High doses of a widely-used drug used in the hormonal treatment of conditions such as excessive hair growth, early puberty, prostate cancer, are linked to an increased risk of meningioma – the most common type of benign brain tumor, finds a University of Bristol-led study of over 8-million patients. The study is published in Scientific Reports.
Typically slow-growing, meningiomas are benign tumors, which are often revealed incidentally by imaging but can cause significant disability due to compressing or squeezing the adjacent brain, nerves and vessels and pressure effects within a fixed cranial vault.
Recent studies have reported an association between the growth of meningiomas and hormonal treatments, particularly prolonged and high dose use of the drug cyproterone acetate (CPA).
High doses of cyproterone acetate (> 50 mg/day) is usually prescribed to male patients with inoperable prostate cancer, a condition which leads to excessive hair growth known as hirsutism, or male-to-female transsexual hormonal therapy. Lower doses (2-10 mg/day) of the drug are typically used in combination with oestradiol to treat androgen-associated alopecia or female seborrhoea.
Given the drug’s widespread use, researchers at the Universities of Bristol, Cambridge and the National University of Singapore, conducted a systematic review and meta-analysis study using four studies comprising a sample of 8,132,348 patients, to assess the evidence of the association between cyproterone acetate and incidence of meningiomas.
The sample included 165,988 patients who were identified as taking cyproterone acetate at varying dose amounts. Using this data, the team analyzed the occurrence of meningioma in patients using high versus low dose cyproterone acetate and found a significant association between high dose usage and increased risk of meningioma. However, this association was not found with low doses.
Keng Siang Lee, a medical student and the study’s lead author from Bristol Medical School at the University of Bristol, said that “the cause of meningiomas is controversial but there is strong evidence to suggest a plausible role for sex hormones in the onset of meningioma. We know it has a predilection for females especially after puberty.
Furthermore, fluctuations in meningioma growth during the menstrual cycle, pregnancy, and breastfeeding have also been well-documented. We are also aware of the well-characterized distribution of progesterone, estrogen, and androgen receptors in certain meningiomas located at the base of the skull.”
“In light of these results, prescription of high-dose cyproterone acetate, especially for off label indications, should be considered carefully. Additionally, we suggest that routine screening and meningioma surveillance by brain MRI offered to patients prescribed with cyproterone acetate is likely a reasonable clinical consideration if given at high doses for long periods of time.”
It is still unknown whether or not cyproterone acetate below a certain threshold may be completely safe in terms of the risk of meningioma. The results obtained herein suggest the necessity for further clinical research on intracranial meningioma associated with cyproterone acetate.”
A meningioma is a tumour of the meninges that surrounds the brain and spinal cord. It is the most frequent type of primary brain tumour, with an age-adjusted incidence of 8.56 per 100.000 person years and over 31,000 events in the United States per year.1 Meningiomas are slow-growing, and in most cases non-malignant, although they may induce severe morbidity and mortality due to pressure on surrounding structures. Consequently, it is recommended that, if possible, symptomatic meningiomas be surgically removed.
Meningiomas have been associated with advancing age, female sex, neurofibromatosis type 2 and ionizing radiation.2 Moreover, the use of the drug cyproterone acetate (CPA) has been associated with the development of meningiomas. CPA may potentially affect meningioma growth due to its anti-androgen and pro-progestin properties, as 2/3 meningiomas express progesterone and androgen receptors.3,4 The medication is used by both males and females, although for varying indications.
Among individuals of the male sex, a high dosage formulation is used to treat prostate cancer, hypersexuality disorder, and in male-to-female gender affirming hormone therapy. In individuals of the female sex it is used in the treatment of acne, hirsutism, seborrhoea, hair-loss, and in a low-dose variant in combination with ethinylestradiol as birth control.5,6
Since 2008, past or present meningioma has been a contraindication to CPA treatment. This was initially based on data from case series, highlighting a potential association between CPA and meningiomas.7
Subsequently, two cohort studies found an increased risk of meningioma among users of high-dose CPA, as compared to non-users (odds ratio of 6.3, 95% confidence interval [CI] 1.4-28.9; rate ratio 11.4 95% CI 4.3-30.8), however both studies included less than 5 exposed cases.8,9
A recent French cohort study, comparing females exposed to high cumulative doses versus low cumulative doses of CPA, found a 6-20 fold increased risk of meningioma. As a consequence, the European Medicines Agency’s recently issued a recommendation to restrict the use of more than 10 milligrams CPA per day.10
In a nationwide register-based cohort study we assessed national trends in use of CPA and the risk of meningioma according to cumulative exposure to CPA, as compared to both non-users among males and females.
Furthermore, we assessed if the risk of meningioma among past users of CPA returned to the baseline risk in the general population.
reference link: https://www.medrxiv.org/content/10.1101/2020.12.29.20248395v1.full
More information: Keng Siang Lee et al, A systematic review and meta-analysis of the association between cyproterone acetate and intracranial meningiomas, Scientific Reports (2022). DOI: 10.1038/s41598-022-05773-z