Cyproterone acetate for transfeminine adolescents

Background

Puberty blockade is an important part of gender affirming medical care for many trans adolescents. Usually, gonadotropin releasing hormone analogues (GnRHas) would be used to inhibit pubertal changes. However, the provision of GnRHas for gender dysphoria has been severely restricted in some parts of the world, including the United Kingdom.

This article examines cyproterone acetate as a potential alternative to GnRHas for transfeminine adolescents specifically. Cyproterone acetate has antiandrogenic effects that can inhibit the pubertal changes in people with testes, and so could potentially have a role in the gender affirming medical treatment of transfeminine adolescents.

What is cyproterone acetate and how does it work?

Cyproterone acetate is a medication that suppresses testosterone production. It is commonly used to treat conditions such as prostate cancer and hirsutism. Given its powerful antiandrogenic effect, it is commonly used as part of feminising hormone treatment in trans women.

How is cyproterone acetate used in gender affirming medical treatment?

Cyproterone acetate has an established history of use as an antiandrogen as part of feminising hormone treatment in trans women and transfeminine adults. Studies consistently show that cyproterone acetate is effective at suppressing testosterone levels and enhancing feminising bodily changes (Angus et al., 2019; Burinkul et al., 2021).

Given its established effectiveness at supporting feminisation in transfeminine adults, cyproterone acetate has also been suggested as an option to inhibit the pubertal changes in transfeminine adolescents who have testes.

What is the evidence base for cyproterone acetate in transfeminine adolescents?

To date, there has only been one study that specifically investigated the use of cyproterone acetate in transfeminine adolescents (Tack et al., 2017). This was a retrospective study of 27 transfeminine adolescents who received cyproterone acetate on its own and then in combination with oestrogen. Cyproterone acetate was shown to be effective at suppressing testosterone and promoting feminising changes. There were some slight and transient elevations elevations of liver enzymes during treatment, but no significant adverse effects were reported.

There is older research which investigated the use of cyproterone acetate to treat precocious puberty in cis boys and cis girls (Kauli et al., 1976). No significant adverse effects were reported in this study. While this study did not investigate trans adolescents, it does provide some evidence that cyproterone acetate is reasonably well tolerated in youth.

Is cyproterone acetate safe?

As with all medicines, cyproterone acetate has side effects. The most significant side effects are hepatotoxicity (liver impairment) and increased risk of meningioma (a benign tumour of the lining of the brain).

Hepatotoxicity occurs in less than 10% of people who take cyproterone acetate (Asscheman et al., 1989; Kumar et al., 2021; Savidou et al., 2006). This can range from mild elevations of liver enzymes to acute severe liver failure. While rare, fatalities have been reported from liver failure induced by cyproterone acetate. For this reason, cyproterone acetate is contraindicated in people with evidence of liver impairment. Also, people who are taking cyproterone acetate are required to have regular blood testing to check their liver markers.

Liver health can be assessed by a blood test for liver markers, also known as liver function tests. These measure enzymes that are produced by the liver and which are elevated in the blood when the liver is damaged. The most sensitive markers of liver injury are the enzymes alanine transaminase (ALT) and aspartate transaminase (AST). However, liver function tests can also include other markers, such as alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), bilirubin, and albumin.

If your ALT or AST levels are elevated beyond the healthy reference range, then it is possible that you have some degree of liver impairment, and so cyproterone acetate is not recommended for you. If you are taking cyproterone acetate and your ALT or AST levels are elevated, it is recommended that you stop taking cyproterone and instead consider a different antiandrogen. It is also recommended that you see your doctor to investigate the liver injury further. Your doctor may wish to monitor your liver health with a repeat blood test or arrange further investigations, such as an ultrasound scan of the liver.

There is evidence that the antiandrogen cyproterone acetate is associated with an increased risk of meningioma. In a study of 10,876 trans women, the risk of meningioma was 2.07 per 10,000 people per year in trans women who were taking cyproterone acetate, compared to 0 in trans women who were not taking cyproterone acetate. Further data on cis girls and cis women found that people who were taking cyproterone acetate were 5 times more likely to develop meningioma than people who were not taking cyproterone acetate. The risk of meningioma was greater with higher doses of cyproterone acetate (Weill et al., 2021). Therefore, while the absolute risk of meningioma remains low, it is important to acknowledge that cyproterone acetate does increase the lifetime risk of developing meningioma.

Conclusion

Cyproterone acetate may be a potential option for an antiandrogen in transfeminine adolescents when other antiandrogens, such as GnRHas and spironolactone, are not available. Based on evidence from research on trans women, cyproterone acetate is effective at suppressing testosterone and promoting the feminising effects of oestrogen. Research on cyproterone acetate in transfeminine adolescents is limited, but provides some evidence that spironolactone is reasonably well tolerated.

However, given the risks of hepatotoxicity and meningioma, other antiandrogens may be preferable if they are available. Anyone commencing cyproterone acetate must be fully informed of the risks of hepatotoxity and meningioma. If the decision is made to use cyproterone acetate, regular monitoring of liver markers, especially ALT and AST, is recommended before and during treatment.

References

Angus, L., Leemaqz, S., Ooi, O., Cundill, P., Silberstein, N., Locke, P., Zajac, J. D., and Cheung, A. S. (2019). “Cyproterone acetate or spironolactone in lowering testosterone concentrations for transgender individuals receiving oestradiol therapy”. Endocrine Connections, 8: 935–940.

Asscheman, H., Gooren, L. J., and Eklund, P. L. (1989). “Mortality and morbidity in transsexual patients with cross-gender hormone treatment”. Metabolism: Clininical and Experimental, 38: 869–873.

Burinkul, S., Panyakhamlerd , K., Suwan, A., Tuntiviriyapun, P., and Wainipitapong, S. (2021). “Anti-Androgenic Effects Comparison Between Cyproterone Acetate and Spironolactone in Transgender Women: A Randomized Controlled Trial”. Journal of Sexual Medicine, 18 (1): 1299-1307.

Kauli, R., Pertzelan, A., Prager-Lewin, R., Grünebaum, M., and Laron, Z. (1976). “Cyproterone acetate in treatment of precocious puberty”. Archives of Disease in Childhood, 51 (3): 202-208.

Kumar, P., Reddy, S., Kulkarni, A., Sharma, M., and Rao, P. N. (2021). “Cyproterone Acetate-Induced Acute Liver Failure: A Case Report and Review of the Literature”. Journal of clinical and experimental hepatology, 11: 739–741.

Savidou, I., Deutsch, M., Soultati, A. S., Koudouras, D., Kafiri, G., and Dourakis, S. P. (2006). “Hepatotoxicity induced by cyproterone acetate: a report of three cases”. World Journal of Gastroenterology, 12: 7551–7555.

Tack, L. J. W., Heyse, R., Craen, M., Dhondt, K., Vanden Bossche, H., Laridaen, J., and Cools, M. (2017). “Consecutive Cyproterone Acetate and Estradiol Treatment in Late-Pubertal Transgender Female Adolescents”. Journal of Sexual Medicine, 14 (5): 747-757.

Weill, A., Nguyen, P., Labidi, M., Cadier, B., Passeri, T., Duranteau, L., Bernat, A. L., Yoldjian, I., Fontanel, S., Froelich, S., and Coste, J. (2021). “Use of High Dose Cyproterone Acetate and Risk of Intracranial Meningioma in Women: Cohort Study”. British Medical Journal, 372: n37.

Updated on June 4, 2024

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