Hormonal contraception is a widely used and very effective method of birth control, but it is not without risks. For decades, women have reported significant mood changes when using hormonal contraceptives, including birth control pills and intrauterine devices (IUDs). Large-scale population studies have confirmed a link between hormonal birth control and depression. In addition, hormonal contraception can cause dangerous blood clots for some women. This article summarizes the latest research and outlines how understanding genetic factors can help lower your risk of depression and blood clots.

Hormonal contraceptives and depression

One recent study analyzed the incidence of depression in over one million women for a period of 14 years, utilizing Denmark’s nationalized health information system. Key findings include:

• Women on birth control pills were 23 percent more at risk of developing depression than women not taking the pill.
• The risk associated with progestin-only pills was even higher at 34 percent.
• Women using progestin-releasing IUDs had a 40 percent greater risk.
• Women using the patch had double the risk.
• Other methods, such as the vaginal ring, had a 60 percent higher risk than non-users.

The group that is most vulnerable to developing depression is adolescents between the ages of 15 to 19. Furthermore, research shows that the first six months after starting hormonal birth control have the highest incidence of depression overall. However, it is still unknown why some women experience depression while others do not.

In the case of IUDs, removing progestin-releasing IUDs or switching continuous hormone-delivery contraceptives to non-hormonal IUDs was found to reverse symptoms of depression and fatigue.

Genetic factors affect the risk of hormonal contraceptive complications

Hormonal birth control comes in two types – a combination of synthetic estrogen and progesterone or a progestin-only formulation. The different pills contain varying types of synthetic progesterone. Liver enzymes metabolize these synthetic hormones, altering their chemical structure to make them easier to eliminate from the body. Because of this, it is necessary to take a daily dose of the pill to maintain a hormonal balance which prevents ovulation.

The liver enzyme responsible for eliminating synthetic estrogen (estradiol) from the body is called CYP3A4. However, due to natural genetic variations, people can have CYP3A4 that functions at different rates. Individuals with slower CYP3A4 metabolism are more susceptible to experiencing a stronger reaction and increased risk of side effects from estrogen.

Hormonal contraceptives and blood clots

It is important to know that all hormonal birth control methods come with a risk of life-threatening side effects such as blood clots and stroke. However, some women are more susceptible to developing blood clots than others. This includes women with a super-clotting gene mutation called Factor V Leiden (F5) and mutations in the prothrombin G20210A variant in the F2 gene. Shockingly, up to one percent of women carry Factor V Leiden or F2 gene variant, and most of them are not even aware of it. Pharmacogenetic tests like Pillcheck, which analyze these variants, can help assess your risk of stroke and blood clots with hormonal contraceptives and help to prevent them.

If you carry Factor V Leiden or prothrombin mutation, you are much more likely to develop a blood clot from using hormonal birth control, tamoxifen and other hormone-modifying medications. So, it is essential to consult your doctor before choosing any hormonal birth control method.

In addition, birth control pills based on the drospirenone (progesterone) formulation, such as Yasmin and Yaz, and those containing desogestrel (progestin), have an even higher risk. A study led by Dr. Ojvind Lidegaard of Copenhagen University found that women taking Yaz or Yasmin had a 64 percent higher risk of blood clots than women taking other types.

These findings demonstrate that hormonal birth control, drugs so ubiquitous they are often referred to only as “The Pill”, are not a one-size-fits-all prescription.

DNA testing can help women make an informed decision

Doctors use family history, age, and whether or not someone smokes to screen for women who may develop serious complications from hormonal birth control. However, women are rarely advised to take a simple DNA test to identify Factor V Leiden or F2 carriers that could save many lives.

Genetic testing can also determine how rapidly your body removes synthetic hormones and other medicines. Women with a high risk of developing blood clots from hormonal contraception (carrying Factor V, prothrombin variations or slow metabolizers of synthetic steroid hormones) may choose non-hormonal contraceptives such as the copper intrauterine device (IUD), diaphragm or cervical cap.

DNA-guided therapy for depression accelerates recovery

If your mood did not improve after switching to non-hormonal contraceptives, antidepressant treatment might be needed. The Pillcheck pharmacogenetic test can help predict your risk of side effects not only for birth control but also for anxiety and depression medications. Pillcheck-guided therapy helps women recover from depression and anxiety sooner and reduces the number of drug trials and dose adjustments that can take many months.

Summary

• Hormonal contraception is a widely used and very effective method of birth control, but it is not without risks.
• Large-scale studies have confirmed the link between hormonal birth control and depression, especially for younger women and adolescents.
• Genetic factors can significantly increase your risk of dangerous blood clots from hormonal contraception.
• Pharmacogenetic testing, such as Pillcheck, can provide insights about your drug metabolism and medication risk to help
• you make informed decisions about your health.

Selected references

Khialani  D et al., The joint effect of genetic risk factors and different types of combined oral contraceptives on venous thrombosis risk Br J Haematol . 2020 Oct;191(1):90-97.

Charlotte Wessel Skovlund, Lina Steinrud Mørch, Lars Vedel Kessing, and Øjvind Lidegaard, Association of Hormonal Contraception with Depression  JAMA Psychiatry 2016;73(11):1154-1162.

Øjvind Lidegaard, Ellen Løkkegaard, Anne Louise Svendsen, and Carsten Agger, Hormonal contraception and risk of venous thromboembolism: national follow-up study BMJ. 2009;339:b2890.

Judy L Kujovich, Factor V Leiden Thrombophilia Gene Reviews. Oregon Health and Science University. March 9, 2010.

Roland N et al., Association Between Doses of Levonorgestrel Intrauterine Systems and Subsequent Use of Psychotropic Drugs in France JAMA. Published online December 22, 2022. doi:10.1001/jama.2022.21471.

Elin Stenhammar  E et al., Levonorgestrel intrauterine device and depression: A Swedish register-based cohort study Int J Psychophysiol. 2023 Aug 21;193:112230.