability of more effective treatments like clomiphene citrate 1.
• Metformin may be considered for women with PCOS who have insulin resistance, but its use should be carefully evaluated and monitored due to the potential for adverse events.
• Women with kidney or liver disease should not use metformin, and vitamin B12 levels should be monitored during long-term use.

From the FDA Drug Label

Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin hydrochloride tablets may result in ovulation in some anovulatory women.

The role of metformin in the treatment of female infertility is to induce ovulation in some anovulatory women, which may lead to unintended pregnancy.

• Key points:
  • Metformin hydrochloride tablets may result in ovulation in some anovulatory women.
  • Premenopausal women should be informed about the potential for unintended pregnancy. 2

From the Research

Role of Metformin in Treating Female Infertility

• Metformin has been shown to improve fertility outcomes in women with polycystic ovary syndrome (PCOS) by ameliorating insulin resistance, which helps to resolve hormonal and metabolic disturbances and increases ovulation, pregnancy, and live birth rates relative to placebo 3.
• A combination of metformin with clomifene citrate is more effective than either alone and is a useful option in women with clomifene-resistant PCOS 3.
• Metformin also has an adjunctive role in women with PCOS receiving assisted reproduction technology (ART) using the long gonadotrophin-releasing hormone agonist protocol, where it appears to increase the pregnancy rate and to reduce the risk of ovarian hyperstimulation syndrome 3.
• However, the use of metformin in non-obese women with PCOS is associated with a slight increase in clinical pregnancy rate compared to placebo, but with a higher risk of miscarriage rate 4.
• Clomiphene is superior to metformin in achieving live birth in infertile women with PCOS, although multiple birth is a complication 5.
• Short courses of metformin administration in patients with PCOS can reduce fasting insulin and improve the efficacy of clomiphene citrate to induce ovulation 6.
• There is insufficient evidence to establish a difference between metformin and clomiphene citrate in terms of ovulation, pregnancy, live birth, miscarriage, and multiple pregnancy rates in women with PCOS and a BMI < 32 kg/m2 7.

Metformin and Clomiphene Citrate Comparison

• Metformin is comparable to clomiphene citrate when the outcome is clinical pregnancy rate, and the risk of multiple pregnancies tends to be lower 4.
• However, metformin had a higher risk of miscarriage rate compared to clomiphene citrate 4.
• Adding metformin to clomiphene citrate treatment decreases miscarriage risk by two folds compared to metformin alone 4.

Metformin and Assisted Reproduction Technology (ART)

• Metformin has an adjunctive role in women with PCOS receiving ART using the long gonadotrophin-releasing hormone agonist protocol, where it appears to increase the pregnancy rate and to reduce the risk of ovarian hyperstimulation syndrome 3.
• However, there is no role for metformin in women receiving short ART protocols 3.