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Recent Developments on Cyproterone Acetate and Meningioma Risk Out of France and Implications for Transfeminine People

By Aly | First published April 24, 2020 | Last modified March 30, 2024

Abstract / TL;DR

Cyproterone acetate is a progestogen and antiandrogen commonly used in transfeminine hormone therapy. At the doses typically used in transfeminine people, it has extremely strong progestogenic effects. Whereas doses of around 2 or 3 mg/day have similar progestogenic effect as normal progesterone exposure during the luteal phase of the menstrual cycle in women, doses of cyproterone acetate of 25 to 100 mg/day have typically been used in transfeminine people. In 2018, the French government published findings from a large epidemiological study showing a strong and dose-dependent increase in the risk of meningiomas, a type of hormone-sensitive brain tumor, with typical high doses of cyproterone acetate. With cyproterone acetate used cyclically (20 days per month) at a dose of 50 mg/day for >5 years or 25 mg/day for >10 years, the risk of surgically operated meningioma was found to be increased by 20-fold. Subsequent studies have since replicated these results. Consequent to these findings, clinical use of cyproterone acetate has been restricted and its doses have been greatly reduced. Fortunately, cyproterone acetate is still a highly effective means of testosterone suppression in transfeminine people at much lower doses (e.g., 5–10 mg/day). Nonetheless, due to the risks of meningioma as well as various other complications, it is recommended that cyproterone acetate now be used cautiously and in a limited fashion in transfeminine people. For instance, it should only be used at low doses for a limited duration (e.g., 2 years) in people without known risk factors for meningiomas.

Introduction

Cyproterone acetate (CPA) is a progestogen and antiandrogen commonly used in transfeminine hormone therapy. Typical doses of CPA used in transfeminine hormone therapy have very strong progestogenic strength. Consequent to the strong progestogenic exposure, CPA is known to have a risk of meningioma, a rare and benign (non-cancerous) form of brain tumor. Meningiomas are tumors of the meninges, the membranes enveloping the brain and spinal cord. While not typically malignant (cancerous), meningiomas can nonetheless result in complications like visual disturbances, headaches, and seizures. They may necessitate brain surgery. Death has also resulted from CPA-induced meningioma. There is some more information on the topic of CPA and meningioma here on Wikipedia. A table of published case reports of meningioma with CPA can be found here on Wikipedia.

Recent findings out of France indicate that the risk of meningioma with CPA is much higher than previously thought (ASNM/CNAM). This article discusses these findings and the implications for use of CPA in transfeminine people, including recommendations for use of CPA more safely.

Recent French Findings

Case reports of meningioma with CPA started in 2007. These reports caused the French government to add a warning to the CPA production information in 2011 and to undertake a large epidemiological investigation into the risk of meningioma with CPA. They announced their findings in 2018 and reported the following (ASNM/CNAM):

  • The study was very large with 290,000 person–years of CPA-treated follow up.
  • The risk of meningioma with CPA was increased 7-fold with >6 months of treatment at an average dosage ≥25 mg/day. It was increased 20-fold with 50 mg/day for 20 days per month for >5 years. It was likewise increased 20-fold with 25 mg/day for 20 days per month for >10 years. As such, the risk is strongly exposure-dependent in terms of dosage and duration of therapy.
  • The risk of surgically operated meningioma with CPA was around 4 in 1,000 patients per year with 50 mg/day for 20 days per month for >5 years. This underestimates the true incidence of meningioma with CPA since it only includes operated cases.
  • There were more than 500 operated cases of meningioma in association with CPA in France between 2007 and 2015. The unoperated incidence is unknown but likely to be much higher.
  • The population incidence of meningioma in general is strongly age-dependent. It’s 0.14 in 10,000 individuals per year at under 20 years of age and 4.9 in 10,000 individuals per year at above 85 years of age (a 35-fold difference). The average risk is 0.8 in 10,000 individuals per year. Accordingly, the risk of meningioma with CPA was found to be highly age-dependent as well.
  • The risk of meningioma decreases strongly after discontinuation of CPA.

As a result of their findings, the following occurred (ASNM/CNAM):

  • A toll-free phone number was set up in France for inquiries about CPA and meningioma.
  • Recommendations were made such that all patients starting CPA should be given an MRI within 6 months of initiation of therapy. Subsequently, all patients taking CPA should get another MRI after 5 years of therapy and then an additional MRI every 2 years of therapy thereafter.
  • It was recommended that CPA not be used in postmenopausal women due to their age.
  • Whether CPA should be withdrawn from the market was discussed but was decided against. Part of this was related to the reliance of transfeminine people on CPA for hormone therapy.
  • CPA sales in France plummeted by 73% from September 2018 to September 2019. Sales of spironolactone increased by a lesser magnitude over the same time period.
  • France is also looking into meningioma risk with other high-dose progestogen formulations, including nomegestrol acetate (Lutenyl) and chlormadinone acetate (Luteran).
  • France requested that the European Medicines Agency (EMA) conduct a review of CPA and meningioma. This review began in mid-2019 (Chustecka, 2019). In February 2020, the EMA announced restrictions on the clinical CPA use in the European Union (EMA, 2020). These included use of CPA only after failure of other treatments and use of the lowest effective maintenance dose of CPA (EMA, 2020; Chustecka, 2020). The restrictions applied to formulations of CPA containing 10 mg/day CPA or more (EMA, 2020; Chustecka, 2019). The Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom published a drug safety update for cyproterone acetate in June 2020 (MHRA, 2020).

This 2018 French news article (translated from French to English via Google Translate) succinctly discusses some of the developments. Several recent literature publications have also discussed the topic (Schmutz, 2018; Gerson, 2018; Coubret et al., 2019; Plu-Bureau, 2019; Senofonte, Pallotti, & Lombardo, 2020). And long-form reports of the epidemiological study by the French government here (PDF; 128 pages) and here (PDF; 106 pages) provide more information. A more succinct report by the French government can also be found here (PDF; 9 pages; English translation here). Unfortunately however, many of these materials are in French or other non-English languages and translations are unavailable for English speakers (Google Translate is useful however).

Implications for Transfeminine People

CPA tends to be used at very high doses in transfeminine people. A dose of CPA of 2 or 3 mg/day is similar in progestogenic exposure to that occurring during the luteal phase of the menstrual cycle in women. Conversely, doses of CPA recommended by guidelines for use in transfeminine people typically range from 25 to 100 mg/day. This progestogenic exposure is similar to or greater than that during pregnancy in women, when progesterone levels increase by up to 20-fold relative to luteal levels. As such, it’s highly supraphysiological relative to typical circumstances in women. In addition to meningioma, high doses of CPA have been associated with blood clots, prolactinomas, and liver toxicity (Wiki; Aly, 2019). Long-term therapy with progestogens like CPA may increase the risk of breast cancer (Aly, 2020; Table; CGHFBC, 2019; de Blok et al., 2019) and cardiovascular problems as well (Table; Stefanick, 2010). There is also a great deal still unknown about high doses of CPA and their safety, as evidenced by the fact that we’re only uncovering the risk of meningioma with CPA now. It’s likely that using the lowest possible doses of CPA will minimize its various health risks.

The doses of CPA used in transfeminine people tend to be far more than are necessary. CPA appears to have maximal effectiveness in terms of testosterone suppression at a dose of only 5 to 10 mg/day. See my article here for a review of this topic. The effectiveness of lower doses of CPA was recently validated by Meyer et al. (2020), who showed that in combination with estrogen, 10 mg/day CPA was no different from 50 mg/day CPA in terms of testosterone suppression in transfeminine people. It seems clear that transfeminine people should not use a dose of CPA higher than 10 or 12.5 mg/day at most. With 50-mg CPA tablets and a pill cutter, a total dose of CPA of 6.25 to 12.5 mg/day can be achieved by taking one-fourth of a tablet once every other day to once every day. As a result of new findings, published CPA dose recommendations for transfeminine people have gone down in the last few years (Aly, 2019). It is likely that this will continue to a greater extent in the future.

Meningiomas express progesterone receptors and activation of these receptors is thought to stimulate growth of meningiomas (Marosi et al., 2008; Li et al., 2013). Other progestogens besides CPA as well as pregnancy have also been associated with meningioma, and spontaneous regression of meningiomas has been reported after pregnancy (Li et al., 2013; Wiki). The incidence of meningiomas is 2- to 3-fold higher in women than in men, and the female-to-male incidence ratio is greatest during the peak female reproductive years (Marosi et al., 2008; Wiemels, Wrensch, & Claus, 2010; Li et al., 2013; Wiki). The luteal phase of the menstrual cycle, when progesterone levels are increased, has been associated with exacerbation of meningiomas in women (Marosi et al., 2008; Li et al., 2013; Wiki). Meningioma has also been associated with birth control pills and menopausal hormone therapy (estrogen–progestogen preparations) (Li et al., 2013). As such, assuming these associations are indeed due to progesterone receptor activation, there may be no fully risk-free dosage of progestogens or CPA in terms of meningioma. Indeed, meningiomas have been reported even with 5 to 10 mg/day CPA, despite the relatively uncommon use of such doses historically (Table). In any case, the data indicate that the risk is dose-dependent, and hence that lower doses should have the least risk. A dose of 2 to 3 mg/day CPA continuously would presumably have minimal excess risk of meningioma relative to normal female physiological circumstances.

Recommendations for Transfeminine People

In light of the risks of CPA and its high testosterone-suppressing effectiveness even at low doses, the following recommendations for use of CPA in transfeminine people seem appropriate:

  • CPA should be used at the lowest effective dosage (generally 5–12.5 mg/day and no greater).
  • CPA should be used for a limited duration (e.g., a few years) and not long-term.
  • Other safer but similarly effective antiandrogenic approaches should be used instead of CPA where possible (e.g., GnRH modulators, gonadectomy, estradiol monotherapy, etc.).
  • CPA should be avoided in older individuals (e.g., >50 years of age).
  • CPA should not be used in people with a personal or family history of meningioma.
  • If possible, CPA should be used under supervision of a physician and people taking CPA should follow monitoring guidelines (e.g., regular MRIs as in France).

At the same time it should be noted that the absolute incidence of meningioma with CPA is low. The risk is likely to be especially small in young people and with low CPA doses (e.g., 5–12.5 mg/day). Use of CPA in a more cautious and restricted fashion may allow for more acceptable safety. In any case, meningiomas and brain surgery are serious, so CPA should not be taken carelessly.

Updates

Update 1: Weill et al. (2021) [French Government Study]

The French government study was finally published in the formal scientific literature in February 2021:

  • Weill, A., Nguyen, P., Labidi, M., Cadier, B., Passeri, T., Duranteau, L., Bernat, A., Yoldjian, I., Fontanel, S., Froelich, S., & Coste, J. (2021). Use of High Dose Cyproterone Acetate and Risk of Intracranial Meningioma in Women: Cohort Study. BMJ, 372, n37. [DOI:10.1136/bmj.n37]

A Medscape article here covers the study and discusses consequent restrictions on CPA use.

Update 2: Mikkelsen et al. (2021) [Danish National Study]

A national study in Denmark was published in June 2021 and has replicated the findings:

  • Mikkelsen, A. P., Greiber, I. K., Scheller, N. M., Hilden, M., & Lidegaard, Ø. (2021). Cyproterone acetate and risk of meningioma: a nationwide cohort study. Journal of Neurology, Neurosurgery & Psychiatry, 93(2), 222–223. [DOI:10.1136/jnnp-2021-326138]

Update 3: VUMC Switching From CPA to GnRH Agonists

As of August 2020, the Vrije Universiteit Medical Center (VUMC) in Amsterdam is switching antiandrogen therapy of all transgender patients from cyproterone acetate to gonadotropin-releasing hormone (GnRH) agonists (VUMC, 2020). This was due to a Dutch Medicines Authority warning about meningiomas with CPA (VUMC, 2020). The VUMC is the home of the Center of Expertise on Gender Dysphoria, one of the largest care and research institutes for transgender hormone therapy in the world, and is highly influential in this area (Wiepjes et al., 2018; Bakker, 2021). The VUMC is said to be the provider of hormone therapy for about 95% of hormone-seeking transgender people in the Netherlands, and has treated about 10,000 transgender people since its gender clinic opened in 1972 (Wiepjes et al., 2018; Bakker, 2021).

Update 4: Millward et al. (2021)

In October 2021, a systematic review of meningiomas with CPA in transfeminine people was published:

  • Millward, C. P., Keshwara, S. M., Islim, A. I., Jenkinson, M. D., Alalade, A. F., & Gilkes, C. E. (2022). Development and Growth of Intracranial Meningiomas in Transgender Women Taking Cyproterone Acetate as Gender-Affirming Progestogen Therapy: A Systematic Review. Transgender Health, 7(6), 473–483. [DOI:10.1089/trgh.2021.0025]

Update 5: Lee et al. (2022)

In February 2022, a systematic review and meta-analysis of meningiomas with CPA was published:

  • Lee, K. S., Zhang, J., Kirollos, R., Santarius, T., Nga, V., & Yeo, T. T. (2022). A systematic review and meta-analysis of the association between cyproterone acetate and intracranial meningiomas. Scientific Reports, 12(1), 1942. [DOI:10.1038/s41598-022-05773-z]

The paper was covered in the news on ScienceDaily and Medical Xpress.

Update 6: Samoyeau et al. (2022)

In September 2022, the following French study of meningioma incidence in people treated with high-dose progestin therapy following institution of systematic screening was published:

  • Samoyeau, T., Provost, C., Roux, A., Legrand, L., Dezamis, E., Plu-Bureau, G., Pallud, J., Oppenheim, C., & Benzakoun, J. (2022). Meningioma in patients exposed to progestin drugs: results from a real-life screening program. Journal of Neuro-Oncology, 160(1), 127–136. [DOI:10.1007/s11060-022-04124-2]

The absolute incidence of meningiomas with CPA was 13 of 103 or a striking 13% of individuals. This was much higher than in the general population, in which rates of incidental meningiomas of about 1 to 2% have been observed. Moreover, the authors noted that the 13% figure observed in this study was likely an underestimate, as most cases of meningiomas with CPA were likely already diagnosed prior to the launch of systematic screening. Relative to the high absolute incidence, the year-adjusted incidence rate of meningiomas with CPA was 13.2 per 100,000 person–years. As with other studies, meningioma incidence was associated with longer CPA treatment duration, greater cumulative CPA dose, and older age. The incidence of meningiomas was much lower with two other progestins, nomegestrol acetate and chlormadinone acetate. These progestins tend to be used at much lower doses than CPA.

Update 7: Roland et al. (2024)

In March 2024, the following French study assessed meningioma risk with various progestogens:

  • Roland, N., Neumann, A., Hoisnard, L., Duranteau, L., Froelich, S., Zureik, M., & Weill, A. (2024). Use of progestogens and the risk of intracranial meningioma: national case-control study. BMJ, 384, e078078. [DOI:10.1136/bmj-2023-078078]

The study found increased risk of surgically operated meningiomas not only with CPA but also with a variety of other progestogens, including nomegestrol acetate, chlormadinone acetate, medrogestone, injectable medroxyprogesterone acetate, and promegestone. Conversely, progesterone, dydrogesterone, and levonorgestrel intrauterine devices showed no increased risk of surgically operated meningiomas. No conclusions could be drawn for dienogest or hydroxyprogesterone caproate due to the small numbers of individuals who received these progestogens. Many other progestogens, such as most 19-nortestosterone derivatives, were not included or assessed in the study. CPA, related to the high doses used in its case, had by far the greatest risk of surgically operated meningiomas. These findings indicate that meningiomas are a dose-dependent risk of many different progestogens.

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