Ciproterona e risco de meningioma 7 a 19 vezes maior em registro dinamarquês; mulheres trans, maioria dos novos usuários

Acetato de ciproterona e risco de meningioma: um estudo de coorte nacional

Estudos de coorte e registros Hormônios do sexo oposto

Authors: Anders Pretzmann Mikkelsen, Iben Katinka Greiber, Nikolai Madrid Scheller, Malene Hilden, Øjvind Lidegaard
Journal: Journal of Neurology, Neurosurgery & Psychiatry
Year: 2022
Source: https://doi.org/10.1136/jnnp-2021-326138

Summary

Cyproterone acetate (CPA) is a drug that blocks testosterone. Outside the US it is widely used in hormone treatment for trans women. Danish researchers used national health records covering nearly everyone in the country to compare rates of meningioma, a usually non-cancerous brain tumour, in CPA users and non-users. Users had about 7 times the risk at lower total doses and 19 times at higher doses, and risk stayed raised after stopping. Most users over the whole period were not trans, but by 2019 two-thirds of new users were, so the finding matters directly for trans women. The fact that risk rose with dose, and that a large French study found the same, makes the link believable. But it rests on only 16 cases and cannot give a risk figure for trans people specifically.

Key findings

O estudo abrangeu cerca de 5,7 milhões de dinamarqueses, dos quais 1.982 haviam tomado acetato de ciproterona (CPA).
16 de 8.957 meningiomas (tumores cerebrais geralmente não cancerosos) ocorreram em pessoas que haviam tomado CPA.
As pessoas com dose total de 0,1 a 10 gramas tinham cerca de 7 vezes o risco dos não usuários, e as acima de 10 gramas tinham cerca de 19 vezes o risco.
Ex-usuários que haviam parado o CPA ainda tinham cerca de 5 vezes o risco de pessoas que nunca o tomaram.
Os novos usuários de CPA subiram de 18 para 62 por milhão de pessoas entre 2013 e 2019, e a proporção de pessoas trans subiu de 18% para 68%.
Para contextualizar, uma dose típica para mulheres trans de 50 mg por dia chega a 10 gramas em menos de 7 meses.
Os resultados coincidem com um grande estudo francês (Weill e colegas, 2021) que também constatou que o risco aumentava acentuadamente com a dose.

Abstract

[No abstract in the published research letter; this is the abstract of the medRxiv preprint, doi 10.1101/2020.12.29.20248395] Cyproterone acetate (CPA) is a synthetic steroid hormone. We assessed the association between the use of CPA and the risk of developing meningioma. In a historical prospective cohort study, using Danish national healthcare registers we included a cohort of 5,730,654 individuals, among whom 1,982 were exposed to CPA. During follow-up, we identified 8,957 cases of meningioma, of which 16 were exposed to CPA. From 2013 to 2019 the number of new users increased from 18.1 to 62.3 new users per million, while the proportion of new users who were transgender increased from 18.4 to 68.3%. Analyses showed a significantly increased risk of meningioma according to cumulative dose of CPA; 0.1-10 grams of CPA, incidence rate 78.8 (95% CI 15.7-141.9) per 100.000 person years and adjusted hazard ratio 7.0 (3.1-15.6); >10 grams of CPA, incidence 187.5 (71.3-303.7) and adjusted hazard ratio 19.2 (10.3-35.8), as compared to the background population. In conclusion, the cumulative dose of CPA was associated with an increased incidence and hazard ratio of meningioma, showing a dose-response relationship. The number of new CPA users increased more than 3-fold from 2013 to 2019, primarily driven by new transgender users.

Conclusion

The cumulative dose of CPA was associated with an increased incidence and hazard ratio of meningioma, showing a dose-response relationship. The number of new CPA users increased more than threefold from 2013 to 2019, primarily driven by new transgender users. The authors note that the association has now been reproduced in two large cohort studies (with the French Weill et al. BMJ 2021 study), with a clear dose-response effect and large measures of association.

Methodological limitations

Very few cases: The risk figures rest on just 16 tumours among CPA users, so they are imprecise, and separate results by sex or reason for use were not possible.
Most users were not trans: Over the whole period, most users were not trans (trans people were 18% of new users in 2013). So there is no risk figure for trans people, and doses and other drugs differ by reason for use.
Few other factors accounted for: The researchers adjusted for year, mother's age, a parent having meningioma, and sex, but not for estrogen use, past radiation treatment, obesity or other hormones that may affect tumour risk.
More scans, more tumours found: Meningiomas are often found by chance on brain scans, and CPA users (such as prostate cancer or gender clinic patients) may be scanned more often.
Records not checked: Tumours came from diagnosis codes and drug use from filled prescriptions, without checking the diagnosis or whether people actually took the drug.
Very short report: The published paper is a two-page letter, so full methods, breakdowns by reason for use and checks of the results are not shown; detailed figures come from an earlier unreviewed version.
Small risk in absolute terms: Among users, there were about 79 to 188 tumours per 100,000 people per year. That is a big relative rise but still a small chance for any one person over a short time.

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Summary

Key findings

Abstract

Conclusion