What is metformin and why is it used for fertility treatments?

**What is metformin? ** Since the 1950’s metformin has been used for the treatment of diabetes, since it helps to maintain blood sugar levels (glycemia) within normal ranges. The way in which metformin generates this effect is by decreasing the glucose production in the liver and the glucose absorption in the intestine (1). Metformin is a small molecule that reaches numerous tissues like muscle, pancreas, hypothalamus, and gonads (1). Because of this, it is not surprising that it can have many diverse effects on our body, lots of them still under research.

**Metformin and fertility. ** Metformin has been proposed for improving ovarian cyclicity in women with polycystic ovary syndrome (PCOS). PCOS is the commonest cause of anovulatory infertility, and the reduced conception rates have been associated with hyperandrogenism (high levels of “male” hormones), obesity and insulin resistance (2). Insulin resistance is produced when the body does not respond or is less sensitive to normal levels of insulin, and because of that, it produces more insulin to try to counteract this effect. The evidence shows that these high concentrations of insulin have a big influence on some of the symptoms associated with PCOS, and can occur in women with or without excess body weight (2). The insulin resistance is associated with higher secretion of androgens by the ovaries and with the suppression of sex hormone-binding globulin secretion by the liver, leading to increased levels of free circulating testosterone (3). Metformin acts as an insulin-response sensitizer drug, playing a role in regulating oocyte maturation by counteracting the negative effects of high levels of androgens (male hormones) and improving the quality of oocytes during PCOS (1). It is important to mention that the benefits of metformin in women with PCOS is restricted to a specific group of patients, and should not be considered as a solution for all types of PCOS (3). The effect of metformin on fertility has not only been studied in women but also in men. It is well-known that type 2 diabetes reduces fertility by affecting the production or development of mature spermatozoa (spermatogenesis). It seems that obesity and the metabolic consequences of this condition are responsible for the infertility issues related to type 2 diabetes. A study that treated obese patients with meformin found an improvement in sperm concentration and motility (1).

The most common side effects of metformin are gastrointestinal discomfort, mainly diarrhea but also nausea and vomiting. Although in some countries it is used for the treatment of diabetes occurring during pregnancy (gestational diabetes), the US Food and Drug Administration (FDA) has indicated that the safety of metformin during pregnancy is still unclear (1). The use of metformin is associated with Vitamin B12 deficiency due to malabsorption of this vitamin in the small intestine. Anemia and damage of nerves are typical symptoms of low levels of vitamin B12. Regular measurements of vitamin B12 are recommended for individuals that are treated with metformin (4).

Lately, there has been a trend to use metformin to lose weight, but it is very important to clarify that there is not enough evidence to support that this drug helps in this way (5). Always remember to ask your doctor before taking any type of medication.

Reference:

1. Faure, M., Bertoldo, M. J., Khoueiry, R., Bongrani, A., Brion, F., Giulivi, C., Dupont, J., & Froment, P. (2018). Metformin in Reproductive Biology. Frontiers in endocrinology, 9, 675. https://doi.org/10.3389/fendo.2018.00675

2. Balen AH, Morley LC, Misso M, Franks S, Legro RS, Wijeyaratne CN, et al. The management of anovulatory infertility in women with polycystic ovary syndrome: an analysis of the evidence to support the development of global WHO guidance. Human Reproduction Update 2016;22:687‐708. [DOI: 10.1093/humupd/dmw025]

3. Morley LC, Tang TMH, Balen AH on behalf of the Royal College of Obstetricians and Gynaecologists. Metformin Therapy for the Management of Infertility in Women with Polycystic Ovary Syndrome. Scientific Impact Paper No. 13. BJOG 2017; 124:e306–e313.

4. Kim, J., Ahn, C. W., Fang, S., Lee, H. S., & Park, J. S. (2019). Association between metformin dose and vitamin B12 deficiency in patients with type 2 diabetes. Medicine, 98(46), e17918. https://doi.org/10.1097/MD.0000000000017918

5. Sharpe, A., Morley, L. C., Tang, T., Norman, R. J., & Balen, A. H. (2019). Metformin for ovulation induction (excluding gonadotrophins) in women with polycystic ovary syndrome. The Cochrane database of systematic reviews, 12(12), CD013505. https://doi.org/10.1002/14651858.CD013505