Extensive androgen exposure and meningioma risk – A matched cohort study

Introduction: Meningiomas frequently occur within the field of neuro-oncology, but it is unclear whether exogenous or imbalanced endogenous hormones are involved in the pathophysiology. A previous case-control study found an almost 20-fold increase in the risk of developing meningioma among users of androgenic anabolic steroids. We, therefore, investigated this hypothesis. Methods: We compared the incidence rate of meningioma in a cohort of males sanctioned for the use of androgenic anabolic steroids with age-and sex-matched controls with an identical enrollment date. Results: We followed 1189 males sanctioned for using androgenic anabolic steroids for a total of 13,305 person-years and found 0 cases of meningioma. The control cohort of 59,450 males was followed for a total of 654,938 person-years, and 16 were diagnosed with meningioma. Thus, the incidence rate ratio was 0 (95% CI: 0 – 12.8). Conclusion: We did not find any evidence supporting the hypothesis of an increased risk of meningioma development with the use of androgenic anabolic steroids. Due to the limited sample size, we cannot exclude androgenic anabolic steroids as a potential risk factor for meningioma development, despite the lack of apparent evidence in this study.


Introduction
Meningiomas are the most common extra-axial, intracranial tumor.It occurs in approximately 2-7 per 100.000 per year for women and 1-5 per 100.000 per year for men, exhibiting great variations according to age [1].As of now, there is a general understanding that the development of meningiomas could be influenced by either endogenous or exogenous hormones [2,3], but the mechanism has yet to be explained.Interestingly, a European case-control study from 2011 found a 19 times higher risk of developing meningioma among men using androgen hormone analogs (testosterone, mesterolone, or fluoxymesterone) compared to non-users [4].Of 196 men diagnosed with meningioma, three were current users of androgenic anabolic steroids (AAS) while there were only two among 2653 age-matched male controls [3].Therefore, we wanted to test this hypothesis in a cohort of males AAS users.

Data sources
Anti-Doping Denmark is a public independent institution in Denmark whose focus is working against doping in sports.Since 2006, 342 fitness centers in Denmark have collaborated with Anti-Doping Denmark and there have been conducted approximately 1000 doping inspections annually until 2018 [5].
All residents in Denmark have a unique personal identification number registered in the Danish Central Person Register which is used in all contacts with the public administration and healthcare system [6].We cross-referenced the patients' personal identification numbers with the Danish Civil Registration System and the Danish National Patient Register, specifically looking for the International Classification of Diseases-10 code (ICD-10): D32 (Meningioma).Furthermore, we investigated the prevalence of a computed tomography (CT) scan of the head during follow-up ICD-10: UXCA.The follow-up of participants continued until the earliest of these events: their date of death, migration, or June 30, 2023.

Study population
The cohort consisted of males who were expelled from Danish fitness centers in an AAS anti-doping program, either due to positive AAS tests or for refusing to provide a sample [5].For each case 50 age-, sex-, and date-matched controls were randomly sampled using the Danish Civil Registration System.The cohort is described in previous publications [7][8][9].

Statistical analyses
The study is a matched cohort study.For descriptive data, continuous variables are presented using mean and standard deviation (SD).The incident rate of meningioma during the follow-up period was calculated with a 95% CI.The incidence rate in AAS users was compared with controls and presented as incidence rate ratios (IRR) with 95% CI.Statistics were applied for the Poisson distribution.We used a statistical significance threshold of 0.05.Statistics were computed in STATA 16.1

Ethics
All data was anonymized, ensuring no individual identification was possible.The study was approved by the Danish Data Protection Agency (BFH-2017-105/05949), and the Danish National Board of Health (FSEID-00006603).

Results
This study included 1189 males who had been doping-sanctioned in the AAS anti-doping program.The matched controls consisted of 59,450 males.The average follow-up period for the AAS users was 11.2 years and 11.0 years for the controls, as shown in Table 1.In this period there were no diagnosed meningiomas among the AAS users, while 16 meningiomas were diagnosed among the controls, leading to an IRR of 0 (95% CI: 0-12.8).Refer to Table 1.During the same period 19.8% of the AAS users had undergone a head CT and the corresponding number was 10.3% in the control cohort.

Discussion
In this relatively large cohort study of 1189 AAS users, we did not find any cases of diagnosed meningiomas.Based on the literature we had expected an almost twenty-fold higher incidence rate among AAS users than in the background population [4], equivalent to an incidence of six meningiomas in our AAS cohort.The AAS users in our cohort had a high frequency of CT scans during the follow-up period.Even though magnetic resonance imaging is the preferred non-invasive method when diagnosing meningiomas, they are also visible on CT scans as most meningiomas appear hyper-or isointense to grey matter on T1 and T2 weighted imaging.Therefore, it could be presumed, that if meningiomas were common among AAS users, they had a high probability of being detected [10].Thus, our study does not support the hypothesis of a link between AAS and meningioma.
However, meningiomas are rare and grow slowly, and our study is limited by the sample size and the relatively short follow-up period in the context of meningiomas.Therefore, we cannot exclude the use of AAS as a risk factor for meningioma development, despite the lack of apparent evidence in this study.

Conclusion
We did not find any evidence supporting the hypothesis of an increased risk of meningioma development with the use of AAS.The results are reassuring for users of AAS.However, these results should be considered in the context of the limitations of the study, including a relatively small sample size and a follow-up period of just over 11 years, which might be insufficient for detecting slowly developing meningiomas.Further research with larger sample sizes and longer follow-up periods is necessary to clarify the association between AAS use and meningioma risk.Our findings contribute to existing knowledge but should be viewed as a preliminary investigation rather than conclusive evidence.Abbreviations: AAS: androgenic anabolic steroids, CI: confidence interval, CT: computed tomography, IRR: incidence rate ratios, SD: standard deviation.

Table 1
Differences between AAS users and controls regarding the incidence of meningiomas.