Previously:
Disclaimer: I am not a medical professional and this is not medical advice.
The antiandrogen cyproterone acetate (CPA), taken as a daily pill, is commonly used outside of the United States as part of hormone therapy to suppress testosterone levels in trans women and transfeminine people who still have their testes (Hembree et al., 2017). Although CPA blocks the action of testosterone at androgen receptors and reduces the body’s production of testosterone, it also strongly stimulates progesterone receptors, potentially producing undesirable effects.
In recent years, increasing attention has been given to the role of CPA in spurring the growth of meningiomas, brain tumors which are usually benign and frequently express progesterone receptors (Roser et al., 2004). While these tumors may have already existed at a very small size without any apparent symptoms, and in many cases may remain unnoticed indefinitely (Yano et al., 2006), the presence of a strong progestogen such as CPA can cause them to grow over time to a size that produces symptoms such as headaches, vision loss, and seizures. Meningiomas are also known to be responsive to the body’s own progesterone levels, with cis women being significantly more likely than cis men to develop meningiomas (Sun et al., 2015), but CPA’s progestogenic effect is substantially stronger than that of progesterone itself (Hammerstein, 1990), and numerous cases of meningioma in trans women taking CPA have been reported in the literature (Nota et al., 2018).
Population-wide data from France, where CPA has been widely used both for trans women and for cis women with androgen-related conditions such as hirsutism or acne, has usefully clarified the relationship between CPA usage and the risk of developing meningioma. Weill et al. (2021), studying 253,777 cis women and 10,876 trans women who had taken CPA, found a strong association between cumulative CPA usage over time and likelihood of needing surgery or radiation treatment for meningioma. Compared to a control group of cis women who had taken less than 3,000mg of CPA in total, those who had taken 12,000-36,000mg in total were 6.4 times as likely to require treatment for meningioma, those who’d taken 36,000-60,000mg were 11.3 times as likely, and those who’d taken over 60,000mg were 21.7 times as likely to require treatment. After stopping CPA for at least one year, the risk of needing treatment for meningioma declined to 1.8 times that of the control group, although among those who had taken more than 12,000mg in total, this risk remained 4.2 times that of the control group.
For these reasons, there is a motivation for trans women taking CPA to reduce their dosage as much as possible. This collides with the historical fact that trans women have often been prescribed far more CPA than is necessary – and recent studies have shown just how unnecessary these high doses actually are for effective testosterone suppression in trans women.
A previous edition of the Endocrine Society’s clinical guidelines for treatment of trans people recommended 50-100mg of CPA daily (Hembree et al., 2009), while the latest edition has lowered this to 25-50mg daily (Hembree et al., 2017). Fung, Hellstern-Layefsky & Lega (2017) found that trans women could achieve equivalent suppression of testosterone levels with 25mg or 50mg CPA, and Meyer et al. (2020) later found no difference in testosterone levels between trans women taking 10mg, 25mg, or 50mg. Now, Kuijpers et al. (2021) have substantially confirmed this finding in a larger number of trans women taking a wider variety of CPA doses.
Studying 882 trans women in the Netherlands, Belgium, and Italy from 2010 to March 2020, the authors reported the testosterone suppression achieved by women taking estrogen and daily doses of 10mg, 25mg, 50mg, or 100mg of CPA, or no CPA (estrogen only). With measurements taken at 3 and 12 months after starting HRT, trans women taking 10, 25, or 100mg CPA had average testosterone levels of 26 ng/dL (0.9 nmol/L), while those taking 50mg CPA had average levels of 32 ng/dL (1.1 nmol/L), which was not significantly different. All of these doses were considered to meet the prespecified threshold for testosterone suppression, staying below 2.0 nmol/L (58 ng/dL), whereas the group taking estrogen without any CPA had average testosterone levels of 5.5 nmol/L (159 ng/dL).
CPA has also been associated with an undesired rise in levels of prolactin and a decrease in HDL (“good”) cholesterol (Fung et al., 2016), but the lowest dose in the study, 10mg, had less of an effect on prolactin than higher doses, and no effect on HDL compared to those who were not taking any CPA. There was no difference observed between liver enzyme levels, total cholesterol, or total triglycerides among the different CPA dosage groups.
Considered in the context of findings regarding meningioma risk, this represents an opportunity to reduce trans women’s cumulative exposure to CPA by a factor of 2.5, 5, or even 10. For example, if 10mg works just as well as 50mg – and it appears to – this is a difference of entering the greater-than-12,000mg meningioma risk group after 3 and ¼ years, or 34 weeks. The authors suggest that additional “research should focus on assessing the effectiveness of an even lower dose of CPA (e.g., 5 mg)”.
Of course, the risk does still exist, and as the authors point out, this is not a matter of a lack of safe and effective alternatives to CPA for testosterone suppression – alternatives that do not come with an elevated risk of brain tumors. It’s a matter of access and affordability of equally effective agents for testosterone suppression, such as GnRH agonists:
Worldwide, the choice of anti-androgen treatment appears to be depending on the preference of trans women, availability, regional experiences, co-morbidity, and costs. Because of the raised concerns, centers are increasingly choosing to switch from CPA to GnRH agonists as the first treatment choice. In the United States, CPA has never been licensed for any indication. In the United Kingdom, GnRH agonists are treatment of first choice and are widely reimbursed. At the beginning of 2020, a safety report on CPA was published by the European Medicines Agency (EMA) on the risk of meningiomas with use of CPA (11), and the restriction of CPA was suggested in situations where alternative treatment options are available. The EMA additionally called for the lowest possible effective dose of CPA to be used if CPA treatment was maintained. Aside from the raised concerns and reported side effects, CPA has shown to be a very effective anti-androgen that leads to adequately suppressed testosterone concentrations in trans women. Therefore, in cases where other anti-androgen agents are unavailable, contra-indicated or not reimbursed, it is important to find the lowest effective dose of CPA.
Other than CPA and GnRH agonists, spironolactone is noted as a safe and inexpensive oral antiandrogen commonly used for trans women, although it may not reduce testosterone levels to the same degree or as consistently as CPA (Angus et al., 2019). Other data shows that the combination of spironolactone and oral medroxyprogesterone acetate, a synthetic progestin that is not associated with increased likelihood of developing meningioma, suppresses testosterone levels in trans women to a greater extent than only spironolactone (Jain, Kwan, & Forcier, 2019). For trans women and transfeminine people who do continue taking CPA, this latest data confirms that reduction to a dose of 10mg daily is an effective means of maintaining testosterone suppression while lowering the risk of meningioma and other CPA-associated side effects. ■
