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• PCOS is sometimes treated with metformin, a drug for insulin resistance.
• 60-70% of women with PCOS are insulin resistant which is why metformin may be prescribed.
• Clinical studies exploring metformin and PCOS symptoms have been small and inconsistent, but there is some evidence metformin increases ovulation rate in women with PCOS when compared to treatment with a placebo.
• Other studies have found that there is no consistent evidence that metformin improves the signs of hyperandrogegism (such as hairiness from excess male hormones).
• However, metformin should not be completely discounted as an option for the management of PCOS

Metformin is the first line treatment approach for type 2 diabetes mellitus (T2DM). It works by improving the way in which the body responds to insulin, preventing blood sugar levels from getting too high. Metformin is not licensed for the treatment of PCOS, but as many women with the condition are insulin resistant, it is often prescribed ‘off label’ to help manage the symptoms.

This article aims to address some questions regarding the use of metformin in the management of PCOS. Is there justification in its use? Can it help to improve the symptoms of the condition, or are there alternative options that will be more effective? Will there ever be a time when metformin is prescribed as standard for all women with PCOS and to treat PCOS side effects?

Why metformin and PCOS?

Metformin is safe and cost effective, hence it’s widespread use in the management of T2DM.

Insulin resistance is not one of the three diagnostic criteria used in defining PCOS, however it is recognised as a common feature. In fact, 60-70% of women with PCOS will be insulin resistant and it is thought that the higher than normal levels of insulin contribute to many of the phenotypic traits of the condition. Thus, it makes sense that treating the insulin resistance might help to alleviate other PCOS side effects, for example regulating the menstrual cycle and improving signs of unwanted hair growth and acne.

What does the science say about PCOS and metformin?

Unfortunately metformin has not turned out to be the wonder drug that some anticipated. The clinical studies to date have largely been small in sample size and results have been inconsistent.

In 2017, the American Society for Reproductive Medicine published guidelines on the use of metformin for the treatment of infertility in women with PCOS. They based these guidelines on the results of a comprehensive literature review. The main conclusions reached were:

• There is some evidence that metformin increases ovulation rate in women with PCOS when compared to treatment with a placebo.

However:

• Clomiphene citrate is more effective at inducing ovulation than metformin.
• Metformin plus clomiphene citrate is more effective than metformin alone.
• There is insufficient data on pregnancy and live birth rates following metformin treatment. Thus, the longer term overall reproductive benefit cannot currently be established.

Furthermore:

• There is insufficient evidence to recommend metformin as an option to reduce the risk of miscarriage in women with PCOS.
• Preliminary work suggesting that preventative treatment with metformin reduces the risk of gestational diabetes has not been replicated in newer studies.

The final conclusion reached by the Society was that they would not recommend metformin as the first line treatment approach for ovulation induction. Medications such as clomiphene citrate, known to be an ovulation inducer, are generally more effective than metformin for women who are experiencing PCOS-related fertility issues.

In addition to these findings, other studies have found that there is no consistent evidence that metformin improves the signs of hyperandrogenism.

The outlook for metformin as a PCOS treatment

Metformin should not be completely discounted as an option for the management of PCOS. Whilst less effective than other options, metformin has been shown to restore ovulation in some women with PCOS.

For women with PCOS clomiphene citrate is commonly used to induce ovulation, however, not all women respond to treatment with this drug. For the women that do not respond, it is possible that combination therapy with metformin may be more successful at inducing ovulation. However, the work on this to date is limited. There is a need for longer term studies on metformin, as most studies have only explored short course treatment approaches.

PCOS varies considerably from woman to woman. The presenting symptoms differ in both type and severity, which is why diagnosing it can be so challenging. Women with PCOS are prone to other conditions such as obesity and insulin resistance; they are also at greater risk of developing T2DM and endometrial cancer. Whether metformin can be given prophylactically to reduce these risks remains unclear and once again highlights the need for longer-term studies with extensive follow-up periods.

Will metformin be prescribed as standard to all women that receive a diagnosis of PCOS?

Unlikely. A more valuable course of action would be for doctors to better understand the various PCOS phenotypes and thus, take a more individualised approach to treatment, deciding which of their patients could genuinely benefit from treatment with the drug.

As a final note, the value of lifestyle modifications should not be understated. Adopting lifestyle changes and losing weight has proven to be, by far, the best approach for managing the symptoms of PCOS. It is also the most effective way for women with PCOS to reduce their risk of developing T2DM. Medication should remain a contingency strategy for use in those who do respond adequately to lifestyle alterations.

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Sources:

• Lashen, Hany. “Review: Role of Metformin in the Management of Polycystic Ovary Syndrome.” Therapeutic Advances in Endocrinology and Metabolism, vol. 1, no. 3, June 2010, pp. 117–128., doi:10.1177/2042018810380215.
• Practice Committee of the American Society for Reproductive Medicine (Penzias, Alan, et al.) “Role of Metformin for Ovulation Induction in Infertile Patients with Polycystic Ovary Syndrome (PCOS): a Guideline.” Fertility and Sterility, vol. 108, no. 3, Sept. 2017, pp. 426–441., doi:10.1016/j.fertnstert.2017.06.026.
• “Summary of Possible Benefits and Harms: Information for the Public: Polycystic Ovary Syndrome: Metformin in Women Not Planning Pregnancy: Advice.” NICE, Feb. 2013, www.nice.org.uk/advice/esuom6/ifp/chapter/Summary-of-possible-benefits-and-harms.
• “Treatment. Polycystic Ovary Syndrome .” NHS Choices, NHS, www.nhs.uk/conditions/polycystic-ovary-syndrome-pcos/treatment/.
• Yarandi, Razieh Bidhendi, et al. “Metformin Therapy before Conception versus throughout the Pregnancy and Risk of Gestational Diabetes Mellitus in Women with Polycystic Ovary Syndrome: a Systemic Review, Meta-Analysis and Meta-Regression.” Diabetology & Metabolic Syndrome, vol. 11, no. 1, 23 July 2019, doi:10.1186/s13098-019-0453-7.
• Zhou, Joseph, et al. “Metformin: An Old Drug with New Applications.” International Journal of Molecular Sciences, vol. 19, no. 10, 21 Sept. 2018, p. 2863., doi:10.3390/ijms19102863.