A systematic review and meta-analysis of the association between cyproterone acetate and intracranial meningiomas

The influence of exposure to hormonal treatments, particularly cyproterone acetate (CPA), has been posited to contribute to the growth of meningiomas. Given the widespread use of CPA, this systematic review and meta-analysis attempted to assess real-world evidence of the association between CPA and the occurrence of intracranial meningiomas. Systematic searches of Ovid MEDLINE, Embase and Cochrane Controlled Register of Controlled Trials, were performed from database inception to 18th December 2021. Four retrospective observational studies reporting 8,132,348 patients were included in the meta-analysis. There was a total of 165,988 subjects with usage of CPA. The age of patients at meningioma diagnosis was generally above 45 years in all studies. The dosage of CPA taken by the exposed group (n = 165,988) was specified in three of the four included studies. All studies that analyzed high versus low dose CPA found a significant association between high dose CPA usage and increased risk of meningioma. When high and low dose patients were grouped together, there was no statistically significant increase in risk of meningioma associated with use of CPA (RR = 3.78 [95% CI 0.31–46.39], p = 0.190). Usage of CPA is associated with increased risk of meningioma at high doses but not when low doses are also included. Routine screening and meningioma surveillance by brain MRI offered to patients prescribed with CPA is likely a reasonable clinical consideration if given at high doses for long periods of time. Our findings highlight the need for further research on this topic.

Exposure and dosages. The dosage of CPA taken by the exposed group (n = 165,988) was specified in three of the four included studies. In the study by Cea-Soriano et al., all female patients had a daily CPA dose of 2 mg or higher, whereas all male patients had a daily dose of 50 mg or higher 40 . In the study by Weill et al., the cumulative dose of patients within the exposed group was greater than or equal to 3 g (at least three standard packets of 20, 50 mg tablets) within the first six months of the first prescription 37 . The studies by Cea-Soriano et al. and Gil et al. defined high dose as ever having a daily dose of 50 mg or higher, while low dose was defined in these studies as all daily doses being less than 50 mg, at a markedly lower dose of 2 mg/day (which may likely be for birth control) 40,45 . The study by Mikkelsen et al., compared the incidence of intracranial meningiomas between groups of high cumulative doses (> 10 g) versus low cumulative doses of CPA (0.1-10 g). Across the three studies (with total sample size being 7,851,805 and number of exposed patients being 26,766), there were a total of 3271 and 23,495 high and low dose patients, respectively 40 46 .
Similarly, Weill et al. found a dose-effect relation between meningioma risk and cumulative dose of CPA, with higher risk associated with a higher cumulative dose 37 . The hazard ratio (HR) was not significantly different from 1 for exposure to less than 12 g of CPA, and it rapidly increased for higher cumulative doses: 11.3 (95% CI 5.8-22.2) for 36-60 g and 21.7 (95% CI 10.8-43.5) for 60 g or higher. In this study, the exposed group comprised only of current users and does not include past users 37 .
We pooled the patients across the four included studies to perform a meta-analysis of binary outcome. The total number of patients in the exposed and non-exposed group was 165,988 and 8,997,360, respectively.

Discussion
To our knowledge, this is the first meta-analysis to investigate the association between CPA use and intracranial meningioma. Limited current evidence suggests an increased risk of meningioma associated with high dose CPA usage. When high dose users were combined with low dose users, this association becomes statistically insignificant. This meta-analysis underscores the current paucity in evidence about the risk of intracranial meningioma associated with low dose CPA. For example, for the purposes of birth control prescribed at 2 mg or 50 mg for short periods. The included studies had also varied in their definition of low dose CPA prescription. It is still unknown whether or not CPA below a certain threshold may be safe in terms of the risk of meningioma.

Location.
A majority of CPA-associated meningiomas have been reported to be preferentially distributed at the anterior (22-75%) and middle base of the skull (25-40%), as opposed to cranial convexity which is the commonest location in the general population 16,32,[37][38][39] . Samarut and colleagues purported that meningiomas located in the anterior and middle skull base appeared to be specific to CPA use, with the risk reducing after termination of CPA 38 . The predominance of anterior skull base meningiomas may be supported by biological plausibility 49 . The embryological biology of meninges differs at the convexity (neural crests) and the base of the skull (mesoderm) 16,32,[50][51][52][53][54][55][56] . Molecular and immunohistochemical studies have established that the progesterone receptor distribution in the skull base follows a rostrocaudal gradient [14][15][16]57 . Thus, we could expect skull base meningiomas to dominate in the anterior cranial fossa with progestogenic CPA exposure.

Risk, causality and interpretation.
A causal relationship between high dose CPA and the development of meningioma is tenable. Based on the Bradford Hill criteria 58 , this may be supported by the strength and dosedependent association. Our findings suggest a modest magnitude of the association between high dose CPA use and intracranial meningiomas, albeit when high dose users were banded together with low dose users in our pooled analysis, this association became statistically insignificant. Although a three-fold increase in clinically significant risk was found in our meta-analysis, the confidence intervals encompassed the null. This is further supported by the specificity of certain tumor locations (anterior skull base) which are highly dense with progesterone receptors, providing a biological plausibility. Reverse causality is acknowledged with observational studies especially if the prescription of CPA was linked to an undiagnosed meningioma. However, this bias may be excluded from our meta-analysis because of the temporal aspect of our findings: the risk of meningioma increased with the duration of CPA use and cumulative doses, and not during the initial phase of drug use. Furthermore, reports of rapid spontaneous meningioma regression or stabilization after CPA withdrawal, can be found in the literature 30,31,33,36,59 . This observation further reinforces the notion of causality 58 . As progesterone have been postulated to accelerate meningioma growth by vascularization, the biology involved is analogous to the spontaneous regression of meningiomas postpartum 60 . Clinical implications and management of CPA-associated meningiomas. Iatrogenic meningioma engendered by high-dose CPA use is a public health issue. Before these results are used to guide clinical decision making, the collective body of data on this safety issue should be scrutinized by drug regulatory authorities and weighed against the benefits of treatment. Nonetheless, patients currently on or previously exposed to high dose CPA should be informed about the increased risk of intracranial meningiomas. The indication of CPA should be clearly defined with the lowest possible daily dose used.
First line management of meningiomas typically involves surgery. Location of the meningioma influences the extent of resection, which, consequently influences outcomes such as recurrence rates 61 . As shown, CPAassociated meningiomas have a predilection for the skull base, which is of considerable importance because skull www.nature.com/scientificreports/ base meningioma surgery is associated with poorer prognosis than surgery for non-skull base meningiomas [61][62][63][64] . Duly, evidence for spontaneous meningioma regression with CPA termination 30,31,33,36,59 , sustained the notion that invasive treatment may be avoided and conservative management of CPA-associated meningiomas might be treatment of choice 30,39,65 . However, it must be noted that such cases are exceptional-a patient with clinoidal meningioma and progressive visual loss must be operated on, in spite of previous treatment with CPA. Conservative management, which may be recommended for small and asymptomatic meningiomas, comprises cessation of CPA and close follow-up magnetic resonance imaging (MRI) in the context of current or past history of high dose exposure. As this screening suggestion was not directly investigated in this study, this requires further cost-benefit analysis by guideline groups and/or policymakers. Despite evidence that antiprogesterone treatment reduces the size of meningioma, both in vitro and in vivo, such therapy has not been recommended in the conservative management of meningiomas.

Limitations.
Although several factors lend support to the strength of the association, including biological plausibility and consistent epidemiological evidence, our findings must be cautiously interpreted in the context of its known limitations. Limitations of our meta-analysis include the retrospective and observational nature of included studies and the significant heterogeneity among the studies. There were no randomized controlled trials in this study, although conducting one could account for potential biases and confounders, the non-randomized evidence to the risk of meningiomas is so extensive that this would unlikely take place, from practical and ethical standpoints 66 . A further limitation of the available data is that there is little known about the impact of past exposure or whether there is a cumulative dose effect, and hence we were unable to weigh the effect of historical doses versus current doses differently. Only two studies had defined past exposure 40,46 . Confounding factors are inevitable in any of our included observational studies. The small number of studies available in the literature could explain the finding of non-significance and limited our ability to perform certain analyses such as meta-regression to explore possible confounders (age and sex) or sources of heterogeneity in our dataset. To minimize the extent of these limitations, we performed sensitivity analyses to attempt to identify outlier studies. Taken together in this light, together with our pooled analysis, we propound that this relationship cannot be proven causal given the aforementioned. Nonetheless, advantages of our meta-analysis include avoiding undue emphasis on individual studies, thus yielding risk estimates that are more reliable.

Conclusion
In light of these results, prescription of high-dose CPA, especially for off label indications, should be considered carefully. Additionally, routine screening and meningioma surveillance by brain MRI offered to patients prescribed with CPA is likely a reasonable clinical consideration if given at high doses for long periods of time. The results obtained herein suggest the necessity for further clinical research on intracranial meningioma associated with CPA.

Methods
The review was conducted according to the PRISMA guidelines 67 . The protocol was registered on the PROSPERO international prospective register of systematic reviews (registration number CRD42021242120).
Search strategy. Searches of the following three electronic databases were undertaken: Ovid Medline, Ovid Embase, and Cochrane Central Register of Controlled Trials (CENTRAL). Searches were performed in each database from its inception until 18th December 2021. The concepts of "cyproterone acetate", and "meningioma", were used in addition to synonyms and related terms. An example search strategy used for OVID Medline/EMBASE/CENTRAL is presented in Supplementary Table 1.
Eligibility criteria. Any randomized or non-randomized study (cohort study; case-control study) that investigated the association between CPA use regardless of indication, and the risk of intracranial meningiomas were included. As it is the progestogenic effect of CPA that has been purported to contribute to intracranial meningiomas, the controls in this study were limited to patients unexposed to CPA or patients only very slightly exposed who discontinued CPA prematurely, as defined by the included studies. Particularly, in the study by Weill et al. the control group was defined as patients who discontinued treatment rapidly after having received a cumulative dose less than 3 g (one or two standard packs) dispensed within the first six months after this first prescription.
The following designs were excluded: case reports/series; non-English; animal studies. Studies that did not report extractable data including odds ratio (OR), RR, HR, or raw data, were also excluded. Patients were included regardless of gender and ethnicity, or presence of symptoms on presentation. Supplementary Table 2 describes the full list of inclusion and exclusion criteria.
Study selection. All titles and abstracts were screened against the pre-defined eligibility criteria developed independently by two reviewers (KSL and JJYZ). Disagreements were resolved by discussion, and where agreement could not be reached, the senior reviewer assisted with decision making (VDWN). Potentially eligible studies were selected for full-text analysis. At each stage, KSL and JJYZ reviewed 100% of the screened studies for inclusion to ensure reliability of study selection. Disagreements were resolved by consensus or appeal to a third senior reviewer (VDWN). Agreement among the reviewers on study inclusion were evaluated using Cohen's kappa 48 .