Meningioma in patients exposed to progestins: results of a real life screening program

Thomas Samoyeau1,2,3 · Corentin Provost1,2,3 · Alexandre Roux1,2.4 · Laurence Legrand1,2,3 ·

Edouard dezamis1,2,4 · Geneviève Plu - Bureau2,5.6 · Johan Pallud 1,2.4 · Catherine Oppenheim1,2,3 ·

Joseph Benzakoun1,3

https://pubmed.ncbi.nlm.nih.gov/36066786/

Received: 4 August 2022 / Accepted: 26 August 2022

© The Author (s), under exclusive license to springer science+business media, LLC, part of Springer Nature 2022

 

Summary

Objective : to report the results of the systematic meningioma screening program implemented by French authorities in patients exposed to progestin treatments (Cyproterone (ACP), Nomestrol (AN) and ChlormaDinone (ACM)).

Methods: We conducted a prospective monocentric study on patients who, between September 2018 and April 2021, benefited from a standardized MRI (Gadolinium injection, then a T2 Flair axial sequence and a 3D-T1 sequence in gradient echo) for meningioma screening.

Results: out of the 210 patients included , 15 (7.1%) had at least a meningioma; Seven (7/15, 47%) had multiple meningiomes. Meningiomas were more frequent in older patients and after exposure to ACP (13/103, 13%) compared to year (1/22, 4%) or ACM (1/85, 1%; p = 0.005). After exposure to ACP, meningiomas were associated with a longer treatment time (median = 20 vs 7 years, p = 0.001) and a higher cumulative dose (median = 91 g vs 62 g, p = 0.014). Likewise, their multiplicity was associated with a higher dose of ACP (median = 244 g vs 61 g, p = 0.027). Most meningiomas were ≤ 1 cm3 (44/58, 76 %) and were convexity meningiomas (36/58, 62 %). At the time of diagnosis, patients were non -symptomatic and all were covered in a conservative manner. Among the 14 patients with meningioma who stopped exposure to progestins, the Meningioma burden decreased in 11 cases (79 %), without any progress during RM follow -up.

Conclusion: Systematic screening by RM in patients exposed to progestins makes it possible to discover small and multiple meningiomas, which can be managed in a conservative manner, their size decreasing after stopping progestins. The high rate of meningiomas after exposure to ACPs reinforces the need for systematic screening . For the year and the ACM, additional studies are necessary to identify the patients most likely to benefit from screening.

Keywords Cyproterone acetate ・ Chlormadinone acetate ・ Nomestrol acetate ・ Mesningioma ・ Mass screening

 

Introduction

Meningiomas are the most frequent primary tumors of the central nervous system [1]. The risk factors for meningioma are age, female sex, personal history of cranial irradiation, family history of meningiomas and type II neurofibromatosis [2]. The relationship between meningiomas and sex hormones is supported by female predominance, the increase in the volume of the tumor during pregnancy and its narrowing after childbirth, associations with breast cancer [3] and the expression of progesterone receptors in two thirds of meningiomas [4]. Progestatives are synthetic drugs with antiandrogen and progesterone activity. They include cyproterone acetate (ACP), Chlormadinone Acetate (ACM) and Nomestrol Acetate (AN). The ACP is both a powerful antagonist of androgens and a progesterone receptor agonist (1000 times more powerful than native progesterone) [5]. The ACM then the year, with lower anti-androgenic and progestogen properties, were marketed later [5, 6]. They are used in various indications, mainly against major female hirsutism [5] (ACP), endometriosis, menopause disorders [7] (ACM, AN), and hyperandrogen symptoms of polycystic ovary syndrome [8] (ACP).

The use of progestins has long been suspected of promoting the training and growth of meningiomas [9-24]. A reduction in the tumor volume after stopping progestins has also been reported for ACM [10], ACP [11, 19, 20, 25, 26] and the year [27, 28], suggesting that the stopping of the taking of progestins and conservative management could be the first -line strategy for meningiomas linked to progestins [29]. Several epidemiological studies have highlighted a high risk of developing meningiomal requiring invasive treatment. This risk was higher for the ACP than for ACM and the year, was a dose-dependent and decreased after stopping progestogen [30, 31]. Recently, a meta-analysis confirmed the association between ACP and Meningioma and validated the need for imaging before undertaking an ACP treatment [32]. These studies have led to French recommendations for systematic MRI screening in patients exposed to progestins [33]: from September 2018 for ACP, and June 2020 for ACM and year [34].

This national systematic screening as well as the information given to clinicians and patients led to a sudden increase in MRI examinations in asymptomatic patients. However, these detected patients were not targeted in previous studies which mainly focused on symptomatic meningiomas, often surgically treated. Consequently, the percentage of asymptomatic meningiomas in the detected population and their type of care, as well as the possibility of detecting other brain lesions (fortuitous or associated with the progestogen) are still uncertain. Our objective is therefore to report the performance of real life screening of meningiomas in this population, in particular their prevalence, the characteristics of MRI and the care they have received in our neurosurgical center.

 

Methods

Study and population design

We conducted a monocentric prospective cohort study including consecutive patients exposed to the progestins referred between September 2018 and April 2021 for an MRI MRIM of MERINGIOME. During this period, via a dedicated email address, we set up an accelerated MRI procedure coupled with the expertise of a neurosurgeon as soon as a meningioma or another accidental lesion was discovered. Patient associations, ambulatory practitioners and hospital services were informed of this procedure. All individual patients have received an online form collecting clinical and hormonal history, and enlightened consent to participate in the study has been obtained. The inclusion criteria were: an age ≥ 18 years, a history of progestin drug treatment (that is to say ACP, ACM or AN), a brain MRI programmed in the context of systematic screening and written enlightened consent. The exclusion criteria were as follows: refusal to participate in the study, anterior diagnosis of meningioma, contraindicates the use of gadolinium and/or MRI, orientation towards an MRI before the initiation of treatment, exposure to a low dose of the ACP (2 mg/day) associated with estrogens, not targeted by systematic screening.

 

Clinical data

We have collected the following data: type of progestin used, history of hormonal drugs, indication of processing, date of initiation and duration of processing, rate and dose of taking and, if necessary, date of stopping treatment. The cumulative dose of progestin was calculated by multiplying the dose, the pace of taking and the duration of exposure. In the event of multiple exposure to progestins, patients were grouped according to the most recent treatment. The incidence per year-person has been obtained by dividing the number of meningiomas by the product of the total exposure duration and the number of patients exposed to the progestogen. We have also collected other known risk factors for meningioma (personal history of cranial irradiation, type II neurofibromatosis, pregnancy and family history of meningioma). Although theoretically asymptomatic, patients were invited to share their recent clinical complaints (<12 months), such as headaches, nausea, epilepsy and visual disorders.

Screening MRI

Brain MRI was carried out on a 1.5 Tesla (Explorer, General Electric Healthcare) or 3 Tesla (MR 750, General Electricare Healthcare) device with a standardized protocol: 0.2 ml/kg injection of Dotaremr (gadoteric acid, Guerbet) 5 min before a T2 axial (Fluid-tentenuated inversion Recovery) and a 3D sequence T1-Weighted Gradient-Echo (≈ 6 min of total acquisition time) (see table S1). The RM images were analyzed in consensus by two radiologists (with respectively 5 years and 1 year of experience), which searched the meningiomas and the fortuitous discoveries.

Meningioma has been defined as an extra-axial and dural mass, with a strong and homogeneous enhancement after injection of contrast [35], confirmed in consensus by the two readers. The following imaging characteristics have been collected: number of meningiomas, location, volume, obstruction of the venous sinus, enhancement, serious mass effect (that is to say, causing obstructive hydrocephalus or cerebral hernia), brain edema, bone reaction and extracranial extension.

The volumes were calculated on the reinforced sequence in T1 3D weighting. Using a semi-automatic segmentation based on a threshold in PACS View (Philips Healthcare), we have obtained a volume of interest (Vo) surrounding the tumors and have corrected it manually if necessary. The volume was calculated automatically by adding the individual volume of each Voxel in Vo. For each patient, the tumor load was calculated by adding the volume of each meningioma.

Management of patients and MRI monitoring

Patients in whom meningioma was diagnosed or who have been the subject of fortuitous discoveries were sent to a senior neurosurgeon (14 years of experience). As far as possible, progesterone was arrested by the referent clinician. In the event of a conservative treatment, a monitoring MRI was scheduled every six months for a year, then every year. Volumetric analysis has been repeated with each monitoring MRI. A change of more than 15 % of the volume or the tumor load was considered significant, as proposed by others [36].

Statistical analyzes

The contingency tables were analyzed using the exact Fisher test. The continuous variables (age, duration of treatment and cumulative ACP) were compared using the Mann-Whitney test. The data was expressed in the form of a median and interquartile interval (IQR). The characteristics of the meningiomas were expressed on average ± standard deviation (SD), for comparison with previous studies. The correlation between the tumor load, the cumulative dose and the duration of exposure to the ACP was evaluated using the Spearman correlation coefficient (RHO). The meaning threshold used was p = 0.05. Statistical analyzes were carried out using Python 3.6.5.

Results

Population and prevalence of meningioma

Among the 243 patients referred during the study period, 210 met the inclusion criteria (fig. 1). The clinical characteristics at the start are summarized in Table 1. Most patients (n = 114, 54%) were sent by gynecologists. There were 209 women and a transgender man-woman. The median age (IQR) was 38 (30-46) years. No patient had a history of skull or neurofibromatosis of type II. Fifteen (7.1 %) of the 210 patients had at least meningioma, with multiple meningiomas in seven (47 %) patients. As shown in Table 1, patients with meningioma were significantly older than those who did not, but did not differ significantly as to the number of pregnancies, the family history of meningioma, the indication of a progestogy treatment or clinical complaints. None of the meningiomas were considered symptomatic.

Treatment associated with the appearance of meningiomas

As shown in Table 1, the appearance of at least a meningioma was significantly more frequent in the ACP group (13/103, 13%) than in groups year (1/22, 4%) and ACM (1/85, 1%) (p = 0.014). Detailed drug history is available in Table S2. The incidence of meningioma was 13.2 per 100,000 years in the ACP group (not calculated for groups An and ACM due to a single case of meningioma in each group).

In the ACP group, patients with at least one meningioma had a longer treatment duration (median: 20 (8-24) years against 7 (3-12) years, p = 0.001) and received a greater cumulative dose (91 g (61-244) against 62 g (37-97), p = 0.014) than patients without meningioma (fig. 2). Among the 13 patients with Méningiome of the ACP group, the six patients with multiple meningomes received a greater cumulative dose of ACP than those with a single meningioma (244 g (192-286) vs. 61 g (49-88), p = 0.027).

 

Table 1 Characteristics of the population

No meningiom meningioma value P

195 patients 15 patients

 

Women, n (%) 194 (99.5) 15 (100) 1

Age, median (IQR) 38 (29-46) 47 (45-52) 0.003

 

Last progestin, n (%) ^has

ACP (n = 103) 90 (87) 13 (13) 0.005

ACM (n = 85) 84 (99) 1 (1)

An (n = 22) 21 (95) 1 (5)

 

Family history of

Méningiome, n (%) 10 (5) 0 -

 

Previous pregnancy ^B ,

n (%) 49 (25) 3 (21) 1

 

Referential doctor, n (%)

Gynecologist 102 (52) 12 (80) 0.057

General practitioner 25 (13) 1 (7) 0.700

Endocrinologist 22 (11) 2 (13) 0.683

Dermatologist 3 (1) 0 -

Psychiatrist 3 (1) 0 -

Other 3 (2) 0 -

Not available 37 (18) 0

–

Indication of the progestin drug, n (%)

Contraception/Treatment

Anti-Gonadotrophin 88 (45) 4 (27) 0.188

Endometriosis 52 (27) 5 (33) 0.557

Hirsutism 38 (19) 3 (20) 1

Polycystic ovary syndrome 37 (19) 4 (27) 0,500

Acne 36 (18) 4 (27) 0.493

Alopecia 9 (5) 0 -

Transgender hormone therapy 1 (1) 0 -

Others (mastodynia, severe dysmenorrhea, ovarian cyst, fibroids, menorrhagia) 14 (7) 0 -

 

Clinical symptoms, n (%) 69 (35) 6 (40) 0.782

Unusual headache 45 (23) 2 (13) 0.529

Morning nausea 22 (11) 3 (20) 0.397

Neurological complaints

Visual disorders 31 (15) 2 (13) 1

Dizziness 6 (3) 1 (7) 0.409

Parasthesia 3 (1) 0 -

Hearing loss 2 (1) 0 -

Others (for example asthenia, drop in libido,

Light cognitive disorders) 7 (4) 1 (7) -

 

IQR Interquartile interval, ACP Acetate of Cyproterone, ACM Acetate of Chlormadinone, an acetate of Nomestrol

^A for this line, the percentages are calculated according to the last taking of progestin.

^B For this analysis, a transsexual man-woman has been excluded.

 

A greater cumulative dose and a longer treatment duration have been observed in the only patient with meningioma in each of the ACM and An ACM groups.

 

Méningiomes imaging characteristics during MRI screening

Detailed and illustrative cases are provided in Figure 3 and Table S3. Among the 15 patients with meningioma, there was an average of 3.9 ± 5.0 tumors per patient, with a maximum of 17. The average tumor load was 2.66 ± 4.39 cm ³ . Among the 13 cases of meningiomas exposed to the ACP, the tumor load was not significantly correlated with the cumulative dose (RHO = 0.38, p = 0.20) nor to the duration of exposure to the ACP (RHO = 0.49, p = 0.09). At the time of diagnosis, meningiomas were in most cases ≤ 1 cm ³ (44/58, 76 %) and they had an average volume of 0.68 ± 0.83 cm ³ (interval 0.01-3.66). With the exception of a meningioma located in the Ponto-Cerebellerian corner, all were supratotory: 36 (62 %) on convexity, 12 (21 %) on the basis of the average skull and 9 (16 %) on the basis of the anterior skull; 13 (22 %) were in contact with the dural sinuses without venous obstruction. All meningiomas have enhancely enhanced after injection of contrast and none was responsible for brain edema or severe mass effect. Fifteen (26 %) were associated with cranial hyperostosis. An extracranial extension through the base of the skull (fig. 3F) and a sheet in sheet (meningioma “in plate”) (fig. 3g) were observed, each in one case (2%).

Patient management and monitoring by MRI

All meningiomas have been considered asymptomatic, even in the six patients with clinical complaints (Table 1). Consequently, a conservative approach with monitoring by MRI was offered to 15 patients with meningioma. Among these, seven had stopped progesterone at the time of MRI screening and seven had arrested a few days after screening; In these 14 patients, median monitoring by MRI was 18 (10.5-25) months. The tumor load decreased in 11 (79%) case (fig. 4). In the remaining case (Case 9, Table S2), a multidisciplinary team recommended to continue the ACP; The 0.15 cm ³ increased slightly, but remained below the predefined threshold of 15 % during the 24 months of follow -up. Overall, no case has shown an increase in tumor load or new meningioma.

Similar results were observed on the analysis by Meningioma after stopping the progestogen (n = 57): 40 (70%) regressed during follow -up, 17 (30%) remained stable and none increased. The average tumor reduction rate was 0.44 ± 0.64 mm3/ day, or 0.16 ± 0.23 cm3/ year.

Fortuitous discoveries

Ten patients (4.7 %) presented incidentalomas that required specific care:

• 4 intracranial aneurysms (one of them was treated by surgical clipping),
• 2 non -secreting pituitary microadenomas (both exposed to ACP, conservative treatment),
• A probable diffuse low grade glioma (ACM presentation, currently followed by MRI),
• 2 cavertens (one presentation to the ACP, the other to ACM, conservative treatment),
• And a single case of idiopathic intracranial hypertension (ACM exposed, conservative treatment).

Discussion

In this monocentric prospective study, initiated after the French recommendations for systematic screening for meningiomas by MRI in patients exposed to progestogen treatment, 15 patients out of 210 (7.1%) had at least one meningioma .

We observed that:

• (1) Meningiomas were more frequent in patients whose last exposure to progestins was at ACP (13%) than in those exposed to the year (5%), or ACM (1%);
• (2) In the ACP group, the occurrence of meningiomas was associated both with the duration of treatment and the cumulative dose, the latter being higher in the event of multiple meningiomas;
• (3) The meningiomas were typically small and multiple, preferentially located on convexity, and none of them was symptomatic;
• (4) After stopping progestin, the tumor load of meningiomas decreased in 79 % of patients and remained stable in others.

This is the first study evaluating the efficiency of systematic screening for meningiomas by MRI in patients exposed to progestins , in accordance with French national recommendations.

The rate of incidence of meningiomas in our study (13% under treatment by ACP) was much higher than that of the general population, since fortuitous meningiomas were found only in 2.3% of the subjects in autopsy [37] and 1% in two other large cohorts [38, 39].

The rate we report does not reflect all the meningomes associated with ACP, since most symptomatic meningiomas have probably been diagnosed before the launch of systematic screening by RM.

Our study completes the great study of previous national cohort focused on meningiomas associated with high -dose ACP and oriented towards neurosurgical resection or radiotherapy [30]. Despite the small size of the ACM and AN (with a single case of meningioma in each of them), the prevalence among ACM users (1 %) and year (5 %) is consistent with a lower meningioma risk under these drugs than in ACP users, as has been reported in the large epidemiological cohort centered on the surgically treated meningiomas.

The main strength of this study lies in its "real life" approach . Indeed, many retrospective cohorts and a meta-analysis have already established the link between progestins and meningiomas [30-32]. However, the yield of RM screening proposed by the French authorities was unknown, in particular with regard to the expected detection rate, and the characteristics of imaging of meningiomas discovered in a pauci/asymptomatic population. Another distinctive point is the prospective inclusion of patients, which guarantees the absence of RM during screening.

Overall, the meningiomas associated with progesterone discovered by systematic screening by RM were all asymptomatic, small, and none of them had a mass or edema effect . An important result of systematic screening is the high rate (47%) of multiple meningiomes in this study , compared to a rate of 1-10% in the general population [40, 41]. This confirms the results of previous studies which also found a multiple meningioma rate as high as 48% [29, 42, 43] in the meningiomas induced by progesterone.

The association between multiple meningiomas and the cumulative dose of ACP is consistent with the recent results concerning surgical meningiomas, based on the database of French national medical records [44]. Overall, this strengthens the hypothesis of a critical role of the taking of progestins in the induction of the tumor initiation of multiple specific meningeal cells in several places [43]. This also reinforces the idea that anterior exposure to progestins must be sought in depth in the event of multiple meningiomas [24, 43] , even if they are small and asymptomatic.

Unlike the great national cohort and the previous series of meningiomas associated with the ACP treated with neurosurgery [30, 44], the most frequent location in our series was convexity and not the base of the skull . This difference can be explained by the fact that the meningiomas of convexity remain silent until they become important when the meningiomas of the base of the skull are more likely to be symptomatic due to the proximity of the cranial nerves.

After stopping the progestin, the tumor load decreased over time in 79% of patients when it remained stable in others. Overall, this evolution of tumors is surprisingly different from the natural history of incident meningiomas without exposure to the progestogen, which have growth over time in more than 60 % of cases [36, 45] and do not decrease. The speed of absolute growth by meningioma that we report here is, however, 10 times lower than that found previously in progestin users (average, 0.44 vs 5.8 mm3 ³ /day in [42]). This apparent divergence can be explained by the much smaller size of meningiomas in our series.

Another strong point of this study is that all patients were subjected to a standardized 6 -minute protocol during screening and during RM follow -up. The administration of Gadolinium in the preparation room optimizes the workflow of patients and increases the sensitivity of the T2-Flair sequence for the detection of extra-axial lesions. Due to the concerns concerning the deposit of gadolinium in the brain [46], the use of an MRI without contrast is often preferred. Although it can be appropriate for monitoring unrealized meningiomas [47], additional studies are necessary to assess whether IRM without strengthening is sufficient for detecting small meningiomas.

All systematic screening exposes patients to the risk of unexpected incident lesions. Their rate and guy were located in the range of other cohorts [39]. Among them, none was probably linked to the progestogen. Although pituitary adenomas have been reported in human-female transgender exposed to ACP [22], in these cases, the ACP was coupled with estrogens, known to promote pituitary adenomas.

Our study has several limits.

First of all, this is a monocentric study with a limited size sample. However, patients were referred by multiple sources. The population examined is therefore probably representative of a wide range of patients exposed to progestins.

Second, we have chosen to group the patients according to the latest progestogen received. This practical approach was aimed at limiting the recall bias inherent in studying hormonal treatments. This led to an underestimation of hormonal exposure in three patients with meningioma, as detailed in Table S2.

Third, some patients addressed by their practitioner have not been strictly targeted by the systematic mr's systematic screening, since they had recently stopped their treatment. Indeed, the pharmacovigilance alert has undoubtedly increased the level of anxiety and non -focal diffuse neurological complaints in patients exposed to progestins. This lived experience could have lowered the meningioma levels discovered.

Fourth, patients were more frequently exposed to ACP than to ACM and year, since French health recommendations for systematic screening first focused on ACP, before being extended to the year and ACM [33, 34].

Fifth, all lesions of dural origin at MRI with typical imaging characteristics have been considered as meningiomas, without histopathological confirmation. However, in a previous study, all the dural lesions removed surgically corresponded to meningiomas with histopathological analysis [29].

Sixthly, the temporal evolution of meningiomas after stopping treatment must be interpreted with caution since the initial kinetics were truncated in patients who stopped treatment before screening, and that we cannot exclude that these meningiomas have already partially shrunk. In addition, the duration of the follow -up was relatively short and some meningiomas will probably continue to decrease in size.

Finally, our observational study did not evaluate blood progestogen activity or the presence of estrogen and progesterone receptors on discovered meningiomas. Indeed, a previous pathological study reported that meningiomas expressed progesterone receptors in more than two thirds of cases , supporting causality between taking progestins and the growth of meningiomas [4]. The relationship between blood progestogen activity and the expression of hormonal receptors in meningiomas induced by progestins could be interesting for future studies.

In conclusion, the high rate of meningiomas reinforces the need for systematic screening by RM , especially in patients exposed to ACP. According to our real experience, the meningiomas detected by the systematic screening program are mostly small, multiple, asymptomatic and likely to decrease after the stop of the progestogen. The lower meningioma rate in patients exposed to the year and to ACM calls for additional studies to determine how to target patients most likely to benefit from screening.

 

Additional information The online version contains additional information available on the https: // DOI website. Org/ 10. 1007/ S11060- 022-04124-2.

Thanks Mr. Thomas Boulliung (Paris, France) has kindly provided statistical advice for this manuscript.

Contributions of the authors all the authors contributed to the design and design of the study. The design of the study was established in collaboration with CO, JP and JB. The preparation of the equipment, the collection and analysis of the data were carried out by TS, JB and CO. The first version of the manuscript was written by TS and all the authors carried out a critical review of the manuscript. All the authors have read and approved the final manuscript.

Financing the authors declare that no funds, grant or other support was received during the preparation of this manuscript.

Data availability The data sets generated and/or analyzed during this study are available from the corresponding author on reasonable request.

Statements

Competing interests The authors have no financial or non -financial interest relevant to disclose.

Ethical approval in accordance with French legislation, the formal approval of an ethics committee was not required and the commitment to comply with the rules of compliance has been completed with regard to the General Data Protection Regulations (reference TDCP-Gest-16, University of Paris).

References

1. Ostrom QT, Gittleman H, Truitt G et al (2018) CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2011–2015. Neuro-oncol 20: 1–86. https: // doi. Org/ 10. 1093/ Neuonc/ Noy131
2. Wiemels J, Wrensch M, Claus EB (2010) Epidemiology and Etiology of Meningioma. J Neurooncol 99: 307–314. https: // doi.org/ 10. 1007/ s11060- 010-0386-3
3. Baldi I, Engelhardt J, Bonnet C et al (2018) Epidemiology of meningiomas. Neurosurgery 64: 5–14. https: // DOI.org/ 10.1016/ J. Neuchi. 2014. 05. 006
4. Pravdenkova S, Husain M (2006) Progesterone and Estrogen Receptors: Opposing Prognostic Indicators in Meningiomas. J Neurosurg 105: 163–173. https: // doi. Org/ 10. 3171/ DNS. 2006.105.2. 163
5. Neumann F (1986) Pharmacology of Antiandrogens. J STEROID BIOCHEM 25: 885–895. https: // doi. Org/ 10. 1016/ 0022- 4731 (86) 90320-1
6. Mueck ao, Sitruk-waare R (2011) Nomegestrol Acetate, a novel Progestagen for oral contraception. Steroids 76: 531–539. https: // doi. Org/ 10. 1016/ d. Stero IDS. 2011. 02. 002
7. Druckmann R (2009) Profile of the Progesterone Derivative Chlormadinone Acetate - Pharmocodynamic Properties and Therapeutic Applications. Contraception 79: 272–281. https: // doi. Org/ 10. 1016/ J. Contraceion. 2008. 10. 017
8. Catteau-Jonard S, Richard-Proust C (2012) Hyperandrogenism in Adolescent Girls. Endocr Dev, pp 181–193
9. 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. https: // doi. Org/ 10. 1056/ NEJMC 071938
10. Shimizu J, Matsumoto M, Yamazaki E, Yasue M (2008) Spontaneous Regression of An Asymptomatic Meningioma Associated With Discontinuation of Progesterone Agonist Administration. Neurol Med Chir (Tokyo) 48: 227–230. https: // doi. Org/ 10. 2176/ NMC. 48.227
11. Goncalves AMG, page P, Domigo V et al (2010) Abrupt regression of a meningioma after discontinuation of cyproterone Treatment: Fig 1. AM J Neuroradiol 31: 1504–1505. https: // doi. Org/ 10.3174/ AJNR. A1978
12. Gil M, Oliva B, Timoner J et al (2011) Risk of Meningioma Among Users of High Doses of Cyproterone Acetate AS Compared with the General Population: Evidence from a Population-Based Cohort Study: Risk of Meningioma Among Users of High Doses of Cyproterone Acetate. BR J Clin Pharmacol 72: 965–968. https: // doi. Org/10. 1111/d. 1365- 2125. 2011. 04031.X
13. Cea-Soriano L, Blenk T, Wallander Ma, Rodriguez Lag (2012) Hormonal Therapies and Meningioma: Is There A Link? Epidemiol cancer 36: 198–205. https: // doi. Org/ 10. 1016/ d. Canep. 2011. 08. 003
14. Knight EJ, McDonald MJ (2013) Reverseness and progression of meningioma in male-to-female transgender individuals during exogenous hormone use. Int J TransgendeRism 14: 18–23. https: // doi. Org/ 10. 1080/15532 739. 2012. 725563
15. Bergoglio Mt, Gomez-Balaguer M, Almonacid Folch E et al (2013) Symptomatic meningioma induced by cross-sex hormone treatment in a male-to-female transsexual. Endocrinol Nutr 60: 264–267. https: // doi. Org/ 10. 1016/ d. Endonu. 2012. 07. 004
16. Razavi HB (2014) Meningioma: The Unusual Growth in A Transsexual Patient After Estrogen-Progesterone Therapy. Soj neurol 1: 1 - 3. Https: // doi. Org/ 10. 15226/ 2374- 6858/1/2/ 00109
17. Papadopoulou S, Chambre C, Baudry C et al (2015) A rare complication of Acetate in an acromegal patient. Ann Endocrinol 76: 388–389. https: // doi. Org/ 10. 1016/ d. Ando.2015. 07. 276
18. Supartototo A, Mahayana it, Christine RN (2016) Exogenous Exogale Sex Hormones is associated with increased risk of orbito-cross-meningioma in female: a case-control study. Int J Ophthalmic Pathol 5: 1–6. https: // doi. Org/ 10. 4172/ 2324- 8599.10001 83
19. Bernat A, Bonnin S, Labidi M et al (2018) Regression of Giant Olfactory Groove Meningioma and Complete Visual Acuity Recovery after Discontinuation of Cyproterone Acetate. J Ophthalmic Vis res 13: 355. https: // doi. Org/ 10. 4103/ JOVR. jovr_ 21_ 17
20. Boer M, Moernaut L, van Calenbergh F et al (2018) Variation of Meningioma in Responsible to Cyproterone Acetate in a trans Woman. Int J TransgendeRism 19: 92–94. https: // doi. Org/ 10. 1080/15532739. 14136 15
21. Mancini I, Rotilio A, Coati I et al (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. https: // doi. Org/ 10. 1080/09513 590. 2017.13958 39
22. Note nm, wiepjes cm, from blok cjm et al (2018) the occurrence of benign brain tumours in transgender individuals during crossex hormone treatment. Brain 141: 2047–2054. https: // doi. Org/ 10.1093/ Brain/ Awy108
23. Roux A, Tauziede-Espariat A, Zanello M et al (2020) Symptomatic Progestin-associated atypical Grade II Meningioma. A first report. Neurosurgery 66: 174–178. https: // doi. Org/ 10. 1016/ J.Neuchi. 2019. 12. 013
24. Froelich S, Dali-Youcef N, Boyer P, et al (2008) does Cyproterone Acetate Promote Multiple Meningiomas? Endocr abstr 158–161
25. Botella C, Coll G, Lemaire JJ, IRTHUM B (2015) Intracranial meningomes and extended use of acetate in conventional dose in women: About two cases of tumor regression after stopping treatment. Neurosurgery 61: 339–342. https: // doi. Org/ 10. 1016/ d. Neuchi. 2015. 05. 002
26. Kalamarides M, Peyre M (2017) Dramatic Shrinkage With Reduced Vascularization of Large Meningiomas After Cessation of Progestin Treatment. World Neurosurg 101: 814.E7-814.E10. https: // doi. Org/10. 1016/d. Wneu. 2017. 03. 013
27. Champagne Po, Passeri T, Froelich S (2019) Combined Hormonal Influence of Cyproterone Acetate and Numegestrol Acetate on meningioma: a case report. Acta Neurochir (Wien) 161: 589–592. https: // doi. Org/ 10. 1007/ S00701- 018-03782-4
28. Passeri T, Champagne Po, Bernat Al et al (2019) Spontaneous Regression of Meningiomas after Interruption of Nomegestrol Acetate: A Series of Three Patients. Acta Neurochir (Wien) 161: 761– 765. Https: // DOI. Org/ 10. 1007/ S00701- 019-03848-X
29. Malaize H, Samoyeau T, Zanello M et al (2021) Evolution of the Neurosurgical Management of Progestin-Associated Meningiomas: A 23-Year Single-Center Experience. J Neurooncol 152: 279–288. https: // doi. Org/ 10. 1007/ S11060- 021- 03696-9
30. Weill A, Nguyen P, Labidi M et al (2021) Use of High Dose Cyproterone

Acetate and Risk of Intracranial Meningioma in Women: Cohort Study. BR MED J 37: 1–13. https: // doi. Org/ 10. 1136/ BMJ. N37

31. Hoisnard L, Laanani M, Passeri T et al (2022) Risk of Intracranial Meningioma With Three Potent Progestogens: A Population-Based Case-CONTROL Study. EUR J neurol. https: // doi. Org/ 10. 1111/ ENE.15423
32. Lee KS, Zhang Jjy, Kirollos R et al (2022) A Systematic Review and Meta-Analysis of the Association Between Cyproterone Acetate and Intracranial Meningiomas. SCI REP 12: 1942. https: // doi. Org/10. 1038/ S41598- 022- 05773-Z
33. ANSM (2018) CSST ≪ Cyproterone acetate and risk of meningiomas ≫ . In: https: // ANSM. health. fr/. https: // ANSM. health. fr/ Actualites/ Andro Cur- et- gener Ica- aceta te- de- CyPro Terone- 50- MG- ET-100- MG- ET- RISK- DE- Menin giomer- Lansm- publie- des- Recom mandations- Pour- taken- in-
34. ANSM (2020) CSST ≪ Macroprogestatives and risk of meningiomas ≫ . In: https: // ANSM. health. fr/. https: // ANSM. health. FR/ Events/ Committee- Macro PROGE STATI FS- Et- RISK- DE- MENIN GIOME
35. Huang Ry, Bi WL, Griffith B et al (2019) Imaging and diagnostic Advances for intracranial meningiomas. Neuro-oncol 21: i44–i61.https: // DOI. Org/ 10. 1093/ Neuonc/ Noy143
36. Hashiba T, Suzuki T, Kato A (2009) Serial Volumetric Assessment of the Natural History and Growth Pattern of Incidentally Discovered Meningiomas. J Neurosurg 110: 675–684. https: // doi.org/ 10. 3171/ 2008.8. JNS08 481
37. Nakasu S, Hirano A, Shimura T, Llena JF (1987) Incidental Meningiomas in Autopsy Study. Surg neurol 27: 319–322. https: // doi.org/ 10. 1016/ 0090- 3019 (87) 90005-X
38. HABERG AK, HAMMER TA, KVISTAD KA and AL (2016) Intracranial Findings and Their Clinical Impact; The Hunt Mri Study in A General Population of 1006 participants Between 50–66 Years. PLOS ONE 11: 1–20. https: // doi. org/ 10. 1371/ day al. pone.01510 80
39. VERNOOIJ MW (2007) Incidental Findings on Brain MRI in the general population. N Engl J Med. https: // doi. Org/ 10. 1056/ Nejmoa0709 72
40. Nahser HC, Grote W, Lohr E, Gerhard L (1981) Multiple Meningiomas. Clin Comput Tomogr Observ Neuroradiol 21: 259–263.https: // DOI. Org/ 10. 1007/ BF021 00156
41. Lusins ​​Jo, Nakagawa H (1981) Multiple Meningiomas Evaluated by Computed Tomography. Neurosurgery 9: 137–141. https: // DOI.org/ 10. 1227/00006 123-19810 8000- 00004
42. Voormolen ehj, champagne po, roca e et al (2021) intracranial meningomas decrease in volume on magnetic resonance imaging after discontinuing progestin. Neurosurgery 89: 308–314. https: // doi. Org/ 10. 1093/ Neuros/ Nyab1 75
43. Peyre M, Gaillard S, de Marcellus C et al (2018) Progestin-associated shift of meningioma Mutational Landscape. Ann Oncol 29: 681–686. https: // doi. Org/ 10. 1093/ Announce/ MDX763
44. Champeaux-Deland C, Weller J, Froelich S, Sartor A (2021) Cyproterone Acetate and Meningioma: A Nationwide-Wide Population Based Study. J Neurooncol 151: 331–338. https: // doi. Org/ 10.1007/ S11060- 020- 03672-9
45. Behbahani M, Skeie Go, Eide GE and Al (2019) A Prospective Study of the Natural History of Incidental Meningioma - Hold your Horses! Neuro-oncol PRACT 6: 438–450. https: // doi. Org/ 10. 1093/ NOP/ NPZ011
46. McDonald RJ, Levine D, Weinreb J et al (2018) Gadolinium Retention: A Research Roadmap from the 2018 NIH/ACR/RSNA Workshop on Gadolinium Chelates. Radiology 289: 517–534. https: // doi.org/ 10. 1148/ radiol. 20181 81151
47. Boto J, Guatta R, Fitsiori A et al (2021) is contrast Medium Really Needed for Follow-Up Mri of Untreated Intracranial Meningiomas? AM J Neuroradiol 42: 1421–1428. https: // doi. Org/ 10. 3174/ AJNR.A7170

 

Publisher's Note Springer Nature Remains Neutral With Regard to Jurisdictional Claims in Published Maps and Institutional Affiliations.

Springer Nature Or its Licensor Holds exclusive Rights to this article Under A Publishing Agrement With the Author (S) or Other Rightsholder (s); Author Self-Archiving of the Acceptance Manuscript Version of this article is solely governed by the terms of Such Publishing Agrement and Applicable Law.