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Women taking the synthetic progestogen cyproterone acetate were at increased risk for brain tumors, a French study found.

The analysis of data on over 250,000 girls and women who filled a prescription for cyproterone acetate showed that these individuals had a six-fold higher risk for developing an intracranial meningiomas compared with women not using the hormone (adjusted hazard ratio 6.6, 95% CI 4.0-11.1), reported Alain Weill, MD, of EPI-PHARE Scientific Interest Group in France, and colleagues in .

Cyproterone acetate, a synthetic progestogen with antiandrogen effects, is currently approved in most European countries but not in the U.S. Across Europe, the drug has varying indications, including for hirsutism or hyperandrogenism spectrum in women and inoperable prostate cancer and paraphilias in men. In addition, given the antiandrogen properties, cyproterone acetate is also used as feminizing hormone therapy for transgender women.

Weill and colleagues also found that the relationship was dose-dependent, with women exposed to a cumulative dose of more than 60 g of cyproterone acetate -- the highest exposure group -- showing a nearly 22-fold increased risk (aHR 21.7, 95% CI 10.8-43.5).

Although the absolute risk for intracranial meningiomas requiring surgery or radiotherapy was low, there were 69 cases of meningiomas reported in women exposed to the hormone (289,544 person-years of follow-up) compared with 20 cases in the control group not exposed (439,949 person-years of follow-up).

This increased risk rapidly dropped off after discontinuation of cyproterone acetate. After the hormone was stopped for 1 year, the risk for meningioma dropped to only 1.8-fold higher than women never exposed (aHR 1.8, 95% CI 1.0 to 3.2). However, the risk was still more than four times higher if the cumulative dose prior to discontinuation was 12 g or more (aHR 4.2, 95% CI 2.2-8.0).

These new meningioma cases specifically tied to cyproterone acetate tended to be located in the anterior skull base and middle skull base -- mostly in the medial third of the middle skull base involving the spheno-orbital region, the researchers noted. In particular, there was a 47-fold (95% CI 14.9 -149.1) increased risk for meningiomas in the anterior skull base tied to prolonged use of cyproterone acetate.

Nearly all were treated with a neurosurgical procedure, while few received radiotherapy alone.

"Most of the participants with meningioma had taken cyproterone acetate for off-label indications, and around 30% had even continued or resumed cyproterone acetate after treatment of the meningioma, which has been formally contraindicated since 2011," the team wrote.

The observational analysis included data from 253,777 girls and women ages 7 to 70 from SNDS, a French administrative healthcare database covering the entire population of the country. All had been recorded as having at least one reimbursement for cyproterone acetate between 2007 and 2014; the majority were prescribed the therapy by a gynecologist (57%), followed by a general practitioner (18%), dermatologist (12%), or endocrinologist (10%).

Similar findings were seen in a separate analysis looking only at transgender patients prescribed the agent. There was a high risk for meningioma among these patients, with an incidence rate of 20.7 cases per 100,000 person-years. Notably, these patients tended to receive much higher daily doses compared with other patient populations, with all cases of meningioma occurring in those taking daily doses of 100-150 mg, the researchers said.

"People who use high-dose cyproterone acetate for at least 3 to 5 years should be informed about the increased risk of intracranial meningioma," Weill's group wrote. "The indication of cyproterone acetate should be clearly defined and the lowest possible daily dose used."

However, if prolonged high-dose use is necessary, patients should be screened for meningioma via magnetic resonance imaging, the researchers advised.

"In patients with a documented meningioma, cyproterone acetate should be discontinued, because the meningioma might regress in response to treatment discontinuation and invasive treatment could be avoided," the team concluded.

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