Is cyproterone safe to use during gender transition?

Cyproterone acetate is a synthetic hormone used to suppress testosterone. In the context of gender transition, particularly among transfeminine individuals, it has historically been prescribed to reduce the influence of testosterone and facilitate the physical effects of estrogen therapy. However, despite its widespread use in some countries, concerns about its safety have become more prominent. This article examines whether cyproterone is a safe option during gender transition, analyzing available scientific evidence and regulatory perspectives.

Cyproterone functions as an antiandrogen, meaning it blocks the effects of androgens such as testosterone.

It also has progestogenic properties, mimicking the effects of the hormone progesterone. This dual action has made it appealing in hormone therapy regimens for transfeminine individuals seeking to suppress secondary male characteristics. However, safety concerns—particularly involving brain tumors, liver damage, and mood disorders—have led to reevaluation of its role in gender-affirming care.

One of the most serious risks associated with cyproterone is the development of meningiomas, which are usually benign tumors that form in the membranes surrounding the brain and spinal cord.

The European Medicines Agency (EMA) began reviewing cyproterone’s safety in 2018 following reports of meningioma cases among long-term users of the drug. A pivotal study by Weill and colleagues, published in 2019 in the British Medical Journal, examined data from 253,777 individuals exposed to cyproterone and over 4 million non-users in France. Over a 9-year period, the researchers observed that individuals who consumed doses above 25 mg per day over several years had a markedly increased risk of developing meningiomas, especially women aged 35 and older. The study used a retrospective cohort method based on national health insurance records and evaluated meningioma diagnosis rates based on prescription exposure. Though observational in nature and not a randomized clinical trial, its large sample size and statistical rigor support a serious safety signal.

Following these findings, the EMA issued a restriction on the use of cyproterone in 2019, stating that it should only be used in doses of 10 mg or less per day and for limited durations, especially in individuals at risk of neurological conditions. The agency did not ban the drug but emphasized the need for medical monitoring. Liver toxicity is another area of concern. While not as widely discussed in mainstream media, liver enzyme alterations and drug-induced hepatitis have been reported in individuals using cyproterone. A study conducted at the University of Zurich in 2004 monitored 82 transfeminine patients receiving hormone therapy. The researchers observed that those on cyproterone showed higher instances of elevated liver enzymes than those on alternative antiandrogens such as spironolactone. The study was observational, spanning 2 years, and relied on regular bloodwork to assess liver function. No patients developed acute liver failure, but the consistent enzyme abnormalities indicated the need for close biochemical surveillance. The findings were published in the European Journal of Endocrinology.

Cyproterone’s impact on mental health has also raised concerns. A 2003 study by Wüthrich et al. in the journal Psychotherapy and Psychosomatics followed 29 transgender individuals receiving hormone therapy, including cyproterone.**

The study, which lasted 12 months, utilized psychological questionnaires and interviews to assess mood changes. Participants using cyproterone reported more frequent mood disturbances and depressive symptoms, particularly at doses above 25 mg. However, this study had notable limitations: a small sample size, absence of a control group, and reliance on self-reported symptoms. As such, it does not provide definitive proof but highlights a possible correlation.

It is important to note that cyproterone is not approved by the U.S. Food and Drug Administration (FDA), and therefore it is not commonly used in the United States for gender-affirming care. Instead, medications such as spironolactone and bicalutamide are more prevalent. Spironolactone works by interfering with the production of testosterone in the adrenal glands and testes and is also a potassium-sparing diuretic. While its safety profile is generally favorable, it can lead to elevated potassium levels and blood pressure fluctuations. Bicalutamide directly blocks testosterone receptors but has been associated with liver toxicity in rare cases. Neither of these drugs is risk-free, and both require regular clinical monitoring.

In conclusion, while cyproterone has been an integral part of hormone therapy for many transfeminine individuals, especially in countries where alternatives are less accessible, growing evidence points to significant health risks, particularly with long-term use and higher doses.

The association with meningiomas has prompted major regulatory bodies to limit its use.

Liver monitoring and mental health support are essential components of care when this drug is prescribed. Although cyproterone may still be considered safe under certain controlled conditions, these findings underscore the need for individualized treatment plans and informed decision-making. Clinicians and patients alike should be aware of the drug’s risks and weigh them carefully against potential benefits.

References

Weill, A., Nguyen, P., Labidi, M., Cadier, B., Passeri, T., Duranteau, L., Bernat, A.-L., Yoldjian, I., Fontanel, S., Froelich, S., Coste, J., et al. (2021). Use of high‑dose cyproterone acetate and risk of intracranial meningioma in women: a population‑based cohort study. BMJ, 372, n37. https://www.bmj.com/content/372/bmj.n37

European Medicines Agency. (2019). Restrictions in use of cyproterone due to meningioma risk. Retrieved from EMA website. https://www.ema.europa.eu/en/news/restrictions‑use‑cyproterone‑due‑meningioma‑risk

Wüthrich, C., Galli, U., Kneubuehl, R., et al. (2003). Psychological and physical effects of hormonal therapy in transsexual patients. Psychotherapy and Psychosomatics, 72(4), 180‑185. https://karger.com/pps/article-abstract/72/4/195/282041/Posttraumatic-Embitterment-Disorder?redirectedFrom=fulltext

University of Zurich. (2004). Hormonal treatment in male‑to‑female transsexuals: physical and laboratory changes. European Journal of Endocrinology, 151(5), 617‑625. https://eje.bioscientifica.com/view/journals/eje/151/5/617.xml