Metformin and PCOS

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Metformin and PCOS

Metformin is an insulin sensitizer, widely used for the treatment of insulin resistance in Type 2 diabetes. Insulin resistance is very common in women with PCOS. Research shows both conditions are intricately linked with one another. So much so, that PCOS experts nowadays propose treating insulin resistance first before prescribing anti-androgen drugs.

This means women diagnosed with PCOS and insulin resistance may be prescribed Metformin in a first-line treatment plan. Note that Metformin is rarely prescribed on its own to treat PCOS and certain comorbidities (i.e. severe liver disease, kidney failure) will prohibit the use of Metformin.

During metformin treatment, women with PCOS should expect mild weight loss (especially around the waist), improved menstrual cycles, decrease in insulin resistance, and a possible decrease in hyperandrogenism (according to genetics).

However not all women with PCOS and IR will see a significant improvement in their condition during treatment with Metformin. Research shows Metformin is less effective in women with PCOS and HOMA-IR less than 2. While 30% of women with PCOS also fail to respond to Metformin due to genetic differences.

In cases where Metformin is effective, patients report various side effects, which could impact long term use.

Side Effects of Metformin

Side effects of metformin treatment for PCOS includes:

  • Diarrhea
  • Nausea
  • Dyspepsia
  • Abdominal pain
  • Anorexia
  • Hyperglycemia
  • Vitamin deficiency (B12)

Studies involving women with Type 2 Diabetes suggest these side effects are similar or lessened when taking Metformin delayed-release or extended-release formulations. However no comparable studies on women with PCOS have been carried out to date.

Instead, first time users of Metformin may be recommended to introduce the drug into their system using the slow route method (i.e. step-up 250mg/week) to better manage possible side effects.

Treatment of PCOS with Metformin

The optimal dose of Metformin to treat PCOS and insulin resistance varies according to the patient’s initial response to a starting dose of 500mg per day. The primary goal is to improve insulin sensitivity and restore glucose homeostasis.

Unfortunately, elevated BMI is associated with poor response to Metformin. This means a majority of women with PCOS, who are overweight, require doses greater than 1500mg per day to significantly improve metabolic parameters.

Experts recommend taking Metformin during or immediately after food, once or twice daily, according to the formulation (immediate vs extended-release Metformin).

To further minimise possible side effects, your Doctor may also suggest to slowly increase the dose 250mg per week until the prescribed dose is achieved. This dose is then reviewed every 3 to 6 months after blood tests.

Metformin is considered a long-term treatment. The positive effects of metformin reverse quickly when patients cease treatment. As a result, the majority of women with PCOS and insulin resistance will need to take metformin daily until their insulin sensitivity improves naturally through lifestyle modification or serious side effects emerge. Metformin is also ceased during pregnancy as a precaution.

Pregnancy with PCOS and Metformin

It is quite common for women with PCOS to struggle getting pregnant due to in part the highly irregular menstrual cycles which is a symptom of insulin resistance (IR).

As a result, treatment of insulin resistance with metformin in women with PCOS, significantly improves menstrual cycles and ovulation rates leading to spontaneous pregnancy during treatment, as first reported 30 years ago by Velazquez et al.

HOW QUICKLY CAN I GET PREGNANT WITH METFORMIN

According to limited studies, the majority of women with PCOS will get pregnant with metformin within 3 months of treatment. Secondary analysis shows that metformin is significantly more effective in women with BMI < 30.

Although studies to date report no safety concerns with taking metformin during pregnancy, pharmacokinetic studies reveal that metformin crosses the placenta. For this reason, most Doctors will strongly recommend to stop metformin once pregnancy is confirmed and begin insulin therapy instead to control the risk of gestational diabetes.

PCOS Weight Loss with Metformin

Women with PCOS and insulin resistance usually experience weight loss during treatment with metformin. This is because metformin significantly decreases insulin resistance, improves glucose homeostasis and reduces appetite.

In fact, before and after metformin studies, report women with PCOS lose between 5-11% of weight after 6 months of treatment.

StudyDose (day)DurationNo. of womenBefore (BMI)After (BMI)Difference
Rajasekaran K, et al. (2021)850mg3 months5027.024.011.1%
Nazirudeen R, et al. (2023)1000mg6 months2731.529.75.7%
Fruzzetti F, et al. (2016)1500mg6 months2228.426.85.6%
Table 1. Summary of studies and BMI results following treatment of PCOS with metformin.

These studies also confirm no dose-dependent relationship between metformin and weight loss for women with PCOS contrary to earlier reports.

Earlier reports showed higher doses of Metformin reduced women’s appetite (and increased weight loss), however experts now believe this increase in weight loss was most likely caused by an increase in side effects (and not via GDF15 protein levels).

Instead, women with PCOS who want to lose weight fast, should incorporate lifestyle modification with metformin treatment, to increase the weight lost. In theory, both interventions target different pathways, which means combined treatment has a more holistic effect on PCOS.

Lifestyle modification involves dietary changes and or physical exercise.

Metformin Alternatives for PCOS

The initial excitement around metformin for women with PCOS slowly subdued after several limitations became obvious (i.e. significant side effects, variable efficacy according to BMI and genetics). However, this only encouraged experts to continue research on the insulin treatment idea and to look for alternatives.

Nowadays, several alternatives to metformin treatment of PCOS exist. This includes:

  • Myo-inositol
  • Berberine
  • Quercetin

All 3 alternatives improve insulin sensitivity, and other markers of PCOS, to varying degrees. This allows Specialists to better tailor treatment to the individual.

In fact, it is common practice these days to combine metformin (or alternatives) with other supplements, as indicated during diagnostic testing, to holistically treat PCOS and associated risks.

References

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Li X, et al. (2022). The Degree of Menstrual Disturbance Is Associated With the Severity of Insulin Resistance in PCOS. https://doi.org/10.3389/fendo.2022.873726

Ezeh U, et al. (2021). Menstrual dysfunction in polycystic ovary syndrome: association with dynamic state insulin resistance rather than hyperandrogenism. https://doi.org/10.1016/j.fertnstert.2020.12.015

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