Lower doses of cyproterone acetate may be similarly effective for blocking testosterone, with a lower risk of adverse effects

Previously:

• Cyproterone acetate and meningioma risk in trans women (March 2018)
• Update on case reports: Cyproterone acetate and meningioma in trans women (November 2018)

Disclaimer: I am not a medical professional and this is not medical advice.

Cyproterone acetate (CPA) is an oral antiandrogen widely used outside the United States (Angus et al., 2019) as a part of feminizing HRT in combination with estrogen. In recent years, increasing evidence has emerged that long-term or high-dose use of CPA, such as in transition treatment for transfeminine people, is associated with a substantially elevated risk of developing meningiomas (Gil et al., 2011). These typically benign brain tumors can cause symptoms such as vision loss, headaches, muscle weakness, and seizures, and can require treatment with radiation or surgery.

The mechanism of CPA’s role in promoting the growth of these tumors is well-understood. CPA is an antiandrogen that occupies androgen receptors as an antagonist to block the binding of androgens like testosterone and prevent them from producing physically masculinizing effects, while also functioning as an antigonadotropin to direct the body to stop producing and releasing androgens. However, CPA is not only an antiandrogen – it’s also a progestogen, binding to progesterone receptors as an agonist and producing a very strong progestogenic effect. Additionally, the antiandrogenic and progestogenic effects of CPA are imbalanced, and so the doses needed to suppress testosterone in transfeminine people also produce a significant excess of progestogenic activity (Hammerstein, 1990).

That progestogenic potency is key to CPA’s association with meningiomas, as the vast majority of meningioma tumors have progesterone receptors (Korhonen et al., 2006). Because of these receptors, even very small asymptomatic meningiomas may be stimulated by CPA’s progestogenic action and grow to the point of producing clinically significant symptoms and requiring invasive treatment (Bernat et al., 2015). The affinity of meningiomas for progesterone agonists, whether progesterone itself or synthetic progestins, is also demonstrated by an assigned sex bias: these tumors occur much more frequently in those assigned female, and have been observed to grow rapidly during pregnancy before spontaneously regressing (Sun et al., 2015). And numerous case reports as well as large cohort studies have found an elevated prevalence of meningiomas in trans women and transfeminine people taking CPA (Nota et al., 2018; Ter Wengel et al., 2016).

The risk of meningiomas from use of CPA in the cisgender population has recently drawn the attention of European regulatory agencies, as cis women have also been treated with CPA for androgen-related conditions such as hirsutism, hair loss, acne and skin oiliness. Weill et al. (2019) reported a strong association between cumulative exposure to CPA over time and occurrence of meningioma: in a cohort of 131,485 cis women in France, among those who had taken a total of at least 3 grams (3,000 milligrams) of CPA, 485 of these women were treated with neurosurgery or radiation for meningiomas. Notably, this number does not include those women who had meningiomas with clinically significant symptoms but did not receive invasive treatment, or women who have developed meningiomas after CPA use which have not yet been recognized or diagnosed. The authors found that the rate of occurrence of diagnosed meningiomas increases dramatically with greater cumulative exposure to CPA (translated):

As for the “incident cohort”, there was a strong dose–effect relationship. Thus for a dose of 12 to 36 grams of cyproterone acetate since 2006 the incidence rate was 97 per 100,000, from 36 to 60 grams was 206 per 100,000, and beyond 60 grams of cyproterone acetate the incidence rate was 387 per 100,000 (or about 4 per 1,000 woman–years).

In February of this year, the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency recommended that daily doses of CPA of 10mg or more “should only be used for androgen-dependent conditions… once other treatment options, including treatment with lower doses, have failed”, while emphasizing that the overall risk of experiencing meningioma from CPA use “is very low”. Germany’s Federal Institute for Drugs and Medical Devices adopted the PRAC recommendations this May, the UK’s Medicines and Healthcare Products Regulatory Agency has also highlighted the French cohort findings, and Ireland’s Health Products Regulatory Authority has advised healthcare professionals of the PRAC findings as well.

What does this mean for trans women and transfeminine people taking CPA as part of their transition? Consider the Endocrine Society’s 2009 clinical guidelines for transition treatment (Hembree et al., 2009): CPA is listed as an option for testosterone suppression at a recommended dose of 50 to 100mg/day. A trans woman taking 100mg of CPA daily would be in the “at least 3 grams” cumulative exposure risk group after only a month, the 12-36g risk group after four months, and the 60g-plus risk group in under two years. The updated 2017 guidelines from the Endocrine Society now specify a daily CPA dose of 25 to 50mg/day (Hembree et al., 2017), but even a dose of 25mg daily would place a trans woman in the highest risk group for meningioma development within about six and a half years – and trans women who don’t undergo gonadectomy, whether as an orchiectomy or as a part of vaginoplasty, are likely to take antiandrogens such as CPA for life.

25 to 100mg is also a rather wide range of recommended dosages. What is this based on, and just how much CPA do trans women and transfeminine people need in order to achieve the intended goal of testosterone suppression? A handful of recent studies shed some light on the differences, or lack thereof, between CPA doses when used in feminizing HRT. Fung, Hellstern-Layefsky, & Lega (2017) found that in trans women, groups given 50mg CPA daily or 25mg daily showed no significant difference in suppression of testosterone; furthermore, no significant change in testosterone levels was seen when trans women taking 50mg daily were switched to 25mg daily. The authors stated that clinicians “should consider using this lower dose of CPA in order to minimize potential side effects”, concluding:

Further research is warranted to confirm our findings and perhaps to explore whether doses even lower than CPA 25 mg may be effective at suppressing testosterone levels in this population in order to mitigate the long-term risks of hormonal therapy in this population.

In an abstract, Even-Zohar et al. (2020) found that trans women taking less than 20mg of CPA daily had “effectively and similarly suppressed” testosterone levels compared to those of trans women taking more than 50mg CPA daily. And Meyer et al. (2020) reported that there were no significant differences in testosterone levels between three groups of trans women taking 50mg, 25mg, or 10mg of CPA daily. In light of these findings, previous recommendations of 50-100mg daily may have led to trans women being administered doses of CPA 10 times greater than necessary.

These results suggest that trans women and transfeminine people taking CPA as part of feminizing HRT may be able to achieve testosterone suppression with much lower doses than are traditionally recommended, ultimately reducing their overall exposure to CPA and their risk of adverse effects such as meningiomas. A lower dose of CPA may also reduce the risk of other side effects known to be caused by this medication, such as lowered HDL (“good cholesterol”) levels (Fung et al., 2016), higher LDL (“bad cholesterol”) and triglyceride levels (Even-Zohar et al., 2020), and elevated prolactin levels (Fung et al., 2016; Even-Zohar et al., 2020; Defreyne et al., 2017). Again, the absolute likelihood that a person will develop meningioma due to using CPA is very low. These latest findings on the nature of that association, as well as the efficacy of lower doses of CPA, demonstrate how trans women and transfeminine people taking this medication can take steps to minimize their personal risk. ■

Special thanks to Reddit user Alyw234237 for locating many of these publications.