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Cyproterone acetate and risk of meningioma: a nationwide cohort study
  1. Anders Pretzmann Mikkelsen1,2,
  2. Iben Katinka Greiber2,3,
  3. Nikolai Madrid Scheller1,4,
  4. Malene Hilden1,5,
  5. Øjvind Lidegaard1,2
  1. 1 Department of Gynaecology, Rigshospitalet, Copenhagen, Denmark
  2. 2 Deptartment of Clinical Medicine, University of Copenhagen, Cobenhavn, Denmark
  3. 3 Department of Obstetrics, Rigshospitalet, Copenhagen, Denmark
  4. 4 Department of Surgery, Queen Ingrid's Hospital, Nuuk, Greenland
  5. 5 Centre for Gender Identity, Rigshospitalet, Copenhagen, Denmark
  1. Correspondence to Dr Anders Pretzmann Mikkelsen, Department of Gynaecology, Rigshospitalet, Copenhagen, Denmark; anders.mikkelsen{at}regionh.dk

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Introduction

Cyproterone acetate (CPA) has in preliminary studies been linked to the development of meningiomas. Possibly, CPA may induce or increase meningioma growth due to antiandrogen and proprogestin properties, as two-thirds of meningiomas express progesterone and androgen receptors.1 Among individuals assigned male sex at birth, CPA is used to treat prostate cancer, hypersexuality disorder, and as feminising hormone therapy. In individuals assigned female sex at birth, it is used in the treatment of acne, hirsutism, seborrhoea, hair loss and in a low-dose variant in combination with ethinylestradiol in birth control pills.2

A recent cohort study comparing females exposed to high cumulative doses versus low cumulative doses of CPA, found a 6–20 fold increased risk of meningioma.3 Subsequently, the European Medicines Agency’s (EMA) issued a recommendation to restrict CPA to less than 10 milligrams per day.4

In this nationwide study, we assessed national trends in use of CPA and the risk of meningioma according to cumulative exposure to CPA, as compared with non-users.

Methods

Study population

In this prospective register-based cohort study, we used nationwide Danish registers to identify all individuals born between 1930 and 2000. Individuals were included in the study at age 15, date of immigration to Denmark or 1 January 1995, whichever came last. Study participants were then followed until a diagnosis of meningioma, neurofibromatosis type 2, death, emigration or 31 December 2017, whichever came first. We excluded individuals with prior meningioma, intracranial surgery, neurofibromatosis type 2 or who died before inclusion. Spinal or cerebral meningioma was the event of interest, defined using diagnosis codes in the National Patient Register or the Cancer Register (details in online supplemental file, table 1).

Supplemental material

Information about prescriptions for CPA since 1 January 1995 was extracted from the Prescription Register, using the Anatomical Therapeutic Chemical Classification System code G03HA01. Cumulative dose of CPA was summed during the follow-up (online supplemental file, text 1), and recipients were categorised into three exposure groups: no CPA, 0.1–10 g of CPA (obtained after the first prescription of CPA), above 10 g of CPA.

New users

To evaluate the temporal trends in CPA use, we identified new CPA users by the first prescription from 1997 to 2019 in the Danish Prescription Register. The number of new users was divided by individuals alive in Denmark above 14 years of age to obtain the annual incidence rate of new users. We determined the likely indication for CPA treatment as either (1) prostate disease, (2) feminising hormone therapy or (3) other or unknown (details in online supplemental file, table 2).

Statistical analyses

Using a time-dependent Cox regression model, hazard ratios (HR) were estimated using age as the underlying time scale. Risk time started at age of inclusion, was split at 5-year intervals, and ended at the age of censoring or an event. To account for confounders, estimates were adjusted for calendar year (numerical variable modelled using penalised splines), age, history of parental meningioma and birth assigned sex. The proportional hazard assumption was assessed in diagnostic plots and accepted.

Past or present use

In a separate analysis, we characterised users according to no, past or present use of CPA. Individuals were considered past users 365 days after the last prescription for CPA.

Results

A total of 5 730 635 individuals were included in the cohort and 1 982 (0.035%) were treated with CPA at some time during the follow-up. The mean follow-up time was 16.8 years (SD 8.0 years). Individuals could contribute risk time in each cumulative exposure group, and thus 1 976 individuals were exposed to 0.1–10 g of CPA, and 781 individuals were later exposed to >10 g of CPA (online supplemental file, figure 1). Among users of CPA, 1 726 (87.0%) were assigned male sex at birth and 1 037 (52.3%) had prostate disease. The number of new users of CPA in Denmark increased from 18.1 new users per million people per year in 2013 to 60.7 in 2019. The proportion of new users using the drug for feminising hormone therapy increased from 8.0% in 2013 to 65.3% in 2019 (figure 1A).

Figure 1

(A) Yearly incidence of new users of CPA in Denmark per million persons above 14 years of age by indication. (B) Association between use of CPA and meningioma. Results from time dependent Cox regressions. Abbreviations: CI, Confidence interval; CPA, Cyproterone Acetate; g, grams; HR, Hazard Ratio. * Crude incidence rate per 100,000 person-years. † Adjusted for calendar year, age, history of parental menigioma, and sex. In the analysis stratified by birth assigned sex, sex was not used as a covariate. ‡ Aggregated due to Danish privacy regulation.

Persons with a cumulative exposure of 0.1–10 g of CPA experienced six meningiomas, incidence rate 78.9 per 100 000 person-years, and adjusted HR 7.0 (95% CI 3.1 to 15.6), as compared with non-users, (figure 1B). Persons with cumulative exposure to >10 g of CPA experienced 10 meningiomas, incidence rate 187.5 and adjusted HR 19.2 (95% CI 10.3 to 35.8), as compared with non-users. (Kaplan-Meier estimator provided in online supplemental file, figure 2). Of the 16 cases diagnosed with meningioma after CPA exposure, none were spinal meningiomas, and the median estimated daily dose taken was 73 milligrams/day (IQR 43–98), and the median duration of CPA use was 5.0 years (IQR 0.4–11.6 years). Notably, eight of these individuals continued using CPA after meningioma diagnosis and surgery.

In subgroup analyses stratified by birth assigned sex, there were three events in the female birth sex group and the adjusted HR was non-significantly increased. In the subgroup with known prostate disease, there were four events, and the adjusted HR was likewise non-significantly increased.

Past users of CPA had an adjusted HR of meningioma of 5.4 (95% CI 2.4 to 12.2), compared with non-users.

Discussion

In this nationwide study, we found that cumulative dose of CPA and past use of CPA was significantly associated with the development of meningioma. Additionally, the incidence of new users increased markedly between 2013 and 2019, driven largely by use of feminising hormone therapy among transgender individuals assigned male at birth.

The major strength of the study was the register-based design and size of the population. However, although the cohort was large, treatment with CPA was very rare in the general population, with only 0.035% fulfilling a prescription during the study period. As users of femininising hormone therapy often self-prescribe hormones,5 the actual number of CPA users may be higher.

Considering our results and existing evidence,3 the current recommendation from EMA may still entail excess risk, assuming the relationship is causal.

Conclusion

In this nationwide study, the cumulative dose of CPA and past use of CPA was associated with an increased risk of meningioma.

Ethics statements

Patient consent for publication

Ethics approval

Data were provided from the Danish Health Data Authority under license FSEID-00003879. Permission was granted from the Regional Data Protection Agency (P-2020–217).

Acknowledgments

Statistics Denmark (DST) provided hosting of patient data for the study.

References

Supplementary materials

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

Footnotes

  • Twitter @apmikkelsen

  • Contributors APM, NMS and ØL conceptualised the study. APM conducted statistical analyses and wrote the initial draft. All authors critically revised the manuscript.

  • Funding The current investigation was funded by a grant from The Research Fund of Rigshospitalet, Copenhagen University Hospital grant number E-22 515–01.

  • Disclaimer The funders had no role in the design of the study, in the collection, analysis, and interpretation of the data, in the writing of the report; or in any decision related to publication.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Author note Software used for data management and statistical analyses was R version 4.0.2, and packages data.table version 1.13.0, and survival version 3.2–3.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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