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Do I have to use metformin to get pregnant with PCOS?

Do I have to use metformin to get pregnant with PCOS?

Chanel Dubofsky | September 13, 2021 | trying to conceive
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Because one of the hallmarks of Polycystic ovary syndrome  is menstrual irregularities absent or erratic periods and ovulation, it can make getting pregnant tricky, but definitely not impossible. Many with PCOS have high levels of insulin (a hormone created by the pancreas that controls the amount of glucose, or simple carbohydrates), as well as insulin resistance, a condition that occurs when your body doesn't properly process insulin. Insulin resistance can lead to Type 2 diabetes, which is also common in folks with PCOS. If you have Type 2 diabetes, your doctor will likely prescribe Metformin, a drug that improves the way your body processes insulin, thereby lowering your blood sugar (1). While Metformin isn't a fertility drug, it might be useful in improving ovulation in those with PCOS. So if you're TTC with PCOS, should you take Metformin? Is it essential to getting pregnant? Let's see what the science says. 

 

Insulin Resistance and Ovulation 

There's a lot that we still don't know about the connection between insulin and reproductive hormones like estrogen, just that there is one. That being said, approximately 70% of folks with PCOS also have insulin resistance, and there is a connection between insulin resistance and inconsistent or absent ovulation (2). When your insulin levels are too high, they can cause an overstimulation of the ovaries, an overproduction of androgens ("male" hormones that people with vaginas also have), and the prevention of ovulation (3).

 

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Metformin and PCOS

Metformin is prescribed for folks with Type 2 diabetes because it helps the body process insulin more effectively, thereby preventing the overproduction of androgens (also called hyperandrogenism)  that inhibit ovulation. While Metformin isn't a fertility drug, it has been shown to improve ovulation and regulate menstruation in people with PCOS, making pregnancy more attainable (4). 

Note: if you are seeking natural alternatives to Metformin, be sure to talk to your doctor. There are alternatives, but you should seek professional guidance on a) whether the alternative is right for you and b) the dosage amount specifically for your needs.  

Metformin has other benefits when it comes to PCOS (5): 

 

  • Can help lower LDL cholesterol and blood fat levels
  • Can reduce the risk of cardiovascular disease
  • May lower the risk of miscarriage
  • May prevent and treat gestational diabetes
  • Delay or prevent Type 2 diabetes in overweight folks (6)
  • Reduces the risk of ovarian hyperstimulation syndrome (OHSS) (an overreaction of the ovaries to fertility medication, people with PCOS are at higher risk for this) in those undergoing IVF and IUI (7) (8)
  • Can help lower BMI (with diet and exercise) 
  • Lowers levels of testosterone (9)
  • May improve the effects of fertility drugs 

Metformin does have side effects for some, including: 

  • Nausea
  • Stomach pain
  • Gas
  • Bloating
  • Diarrhea
  • Vitamin B-12 deficiency when taken at high doses over a long period of time (10) 
  • Those with a history of kidney problems should not take metformin, to avoid a rare and serious condition called lactic acidosis

In May 2020, the Food and Drug Administration recalled some versions of Metformin, announcing  that a few preparations of extended-release Metformin contained N-nitrosodimethylamine (NDMA), an environmental contaminant and known carcinogen, found in low levels in smoked meats and cheeses, as well as beer and whiskey and other drugs(11). The FDA has set an acceptable intake limit for NDMA is 0.096 µg (microgram) per day, and the amount that occurs in drugs such as Metformin varies (12). If you are nervous about whether or not your prescription has a higher than is safe level of NDMA, consult your healthcare provider — don't just stop taking it. 

 

Ask your healthcare provider to test your insulin levels in order to assess whether or not you're insulin resistant. Not everyone with PCOS is insulin resistant, but some doctors choose to prescribe Metformin anyway, since it may improve reproductive and hormonal abnormalities and prevent one from developing diabetes and heart disease in the future (13). 

 

Metformin + Clomiphene? 

Metformin can be helpful to folks with PCOS who want to get pregnant. However, If you're living with PCOS and you're interested in getting pregnant soon, Metformin may not be right for you. It actually takes some time for the drug to accumulate in your body enough to start making an impact on ovulation  up to 6 months (14)  There's the question of whether or not Metformin should be prescribed in conjunction with Clomiphene (also known as Clomid), another ovulation-inducing drug, to jump start ovulation, as well as if one should take Metformin and then Clomiphene (or another fertility drug, such as Letrozole, if necessary (15). 

 

Studies indicate that pregnancy rates with Metformin are higher for those taking the drug than those who aren't, but it's also not clear if those rates are as high as those taking Clomiphene, another ovulation-inducing drug. For those with PCOS who are resistant to Clomiphene (15-40%), a  2009 study revealed that the short term use of Metformin decreased insulin resistance and hyperandrogenism and increased pregnancy rates (16). 

More Options 

While Metformin on its own or in conjunction with Clomiphene may be enough to help folks with PCOS to conceive, that's not always the case. Many people conceive successfully with Clomiphene, but if neither of these drugs work, your healthcare provider may direct you towards: 

 

  • Letrozole. Letrozole isn't a fertility drug (it's actually a cancer drug, but the side effects are pretty mild), but it could be more effective at inducing ovulation in people with PCOS and those who can't tolerate the side effects of Clomiphene or shouldn't use it (17).

 

  • Gonadotropins (injectable fertility drugs). These are made up of follicle stimulating hormone (FSH), luteinizing hormone (LH), or a combination of the two. You might have just gonadotropins for a cycle in order to trigger ovulation, or your doctor might combine an oral fertility drug like Clomiphene and an injection of FSH or LH. Another option may be IUI (intrauterine insemination) in partnership with gonadotropins. Ovarian hyperstimulation syndrome is a possible risk with gonadotropins, so your doctor may use lower doses to avoid this. 

 

  • IVF or IVM. If gonadotropins aren't successful, your doctor may move to IVF, which you've likely heard of, as well as the lesser known option of IVM, or in vitro maturation. In IVM, immature eggs are retrieved without any use of fertility drugs, and those eggs mature in a lab before they're fertilized and implanted. 
PCOS and Lifestyle 

Whether or not you and your healthcare provider decide that Metformin is right for you, nutrition and exercise are vital for the management of PCOS. Developing a sustainable means of healthy eating, avoiding smoking, alcohol consumption, and decreasing stress as much as possible can help minimize symptoms, as well as the long-term risk of developing diabetes and reproductive health challenges (18). 

So do you have to use metformin to get pregnant with PCOS? 

 

The bottom line remains that PCOS is a complicated syndrome with many variables. Speak to your healthcare provider about insulin resistance and Metformin, and consider your timeline for TTC are you in a hurry to have a child, or are you thinking of waiting for a while? Metformin may or may not be right for you, depending on your current medical status, your health history, and your plans for the future.

References +
1
  1. Salber, G. J., Wang, Y.-B., Lynch, J. T., Pasquale, K. M., Rajan, T. V., Stevens, R. G., Grady, J. J., & Kenny, A. M. (2017). Metformin use in practice: Compliance with guidelines for patients with diabetes and preserved renal function. Clinical Diabetes, 35(3), 154–161. 
  2. Fica, S., Albu, A., Constantin, M., & Dobri, G. A. (2008). Insulin resistance and fertility in polycystic ovary syndrome. Journal of medicine and life, 1(4), 415–422.
  3. Insulin Resistance. (2021). Retrieved August 3, 2021, from https://www.ingenes.com/international/are-you-a-candidate/female-infertility-causes/insulin-resistance/#:~:text=Elevated%20blood%20insulin%20levels%20are,%2C%20in%20turn%2C%20prevent%20ovulation
  4. Sharpe, A., Morley, L. C., Tang, T., Norman, R. J., & Balen, A. H. (2019). Metformin for ovulation induction (excluding gonadotropins) in women with polycystic ovary syndrome. Cochrane Database of Systematic Reviews. 
  5. Wang YW, He SJ, Feng X, Cheng J, Luo YT, Tian L, Huang Q. Metformin: a review of its potential indications. Drug Des Devel Ther. 2017;11:2421-2429
  6. Priya G, Kalra S. Metformin in the management of diabetes during pregnancy and lactation. Drugs in Context 2018; 7: 212523. 
  7. Palomba, S., Falbo, A., Carrillo, L., Villani, M. T., Orio, F., Russo, T., Di Cello, A., Cappiello, F., Capasso, S., Tolino, A., Colao, A., Mastrantonio, P., La Sala, G. B., Zullo, F., & Cittadini, E. (2011). Metformin reduces risk of ovarian hyperstimulation syndrome in patients with polycystic ovary syndrome during gonadotropin-stimulated in vitro fertilization cycles: A randomized, controlled trial. Fertility and Sterility, 96(6).
  8. Lin, H., Li, Y., Li, L., Wang, W., Yang, D., & Zhang, Q. (2014). Is a gnrh antagonist protocol better in pcos patients? A meta-analysis of rcts. PLoS ONE, 9(3). 
  9. Jensterle, M., Kravos, N. A., Ferjan, S., Goricar, K., Dolzan, V., & Janez, A. (2020). Long-term efficacy of metformin in overweight-obese PCOS: longitudinal follow-up of retrospective cohort. Endocrine connections, 9(1), 44–54. 
  10. Aroda, V. R., Edelstein, S. L., Goldberg, R. B., Knowler, W. C., Marcovina, S. M., Orchard, T. J., Bray, G. A., Schade, D. S., Temprosa, M. G., White, N. H., & Crandall, J. P. (2016). Long-term metformin use and Vitamin B12 deficiency in the Diabetes prevention Program Outcomes Study. The Journal of Clinical Endocrinology & Metabolism, 101(4), 1754–1761
  11. Public Health statement. (n.d.). Retrieved September 9, 2021, from https://www.atsdr.cdc.gov/toxprofiles/tp141-c1.pdf 
  12. NDMA, a contaminant found in multiple drugs, has industry seeking sources and solutions. (2020, April 20). Retrieved September 9, 2021 from https://cen.acs.org/pharmaceuticals/pharmaceutical-chemicals/NDMA-contaminant-found-multiple-drugs/98/i15 
  13. Marshall, J. C., & Dunaif, A. (2012). Should all women with PCOS be treated for insulin resistance?. Fertility and sterility, 97(1), 18–22. 
  14. Lashen H. (2010). Role of metformin in the management of polycystic ovary syndrome. Therapeutic advances in endocrinology and metabolism, 1(3), 117–128. 
  15. Nestler, J. E. (2008). Metformin in the treatment of infertility in polycystic ovarian syndrome: An alternative perspective. Fertility and Sterility, 90(1), 14–16. 
  16. Kazerooni, T., Ghaffarpasand, F., Kazerooni, Y., Kazerooni, M., & Setoodeh, S. (2009). Short-term metformin treatment for clomiphene citrate-resistant women with polycystic ovary syndrome. International Journal of Gynecology & Obstetrics, 107(1), 50–53. 
  17. Kar S. Clomiphene citrate or letrozole as first-line ovulation induction drug in infertile PCOS women: A prospective randomized trial. J Hum Reprod Sci 2012;5:262-5.
  18. Norman, R. J., Davies, M. J., Lord, J., & Moran, L. J. (2002). The role of lifestyle modification in polycystic ovary syndrome. Trends in endocrinology and metabolism: TEM, 13(6), 251–257.
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