Study the characteristics of surgical meningiomas in patients who have taken ACP and compare this population to a control group that has not taken ACP (Androcur).

Charles Champeaux - Fans ^1.2 · Joconde Weller ³ · Sebastien Froelich ¹ · Agnes Sartor ⁴

Original article here

Summary

Context: Study the characteristics of surgical meningiomas in patients who have taken ACP and compare this population to a control group that has not taken ACP.

Materials and methods : We have processed the French database of the National Health Data System (SNDS) to find the appropriate cases operated between 2007 and 2017.

Results : 

•  1,101 patients (3.8%) who used to gain ACP and underwent meningiom surgery were extracted from a national cohort based on the population of 28,924 patients.
• The median age at the time of the prescription of the ACP was 42 years ei [36,7-48,9]. The median time between the start of the APC and surgery was 5.5 years IS [3,1-7.9]. The median age at the time of surgery was significantly lower in patients treated with ACP (47, IS [42-54]) compared to the population not treated by ACP (61 years old, IS [51-70], p <0.001).
• The median dose of ACP was 40 g, IS [19-72]. There was a strong correlation between the ACP dose and the duration (R = 0.58, 95%CI [0.54-0.62], p <0.001). The base of the average skull was the most frequent location (39%) with an earlier insertion of the base of the skull being also much more frequent compared to the usual population with 21.9% of the tumor.
• This predominance of the skull base for meningiomas associated with ACP is highly significant (p <0.001). The increase in ACP dose has increased the risk of having multiple meningioma surgeries (p <0.001) and multiple locations of meningioma (p <0.001). The classification of tumors was not modified by the treatment with the ACP (p = 0.603).
• Meningiomas benign or grade I represented 92%, atypical or grade II 6.1%and clever or grade III 1.9%.

Conclusion in the past 10 years, a large number of meningiomas induced by the ACP have been removed, modifying the global age pyramid at the time of surgery for patients. These tumors occur long before the usual age and are preferentially located on the anterior and average skull base.

keywords · Cyproterone · SNDS · Progestative · Epidemiology

Abbreviations

 ACP Cyproterone Acetate

IS Interquartile Ecart

1- Department of Neurosurgery, Lariboisière Hospital, 2, rue Ambroise- Pare, 75475 Paris Cedex 10, France

2- Inserm U1153, Statistic and Epidemiologic Research

Center Sorbonne Paris Cité (Cress), Eccsrra Team, University of Paris, Paris, France

3- Regional health agency, 2bis, avenue Georges Brassens, CS 61002, 97743 Saint Denis Cedex 9, France

4- CHU Toulouse, obstetric gynecology pole, Viguier Paule Hospital, 31059 Toulouse, France

Introduction

Méningiomes are generally non -clever neoplasms , slowly growing, from meningothelial cells of the arachnoid. They constitute the most frequent extra brain intracranial tumors representing 36.8 % in the central register of brain tumors in the United States [1]. The 2016 classification of the World Health Organization (WHO) of tumors affecting the central nervous system (SNC) recognizes three grades of meningiomas [2]. Méningiomes de Grade I of WHO, or Méningiomes Benin (MB), occur for two thirds in women and generally have a good evolution [3, 4].

The Méningiomes de Grade III of the MS WHO or Maline Méningiomes (MM) are rare and aggressive neoplasms whose prognosis is bad [5]. The behavior and the outcome of the atypical meningiomas of the Grade II of the WHO (MA) are intermediate [6, 7]. The vast majority (~ 90%) of meningiomas are mild, the malignant forms being rare, representing only 1 to 3% [1, 8].

Although Grade II meningiomas have only been recognized in approximately 5 % of cases, after the changes to the diagnostic criteria in the 2007 WHO classification, they represent around 10 % today. In the most recent classification of the 2016 WHO SNC, no molecular prognostic marker has been introduced for the classification of meningiomas, which is always based solely on histological criteria subject to sampling and observation biases [2].

Support options include regular monitoring , especially in the event of incident meningioma, symptom control, surgical excision, radiation therapy and sometimes chemotherapy, but maximum safe and adapted resection remains the treatment of choice. Most meningiomas are sporadic and their incidence in France is around 5/100,000 people per year [3, 4]. Ionizing radiation is the only unequivocal risk factor identified, although others have been suspected. Proofs suggest the influence of sex hormones because meningiomas are known to be hormonosensitive and generally express progesterone receptors (PR). Despite the abundant expression of PR, which is found in 88% of meningiomas, it is however not known how the expression of PRs is regulated, especially since estrogen receptors are practically absent from these tumors [9, 10].

A progestogen is a drug that produces effects similar to those of natural progesterone. Synthetic or progestin progestins are used alone or in combination with estrogens, most often in hormonal contraception and menopause hormone therapy. They can also be used in the treatment of gynecological conditions, to promote fertility, lower sex hormones to various ends, and for other indications. Previous studies suggest that hormone therapy could play a role in the development of meningiomas. Among all the progestins available in France, cyproterone acetate (ACP) sold under the Androcur® brand which has an anti-Androgen, progestogen and antigonadop effect is indicated in women only in severe hirsutism altering daily life. Exposure for more than a year at high doses of ACP increased the risk of meningioma [11].

The medico -administrative databases (BDMA) are massive deposits of health data collected for various purposes. They may contain requests for reimbursement of medical expenses, health services, medical procedures, prescriptions and diagnostics. BDMAs provide a variety of data already stored with a constant and often increasing collection process [12]. They include a very large population and often the whole nation, which guarantees a high statistical power without bias linked to the representativeness of a sample. BDMA can be used to conduct epidemiological studies and assess medical practices. The use of these databases is less expensive than carrying out specific surveys of dedicated populations by allowing rapid access to the data collected in a standardized format [13].

In this regard, the recent opening of access to the National Health Data System (SNDS) is an excellent opportunity to carry out complete health studies at the national level. The SNDS includes a lot of information such as demographic data, medical and surgical acts with associated diagnoses or the date of death [13]. It is continuously evolving towards an enrichment by medical information [13].

About 3,000 patients are made with meningioma each year in France . There are very few cohort studies on ACP and meningiomas and we know little about the natural history of meningiomas associated with ACP. Using this unique database, we have sought to assess the relationship between ACP and meningiomas withdrawn surgically because to date, such research has not been carried out in France.

Objective

The objective was to assess the characteristics of the meningiomas operated in patients who have taken ACP and to compare this population to a wider control group having not taken ACP.

Material and methods

• We carried out a retrospective study descriptive observational and analytical based on a national population.
• Méningiomes incidents never operated on have not been taken into account in this study ; Only surgically treated tumors have been taken into account . The data has been taken from the National Health Data System (SNDS), the French national medico-administrative database.
• Patients who have undergone surgical resection of meningiom between 2007 and 2017 were included . The cases were extracted using an algorithm combining two variables such as described above: the type of surgical procedure identified by the common classification of medical acts (CCAM) and the main diagnosis according to the international classification of diseases (CIM-10) as described above [3, 14, 15].
• The meningiomas have been classified into 8 anatomical locations according to their insertion in the Dural base, after an additional categorization of the 40 CCAM codes aimed at describing the resection of extra cerebral intracranial tumors. Male patients and those under the age of 18 have not been taken into account in this study. Patients having only had a prescription for a box of ACP were excluded from this study (n = 56).
• The ACP female population has been compared to a larger non -ACP female population serving as a control group . The 56 patients were completely excluded from the analysis and were not transferred to the control group.

Statistical methods

For the description of the cohort presented in Table 1, the continuous variables are reported in the form of a means and standard deviations or medians and interquartile deviations (IS) for non -Gaussian distribution variables; The categorical variables are reported in the form of frequencies and proportions. All tests were bilateral and statistical significance was defined with an alpha level of 0.05 (p <0.05). The analyzes were carried out with the SAS Enterprise guide Version 7.15, the programming language and the R software environment for statistical calculation and graphics (R version 4.0.2 (2020-06-22)) [16]. The statistical program and the workflow were written in R Markdown V2 with RSTUDIO® for dynamic and reproducible research [17].

Results

Population description

• 1,101 women (3.8%) accustomed to ACP and having undergone meningiom surgery were extracted from a national cohort based on the population of 28,924 patients who underwent meningiomal surgery between 2007 and 2017.
• The median age at the time of the prescription of the ACP was 42 years ei [36,7-48,9].
• The median time between the start of the ACP and surgery was 5.5 years IS [3,1-7.9]. The median age at the time of surgery was significantly lower in patients treated with ACP (47 years old, IS [42-54]) compared to the non-ACP population (61, IS [51-70], p <0.001) (Table 1 and fig. 1a, b).
• When they were available, treatment indications were, for example, ovarian dysfunction (3.1 %), endometriosis (2.4 %), hypertrichosis (2.5 %), uterus leiomyoma (1.5 %).
• The median dose of ACP was 40 g , IS [19-72], which corresponds to a median duration of treatment of 5.2 years, IS [2,6-7,7]. 356 patients (32.3 %) received 60 g of ACP or more. There was a strong correlation between the ACP dose and the duration. A long absorption period of the ACP was correlated with a high dose of ACP (R = 0.58, 95%CI [0.54-0.62], p <0.001).
• The base of the average skull was the most frequent location (39%), the insertion of the base of the previous skull is also much more frequent compared to the usual population with 21.9% of the tumor. This predominance of the skull base for meningiomas associated with ACP is highly significant (p <0.001). (Table 1 and fig. 1D).
• A dose of ACP of 40 g or more has significantly increased the risk of having multiple meningiomal surgeries at different moments (11.3 %) (p <0.001) and multiple locations of meningioma (17.3 %) (p <0.001) (fig. 1F).
• If the ACP was associated with a significant change in age at the time of meningioma surgery and its location, the classification of the tumor was however not modified by the treatment with ACP (p = 0.603). Benine or grade I meningiomas represented 92%, atypical or grade II 6.1% and clever or grade III 1.9% (Table 1, fig. 1st).

Table 1 Characteristics of patients (n = 1101)

Variable no cyproterone n = 16 158 Cyproterone n = 1 101 p -Value

Age Surgery (continuous) A 61, 51–70 47, 42—54 <0.001

Classification tumors (5 cat.)

<40 years 1325 (8.2%) 217 ​​(19.7%)

<40 to> 50,2506 (15.5%) 486 (44.1%)

<50 to> 60,3828 (23.7%) 256 (23.3%)

<60 to> 70,4711 (29.2%) 112 (10.2%)

> 70                                         3788 (23.4%)                                                 30 (2.7%)                   < 0.001

Location

Cranial convexity 3817 (23.6%) 254 (23.1%)

Anterior skull base 2038 (12.6%) 241 (21.9%)

FALX CEREBRI 1250 (7.7%) 49 (4.5%)

Average skull base 3303 (20.4%) 429 (39%)

PARSAGITTAL 1515 (9.4%) 52 (4.7%)

Skull posterior base 2147 (13.3%) 64 (5.8%)

Dorsal Epine 1977 (12.2%) 11 (1%)                    < 0.001

Tumor classification

Benign 14,940 (92.5%) 1013 (92%)

Atypical 878 (5.4%) 67 (6.1%)

Maligne 340 (2.1%) 21 (1.9%) 0.6

Dose (g) - 40, 19–72

Duration (years) - 5.2, 2.6—7.7

Time between the start of cyproterone and surgery (years) - 5.5, 3.1—7.9

Time between the end of cyproterone and surgery (years) - 0.2, 0—0.8

Cyproterone stop before surgery - 534 (48.5%)

Judgment of my cyproterone during the last follow -up - 762 (69.2%)

p -The values ​​displayed in bold have reached statistical significance

a median and ei interquartile separateness

Discussion

Main results

In this study, we evaluated the characteristics of meningiomas treated surgically after processing by ACP using the National SNDS French Health Insurance Database . In our main cohort of 28,924 patients, the bimodal form of the curve for female patients makes us wonder about this unusual characteristic not reported previously in epidemiological studies on meningiomas (fig. 1A) [1, 20, 21].

It seems that this unexpected characteristic can be linked to hormonal treatments [22]. Weill et al. identified 253,777 women who used to take at least 3 g of ACP between 2007 and 2014 [22]. The density diagrams of the 1B subfigure confirmed this suspicion and show a distribution of ages at the time of well-separated and much younger surgery for patients who have taken ACP, with a median age at the time of 14-year-old meningioma surgery compared to the non-ACP population (p <0.001). A series of 30 cases confirms our results with an average age at the time of 50 -year surgery for meningiomas induced by the ACP against 58 years for the controlled group [23]. The ACP was the most suspected molecule of being responsible for this second peak at 51 years visible on the 1A subfigure.

Two other molecules, Chlormadinone acetate (Lotéran) and Nomestrol (Lotényl) acetate, also largely prescribed in the French female population, are also suspected of increasing the risk of meningioma and will therefore be studied in the near future [24].

We found a median time between the start of ACP treatment and 5.5 years surgery, IS [3.1-7.9] or about 66.1 g of ACP for uninterrupted treatment of 50 mg per day, 20 days a month for 5.5 years. In fact, the median total dose taken by the patient is a little lower (40 g, IS [19-72]) due to the periods of interruption of treatment. However, meningioma can only develop when a sufficient cumulative dose has been reached for sufficient treatment period.

For Portet et al. 86.7% of 30 patients had prolonged exposure of more than 10 years and Bernat et al. found an average exposure duration of 18.6 years with an average dose of 40 g [23, 25]. Patients who used to take 40 g or more ACP had a significantly higher number of meningiomous locations (17.3%) compared to those who have taken fewer ACP (4%, p <0.001). This is also true for a dose of 60 g (21.1 %, against 5.2 %, p <0.001) and if we take into account the number of neurosurgical interventions (14.3 %) compared to those who took fewer ACP (3.3 %, p <0.001). The resulting curves are sigmoid functions (fig. 1F).

Boundaries

The SNDS strong points reside both in the high number of patients and in the exhaustiveness of the data available from all hospitals in France. The representativeness of the database is almost perfect, since it includes the entire population of the country, or nearly 68 million inhabitants, thus constituting one of the largest BDMA in the world [13].

However, this data was not initially collected for research purposes and they can therefore be subject to random or systematic measurement errors, which can have consequences when defining the populations studied, events and covariables. Important variables such as the quality of resection are not recorded in the SNDS [26]. The retrospective nature of this study, as well as the lack of clarity concerning the reasons for treatment without random assignment, must be taken into account when evaluating the results.

BDMA studies are built from what is available in them, which sometimes limits the possibilities of exploring interesting potential associations. Despite these limits, the SNDS is an invaluable tool to assess the future of meningiomas. It offers an incomparable way to explore associations with other pathologies, drugs or combined treatments that could not be evaluated before. In addition, the use of these databases is less expensive than carrying out specific surveys in dedicated populations.

Interpretation

The role of sex hormones in the development of intracranial meningomes has been proposed as a hypothesis to explain the predominance of these tumors in women. Although this link has long been suspected, it has not been quantified until recently ; previous epidemiological studies that have given contradictory results [27]. WIGERTZ et al. Among the first to find a high risk of meningioma associated with the use of a substitute hormonal treatment [28].

An increased risk has been found in menopausal women who have already used a hormone substitute treatment (rib report (RC) = 1.7 CI 95 % [1.0-2.8]) and in hormonal contraceptives with prolonged action for 10 years or more (RC = 2.7 CI 95 % [0.9-7.5]) [28].

The risk of ACP meningioma has been suspected for the first time in transsexual patients requiring high doses of ACP [29]. CEA-Soriano et al. confirmed the significant increase in the risk of meningioma in three men using high doses of ACP [27]. Other reports on transsexual men-female patients have confirmed these results [30, 31]. Note et al. concluded that transsexual hormonal treatment is associated with a higher risk of meningiomas in transsexuals, probably linked to ACP [32].

observations , often multiple, in users of high doses of ACPs have given rise to suspicion that this substance could promote the rapid growth of pre -existing or new meningiomas. We have therefore legitimately issued the hypothesis that if the ACP stimulates the development of meningiomas, its judgment should lead to the decrease in the tumor. Case studies of regression of meningiomas after stopping the ACP confirmed this idea in women or transsexuals [33, 34].

It was therefore suggested that the conservative management of the meningiomas induced by the ACP could be the best option since spontaneous regression can occur after stopping treatment, including the improvement of symptoms [35].

Current practice in the event of probable meningioma induced by the ACP is stopping treatment and regular monitoring by MRI (https: //www.ema.europ A.eu/en/News/restrictio ns-use-usecy teron e-due-meningioma -risk ) [25, 33-37].

Generalization

The ACP is indicated in severe hirsutism possibly linked to a syndrome of polycystic ovaries with a dosage of 50 mg per day. In fact, it was widely used in France, often outside its official indication as for example means of contraception, acne treatment or ovarian dysfunction.

Weill et al. found that around 80% of ACP prescriptions were outside official indications [22]. We can assume that the ACP was mainly used as a means of contraception in our cohort, since only 14.5 % of patients had a related diagnosis of gynecological or endocrine problem. ACP is also present in smaller quantities (2 mg) in combined oral contraceptives to treat seborrhea, acne, hypertrichosis and moderate alopecia linked to androgens. Weill et al. found a relative risk of meningioma of 6.6 CI95% [0, 1, 4, 11] above 3 g of ACP and a marked dose effect (Hazard Ratio adjusted = 21.6 CI95% [5, 8, 10, 43]) above 60 g [22].

For Gil et al. Patients exposed to high doses of ACP showed an increased risk of meningioma of 11.4 95%CI [4.3-30.8] [11]. Although the association between ACP and the development of intracranial meningiomas is now established, the underlying mechanisms remain unknown. It was quickly noticed that the meningiomas induced by the ACP probably developed near the base of the skull and preferentially on the previous or average part [29]. In our study, the meningiomas induced by the ACP at the base of the skull were the most frequent (39%), unlike the cranial convexity which is the unquestionably the most usual location in the general population with 23.6% in the main cohort study.

For Portet et al. A significant relationship links the ACP and the location of the skull base where 86.7% of the meningiomas were inserted [23]. In addition, Bernat et al. suggested that patients with multiple tumors used ACP for a longer period (20.4 years on average) than the two patients with a single meningioma (10 years).

ACP does not promote the occurrence of aggressive meningiomas, a conclusion supported by the study of Portet et al. which has also found a positive association between meningothelial or microocystic histology and ACP [23].

In October 2018, the National Agency for the Safety of Medicines and Health Products had issued several recommendations, including the need to follow a more rigorous indication of prescription and to carry out a brain MRI at the start of treatment and regularly from ACP treatment cannot be deleted (severe hirsutism). This orientation was reinforced in July 2019 by the obligation for the prescriber to inform the patient annually of the risk associated with the meningiom of the ACP who must in return fill and co -signing a certificate to obtain the treatment in pharmacy. Thus, the level of prescription of the ACP which was authorized in France in 1980 dramatically decreased.

The conservative management of meningiomas induced by the ACP being the recommended attitude given the usual regression after stopping treatment , combined with the drastic decrease in the prescription of ACP, we should observe in the near future, a slight decrease in the frequency of resection of meningiomas around 50 years and therefore the disappearance of this bimodal distribution.

Conclusion

Over the past 10 years, a significant number of meningiomas induced by the ACP have been removed, modifying the global age pyramid at the time of surgery for patients. These tumors occur long before the usual age and are preferentially located on the anterior and average skull base.

Acknowledgments The authors would like to thank Marjorie Boussac, Julius Kemme, and El Mehdi Gabbas du Cnam for their help in the extraction of the data.

Contributions of CC authors : design and design, data acquisition, data analysis and interpretation; Drafting and revision of the manuscript, final approval. JW: design and design, data acquisition, data analysis and interpretation; Revision of the manuscript, final approval. SF: Design and design. AS: design and design, revision of the manuscript, final approval.

None funding

Availability of data and restricted equipment , the authors do not have permission to share the data. Availability of the code on request.

Compliance with ethical standards

Conflict of interest the authors declare that they have no conflict of interest.

Ethical approval This study was conducted according to ethical directives for epidemiological research in accordance with the ethical standards of the Helsinki Declaration (2008), with the National Commission for Data Protection (CNIL), an independent national ethics committee, authorization number: 2008538; According to record directives for studies carried out from health data collected routine and, according to SAMPL directives [18, 19].

Informed consent The informed consent was not required due to the retrospective nature of the study. The SNDS crypt the personal information of patients to protect confidentiality and provides researchers from anonymous identification numbers.

References

1. Ostrom QT, Gittleman H, Liao P, Vecchione-Koval T, Wolinsky Y, Kruchko C, Barnholtz-Sloan JS (2017) CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Tumors Diagnosed in the United States in 2010–2014. Neuro-oncology 19: V1–V88
2. Louis Dn, Perry A, Reifenberger G, Von Deimling A, Figarella- Branger D, Cavenee WK, Ohgaki H, Wiestler Od, Kleihues P, Ellison DW (2016) The 2016 World Health Organization Classification of Tumors of the Central Nervous System: A Summary. Acta Neuropathol 131: 803–820
3. Champeaux C, Weller J, Katsahian S (2018) Epidemiology of meningiomas. A Nationwide Study of Surgically Treated Tumours on French Medico-Administrative Data. Epidemiol cancer 58: 63–70
4. Zouaoui s, Darlix A, Rigau v et al (2015) Descriptive Epidemiology of 13,038 newly diagnosed and histologically confirmed meningiomas in France: 2006–2010. Neurosurgery. https: //doi.org/10.1016/j.neuch I.2014.11.013
5. Champeaux C, Jecko V, Houston D, Thorne L, Dunn L, Fersht N, Khan Aa, Resche-Rigon M (2018) Malignant Meningioma: An International Multicenter Retrospective Study. Neurosurgery. https://doi.org/10.1093/neuro s/nyy61 0
6. Champeaux C, Houston D, Dunn L (2017) Atypical Meningioma. In Study on reappetence and disease-Specific survival. Neurosurgery 63: 273–281
7. Champeaux C, Dunn L (2016) World Health Organization Grade II Meningioma: A 10-Year Retrospective Study for Revance and Prognostic Factor Assessment. World Neurosurg 89: 180–186
8. Hanft S, Canoll P, Bruce Jn (2010) A Review of Malignant Meningiomas: Diagnosis, Characteristics, and Treatment. J Neurooncol 99: 433–443
9. Blankenstein MA, Verheijen FM, Jacobs JM, Donker Th, Van Duijnhoven MW, Thijssen JH (2000) Occurrence, Regulation, and meaning of Progesterone Receptors in Human Meningioma. Steroids 65: 795–800
10. Goffin J (1986) Estrogen- and Progesterone-Receptors in Meningiomas. Review article. Clin neurol neurosurg 88: 169–175
11. Gil M, Oliva B, Timoner J, Maciá Ma, Bryant V, De Abajo FJ (2011) Risk of Meningioma Among Users of High Doses of Cyproterone Acetate as Compared With the General Population: Evidence from Population-Based Cohort Study. BR J Clin Pharmacol 72: 965–968

12. Gavrielov-yusim n, Friger M (2014) Use of Administrative Medical Databases in Population-Based Research. J Epidemiol Community Health 68: 283–287
13. Tuppin P, Rudant J, Constantinou P et al (2017) Value of A National Administrative Database To Guide Public Decisions: From the National Information System Interregic Health Insurance (SNIIRAM) To the National System of Health Data (SNDS) in France. Rev Epidemiol Sante Public 65 (Suppl 4): S149–S167
14. Champeaux-Deland C, Constantinou P, Weller J (2020) Causespecific survival after meningioma Surgery: A Nationwide Population- Based Competing Risk Study. World Neurosurg. https: //doi.org/10.1016/j.wneu.2020.10.012
15. Champeaux-Deland C, Weller J, Resche-Rigon M (2020) Neurofibromatosis Type 2: A Nationwide Population-Based Study Focused on Survival after meningioma Surgery. Clin neurol neurosurg 198: 106236

16. R Core Team (2014) R: a Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna
17. RSTUDIO Team (2015) RSTUDIO: Integrated Development Environment for R. RSTUDIO INC, Boston
18. Lang Ta, Altman DG (2015) Basic Statistical Reporting for Articles Published in Biomedical Journals: The “Statistical Analysis and Methods in the Published Literature” or the Sampl Guidelines. Int j nurs Stud 52: 5–9
19. Nicholls SG, Quach P, Von Elm E, Guttmann A, Moher D, Petersen I, Sørensen HT, Smeeth L, Langan SM, Benchimol EI (2015) The Reporting of Studies Conducted Using Observational Routinery-Collected Health Data (Record) Strict Guidelines reporting. PLOS ONE 10: E0125620

20. Baldi I, Engelhardt J, Bonnet C, Bauchet L, Bertaud E, Grüber A, Loiseau H (2014) Epidemiology of meningiomas. Neurosurgery. https: //doi.org/10.1016/j.neuch I.2014.05.006
21. Cea-Soriano L, Wallander Ma, García Rodríguez la (2012) Epidemiology of Meningioma in the United Kingdom. Neuroeidemiology 39: 27–34
22. Weill A, Nguyen P, Yoldjian I, Fontanel S, Froelich S, Coste J (2020) prolonged exposure to high doses of cyproterone acetate and risk of meningioma in women: a public health research in France. Epidemiol Reve Public Health 68: S3–S4
23. Portet S, Naoufal R, Tachon G, Simonneau A, Chalant A, Naar A, Milin S, Bataille B, Karayan-Tapon L (2019) Histomolecular Characterization of Intracranial Meningiomas Developed in Patients Exposed to High-Dose Cyproterone Acetate: An Antiandrogen Treatment. Neurooncol adv. https: //doi.org/10.1093/noajn l/vdz00 3
24. Passeri T, Champagne Po, Bernat Al, Hanakita S, Hall H, Mandonnet E, Froelich S (2019) Spontaneous Regression of Meningiomas after Interruption of Nomegestrol Acetate: A Series of Three Patients. Acta Neurochir (Wien) 161: 761–765
25. Bernat Al, Oyama K, Hamdi S, Mandonnet E, Vexiau D, Pocard M, George B, Froelich S (2015) Growth Stabilization and Regression of Meningiomas after Discontinuation of Cyproterone Acetate: A Case Series of 12 Patters. Acta Neurochir (Wien) 157: 1741–1746
26. Simpson D (1957) The Reverse of Intracranial Meningiomas After Surgical Treatment. J neurol neurosurg psychiatry 20: 22–39
27. Cea-Soriano L, Blenk T, Wallander Ma, Rodríguez Lag (2012) Hormonal Therapies and Meningioma: Is there a link? Epidemiol cancer 36: 198–205
28. WIGERTZ A, Lönn S, Mathiesen T, Ahlbom A, Hall P, Feychting M, Swedish Intercom Study Group (2006) Risk of Brain Tumors Associated With Exogeuvous to Exogengous Female Sex Hormones. AM J Epidemiol 164: 629–636
29. Gazzari R, Galarza M, Gazzi G (2007) Growth of A Meningioma in a transsexual patient after Estrogen-Progestin Therapy. N Engl J Med 357: 2411–2412
30. Raj R, Korja M, Koroknay-Pál P, Niemelä M (2018) Multiple MeningiMas in Two Male-to-Female Transsexual Patients With Hormone Replacement Therapy: A Report of Two Cases and A Brief Literature Review. Surg neurol int 9: 109
31. Mancini I, Rotilio A, Coati I, Seracchioli R, Martelli V, Meriggiola Mc (2018) Presentation of A Meningioma in a transwoman after nine Years of Cyproterone Acetate and Estradiol Intake: Case Report and Literature Review. Gynecol Endocrinol 34: 456–459
32. Note nm, wiepjes cm, from Blok CJM, Gooren LJG, Peerdeman SM, Kreukels BPC, Den Heijer M (2018) The occurrence of Benign Brain Tumours in Transgender Individuals During Cross-Sex Hormone Treatment. Brain 141: 2047–2054
33. Gonçalves AMG, Page P, Domigo V, Méder JF, Oppenheim C (2010) Abrupt Regression of A Meningioma after Discontinuation of Cyproterone Treatment. AJNR AM J Neuroradiol 31: 1504–1505
34. Cebula h, Pham TQ, Boyer P, Froelich S (2010) Regression of meningiomas after discontinuation of cyproterone acetate in a transsexual patient. Acta Neurochir (Wien) 152: 1955–1956
35. Bernat Al, Bonnin S, Labidi M, Aldahak N, Bresson D, Bouazza S, Froelich S (2018) Regression of Giant Olfactory Groove Meningioma and Complete Visual Acuity Recovery after Discontinuation of Cyproterone Acetate. J Ophthalmic Vis res 13: 355–358
36. Botella C, Coll G, Lemaire JJ, IRTHUM B (2015) Intra Cranial Meningiomas and Long Term Use of Cyproterone Acetate With A Convention Dose in Women. A Report of Two Cases of Tumor Decrease after treat withdrawal. Neurosurgery 61: 339–342
37. Zairi F, Aboukais R, Le Rhun E, Marinho P, Maurage CA, Lejeune JP (2017) Close Follow-up-up after discontinuation of Cyproterone Acetate: a possible option to Ferry in Patients with voluminous intracranial meningioma. J Neurosurg SCI 61: 98–101

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