Study of entire French population offers further data on cyproterone acetate and meningioma risk

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

Zinnia JonesCyproterone acetate (CPA) is widely used as an antiandrogen for trans women and transfeminine people outside of the United States, lowering testosterone levels as part of feminizing HRT. In addition to blocking androgen receptors, CPA is also a strong synthetic progestin, acting on the progesterone receptor more powerfully than bioidentical progesterone itself (Hammerstein, 1990). Long-term use of CPA has been established as a risk for developing meningiomas, a type of usually benign brain tumor that expresses progesterone receptors and is stimulated to grow by strong progestins such as CPA (Korhonen et al., 2006). Many of these tumors would otherwise be small and asymptomatic; CPA may not produce them, but it can cause them to grow larger and become symptomatic, requiring treatment with surgery or radiation.

Meningioma has been found to occur more often in those assigned female, who as a group tend to experience higher progesterone levels over their lifetime than those assigned male (Wiemels, Wrensch, & Claus, 2010). Multiple studies of large cohorts of trans women taking CPA have found that they are more likely to develop meningiomas than the general population (Ter Wengel et al., 2016; Nota et al., 2018), and studies of cis women and cis men revealed that high doses of CPA were linked to a greater likelihood of meningioma (Gil et al., 2011). Weill et al. (2019), examining a cohort of 131,485 cis women in France, established that greater cumulative exposure to CPA over time was associated with a steadily increasing meningioma risk, and the European Medicines Agency subsequently stated that any dose of 10mg or more should only be used “once other treatment options, including treatment with lower doses, have failed”.

A broader look at CPA-associated meningiomas

A more recent report by Weill et al. (2021) used France’s administrative healthcare database to study the frequency of meningiomas among a sample of 139,222 cis women who took at least 3 grams of CPA in total and a control group of 114,555 cis women who had a cumulative dose of less than 3 grams. 10,876 trans women prescribed CPA were also included and divided into an exposed group and a control group using the same 3g threshold. This study only recorded meningiomas that were treated with surgery or radiation rather than including all meningiomas regardless of treatment; the data compares the frequency of these events between groups. Once again, the risk of meningioma was proportional to the cumulative dose of CPA:

The hazard ratio was not significantly different from 1 for exposure to less than 12 g of cyproterone acetate, and it rapidly increased for higher cumulative doses: 11.3 (5.8 to 22.2) for 36-60 g and 21.7 (10.8 to 43.5) for 60 g or higher (table 3).

Those who had taken between 12-36 grams in total were 6.4 times as likely as the control group to develop meningioma. Among trans women, those who took more than 3 grams in total had an incidence of meningioma of 20.7 per 100,000 person-years, comparable to the incidence of 26 per 100,000 person-years among cis women who took 12-36 grams in total. The link between cumulative exposure and meningiomas was particularly clear among trans women:

The three people with meningioma in the exposed group who required surgery were those taking very high daily doses of 100-150 mg for relatively short exposure periods of 3-4.5 years.

As part of feminizing HRT, CPA has typically been prescribed in doses of 25-100mg/day (Hembree et al., 2009; Hembree et al., 2017), although a recent study reported that 10mg can be as effective at suppressing testosterone in trans women as 25 or 50mg (Meyer et al., 2020). The findings of the France study suggest that within only 16 months, a trans woman taking 25mg of CPA daily would be at a significantly higher risk of developing a meningioma requiring invasive treatment. Trans women typically continue taking antiandrogens until any surgery that removes the testes, which may be years for some, and a lifetime for others.

Interestingly, the sample size of this study was large enough to show that the distribution of locations of meningiomas within the skull was substantially different among the CPA-exposed group of cis women compared to the control group, with meningiomas in the CPA group being much more likely to occur at the skull base:

Several authors have reported a heterogeneous distribution of progesterone receptors according to the site of meningiomas. A rostrocaudal gradient of progesterone receptors, with a higher density of receptors in the skull base, has often been reported, and was confirmed by several publications. Our finding of a predominance of anterior skull base meningiomas related to use of cyproterone acetate, a progestogen, is consistent with these biological findings.

This location can pose a particular difficulty, as “skull base meningioma surgery is one of the most challenging forms of surgery and is associated with a much higher risk than surgery for convexity meningiomas.” Complications are relatively frequent, with a previous study of meningioma surgeries finding that “40% of patients who had surgery for meningioma experienced cognitive or emotional disorders for an average of 2.5 years after surgery”.

Alternatives to CPA for feminizing HRT

While continuing CPA increases cumulative dose and in turn increases the risk of meningioma, discontinuing CPA can in turn begin to reduce one’s future risk of meningioma. While those who had taken a total of 3g or more were overall 6.6 times more likely than the control group to develop a meningioma, after one year of discontinuing CPA, this group’s likelihood of meningioma was now only 1.8-fold greater. In patients with symptomatic tumors, stopping CPA has also sometimes been found to shrink those tumors, and some of these patients have ultimately not needed treatment with surgery or radiotherapy (Bernat et al., 2015).

But it’s not as simple as just stopping CPA for trans women who are still in need of a testosterone blocker. Those who prefer not to take CPA have several options: spironolactone is usually used for trans women in the United States but may not produce as reliable a suppression of testosterone levels as CPA; bicalutamide is an uncommonly used non-steroidal antiandrogen that may rarely cause elevation of liver enzymes or liver toxicity; GnRH analogues to shut down all production of testosterone, such as Lupron, Zoladex and Decapeptyl, are only available as long-acting injections and can be prohibitively expensive.

Jain, Kwan, & Forcier (2019) studied an antiandrogen regimen in trans women of both spironolactone and medroxyprogesterone acetate (MPA), another synthetic progestin with antiandrogenic effects, and found that spironolactone and MPA suppressed testosterone levels further than spironolactone alone. Trans women using MPA also frequently reported better breast development, a possible effect of progestins. However, unlike CPA, MPA has not been found to increase the likelihood of meningiomas, and was previously tested as a potential treatment for meningiomas, which also had no effect (Jääskeläinen et al., 1986; Markwalder et al., 1987). As always, medical transition is ultimately an individual matter – and this latest data on the risk profile of CPA helps empower trans women in making the decisions they consider best for their transition and their overall health. 

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About Zinnia Jones

My work focuses on insights to be found across transgender sociology, public health, psychiatry, history of medicine, cognitive science, the social processes of science, transgender feminism, and human rights, taking an analytic approach that intersects these many perspectives and is guided by the lived experiences of transgender people. I live in Orlando with my family, and work mainly in technical writing.
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