Risk of intracranial meningiomal with three powerful progestins: a case-to-test study based on the population

Risk of intracranial meningioma with three powerful progestins

Current title: progestins and risk of meningioma

Léa Hoisnard1, Moussa Laanani1, Thibault Passi2, Lise Duranteau, Joël Coste4, Mahmoud

Zureik1, Sébastien Froelich2, and Alain Weill1

Affiliations of authors:

1 Scientific interest group of epidemiology of Epi-Phare health products, National Agency for the Safety of Medicines and Health Products, French Health Insurance, 93200 Saint-Denis, France

2 Department of Neurosurgery, Lariboisière Hospital, AP-HP, University of Paris, 75010 Paris, France

3 Medical gynecology service, Bicêtre Hospital, AP-HP, Paris Saclay University, 94270 Le Kremlin-Bicêtre, France

4 unit of biostatis and epidemiology-Cochin hospital, AP-HP, 75010 Paris, France

Correspondence to: Léa Hoisnard Scientific Interest Group Epi-Phare, 42 bd de la Liberation, 93200 Saint-Denis, France lea.hsnrd@gmail.com

This article was accepted for publication and was the subject of a complete peer examination, but was not subject to the processes of revision, composition, layout and correction of tests, which can lead to differences between this version and the official version. Please quote this article as DOI: 10.1111/ENE.15423

Keywords : progestins, meningioma, cyproterone acetate, nomestrol acetate, chlormadinone acetate

 

Introduction

Meningiomas are the most frequent intracranial tumors, representing 39 % of primitive tumors of the central nervous system1.

The main risk factors for meningioma are age, being a woman, exposure to ionizing radiation and type 2 neurofibromatosis (NF2) 2. A certain number of observations have long suggested an association between endogenous sex hormones and meningiomas, on the basis of epidemiological data and histopathological studies: there is a higher incidence in women (report 2.5/1), in particular of childbearing age1; Case reports have suggested that the size of meningiomas increases during pregnancy and decreases after childbirth 3.4; And biological studies have shown that the expression of the progesterone receptor could be involved in the occurrence of certain types of meningiomas5-8.

No association has been identified for oral contraceptives, for which the doses of progestins are low . With regard to hormonal substitutive treatment (HRT) of menopausal women, a certain number of epidemiological studies seem to support a slightly increased risk of meningioma but the evidence is limited9,10.

On the other hand, a high risk of meningioma was observed during the use of high doses of cyproterone acetate (ACP), a powerful progestin with antiandrogen activity, in women, men and transsexuals11-13.

In addition, stopping long-term treatment with ACP induces tumor regression , which was also observed after the stopping of two other powerful progestins: nomestrol acetate (nomac) and chlormadinone acetate (CMA) 14-23, which suggests that these two progestins are also associated with the risk of meningioma.

However, unlike ACP, no large -scale epidemiological study has yet been published on the risk of meningioma associated with exposure to the Nomac or CMA.

We therefore sought to assess, in real situations, the association between intracranial meningomes surgery and exposure to three powerful progestins for which a regression of the volume of meningioma after stopping treatment was described: ACP, Nomac and CMA.

 

Methods

Data source

In this national case-to-test study based on the population, the data has been extracted from the National Health Data System (SNDS), which covers 99% of the population living in France-67 million residents. The SNDS includes demographic data, the dismissal of ambulatory drugs and information on hospital care (hospital diagnostic codes according to the international classification of diseases, tenth revision [CIM-10], and acts carried out during the hospital stay coded according to the medical classification of clinical acts [CCAM]).

These data are all prospectively recorded at the individual and anonymized level. This database is a useful and reliable source for the evaluation of the efficiency and safety of drugs24,25. This study was carried out within the framework of the regulatory decision of the French Agency for Data Protection CNIL-2016-316.

Case and witnesses

The eligible cases were all the individuals living in France and having undergone surgery for intracranial meningioma L between January 1, 2009 and December 31, 2018 in France.

Surgery for intracranial meningioma was defined by the following combination recorded for the same hospital stay: a meningioma neoplasm (CIM-10 codes: D32, D42 or C70) coded as the main diagnosis of hospitalization and surgery corresponding to intracranial surgery (additional table 1).

The first surgical intervention for intracranial meningioma during the study period was included and the absence of a hospital stay for intracranial meningioma surgery since June 2007 has been verified. The index date has been defined as the date of admission to the hospital for a first meningioma surgery. For the sake of simplicity, the expression "intracranial meningioma surgery" is designated below by the term "meningioma" in the results.

Five witness individuals have been paired with each case for the year of birth, sex at birth and the area of ​​residence (100 geographic administrative zones), because age and sex are two major confusion factors in the association between exposure to progestins and meningioma. The witness individuals were selected randomly with at least one reimbursement of extrahospital care during the study period, excluding cases. The witnesses were awarded the same index date as their corresponding case and were alive on that index date.

Exposure

For cases and witnesses, exposure to progestogen has been defined as at least one of the following drugs (coded according to the chemical therapeutic anatomical classification system, ATC) during the year preceding the date of index: ACP (G03HA01), Nomac (G03DB04) and CMA (G03DB06).

ACP is a synthetic progestogen with anti-diandal activity indicated for inoperable prostate cancer or paraphilies in men (50-100 mg/day) and for various disorders of the spectrum of hirsutism or hyperandrogenism in women (50 mg/day). In addition, the ACP is used in an unauthorized manner as a feminizing hormone therapy for transsexuals. The ACP can also be used at a dose of 25 mg/day, because the tablets are divisible. Nomac (3.75-5 mg/day) is a synthetic progestogen prescribed mainly for HOS and contraception.

Finally, CMA (2-10 mg/day) is another progestogen indicated in the treatment of menstrual disorders, HOS, endometrial hyperplasia and endometriosis.

Nomac and CMA are not indicated for men in France.

Exposure to progestins has been defined using three indicators:

• - "current use" has been defined as exposure to progestins with at least a delivery of the drug during the 365 days preceding the date of index, whether the subject has been exposed before or not;
• - "short -term use" as exposure to progestins during the 365 days preceding the index date, without exposure during the period between 366 and 730 days before the index date;
• - and "prolonged use" as exposure to progestins both during the 365 days preceding the index date and between 366 and 730 days before the index date, without taking into account the previous exposure.

We studied prolonged use by assessing exposure to progestins for the period 2013-2018, for which cases and witnesses had at least six years of history in the database. We have defined "prolonged use" as explained above for cases and witnesses and added five additional indicators of prolonged use: "prolonged use for two years" was defined as at least one of a progestogen per year for two years (that is to say before the 365 days preceding the date of the index and between 366 and 730 days before the date of the index, but not between 731 days and 1 096 days before date of index). “Prolonged use for three years”, “four years”, “five years” and “six years or over” were defined according to the same logic.

Covariable

The population studied has been described according to the following basic socio-demographic characteristics: sex at birth, age and area of ​​residence (six groups). Information on meningiomas included the year of surgery, the anatomical site (five main sites and 16 detailed sites, described in the additional table 1), the rank of the tumor according to the CIM-10 and the radiotherapy associated with surgery. The mortality of all causes was estimated at two years after meningiomal surgery for the entire case of cases and five years for the subset of cases for which sufficient monitoring data were available , that is to say for those who have undergone meningiomal surgery before January 1, 2016.

Statistical analyzes

The incidence rates of intracranial meningomes surgery per 100,000 people-years for the entire French population have been estimated by age class with the publicly available data from the National Institute of Statistics and Economic Studies. Logistic regression models packaged by paired pairs (to control the pairing variables) have been used to estimate the ODDS ratios (gold) and their confidence intervals (CI) at 95% for the association between meningioma and anterior exposure to progestins. The risk of meningioma associated with exposure to progestins has been estimated by considering either exposure to at least one of the three progestins, or each progestogen separately, depending on the current, short -term and prolonged use. The analyzes were then stratified by age group and sex, grade of the tumor and anatomical site. We also estimated the association between the NF2 (CIM-10 Q851 Code) and the meningioma to determine whether this well-documented association2 was also found in our studied population.

The fraction of cases attributable to the population was calculated from the gold obtained for global exposure, assuming adequate control of all confusion factors26,27. This attributable fraction was applied to the total number of cases during the study period to estimate the number of meningiomal cases attributable to the three powerful progestins, assuming a causal association between exposure to powerful progestins and meningioma. This estimate was also carried out for men and women separately. Finally, we estimated the number of cases of meningiomas attributable to the NF2.

Results

In total, 25,216 cases having undergone surgery for intracranial meningioma and 126,080 witness individuals were included (Figure 1).

Their characteristics (women 75 %, median age: 58 years [Q1-Q3: 48-67]) are presented in Table 1.

The raw incidence of intracranial meningiomes surgery was 4/100,000 people-years, with a maximum woman/man ratio (4.6) reached between 45 and 54 years (Figure 2).

Most intracranial meningiomas were located in the convexity area (37.9 %) and the anterior skull base (20.9 %) . Ninety-one percent of tumors were classified as benign (Table 1).

About 7 % of patients died within five years of the operation, with higher mortality (25.5 %) for those with malignant tumors.

The current use of at least one of the progestins the year preceding the date of the index was found for 2,497 cases (9.9 %) and 2,382 (1.9 %) witnesses (Table 2). Most current progestogen users had prolonged use (91.8 % [2291/2497] in the case group and 63.9 % [1521/2382] in the control group).

For the subjects included in the period 2013-2018 with prolonged use of progestins, 79.0% of cases (1130/1430) and 43.4% of witnesses (392/903) had been exposed each year for at least six years (additional table 2). Cases and witnesses used doses of similar drugs (additional table 3): 50 mg for ACP (95 %), 5 mg for the nomac (86 %) and 10 mg for the CMA (81 %).

The estimated gold of meningioma for interest exposure are presented in Table 2. The NF2 was associated with an increased risk of meningioma: or = 19.5 [95%CI: 13.1-29,1]. Exposure to at least one of the progestins for current use, short-term use or prolonged use was associated with an increased risk of meningioma: or = 6.7 [6,3-7,1], 1.2 [1.0-1,4] and 9.5 [8,8-10,2], respectively. The extent of the risk has decreased between ACP, nomac and AMC: or = 22.7 [19.5-26.4], 6.5 [5,8-7,2] and 4.7 [4,5-5,3], respectively.

The current use of progestins was associated with a risk of meningioma in women , with a gold of 6.6 [6,3-7,1] (Table 3 and additional table 4). The RC decreased from the ACP to the nomac and the AMC: RC = 19.7 [17,0-22.7], 4.7 [4,3-5,1] and 3.3 [3,0-3,6], respectively.

Gold in men exposed only to ACP was 8.0 [5,2-12.3]. The magnitude of the association increased with age in women but decreased in men. Exposure to a progestin was associated with an increased risk of meningioma in women for benign, atypical and malignant tumors : gold = 6.6 [6,2-7,1], 7.0 [5,4-9,1] and 6.6 [4,0-10,8], respectively.

Exposure to a progestogen was also significantly associated with mild and atypical meningiomas in men.

The anatomical sites for which the risk of meningioma associated with the progestins was the highest were the previous and average skull base : or = 10.2 [8,9-11,6] and 9.7 [8,6-11,1] respectively, for all progestins; Or = 35.7 [26.5-48,2] and 23.9 [17,8-32,2] respectively, for the ACP; Or = 6. 2 [5,2-7,4] and 6.8 [5,7-8,1], respectively, for the nomac; and gold = 3.5 [2,9-4,4] and 4.7 [3,9-5,7], respectively, for AMC (Table 3). After a more precise evaluation of this association by anatomical site (additional table 5 and additional table 6), the sites presenting the highest gold were the optochematic zone (gold = 12.6 [10,0-15.8]) and the medial third of the average skull base involving the spheno-orbital angle (or = 12.0 [10,2-14,1]). The risk associated with ACP was particularly high for the optochematic zone (or = 49.1 [28,9-83.5]).

The fraction attributable to the population (FAP) of meningiomes treated surgically for current use of at least one of the three powerful progestins studied in France between 2009 and 2018 was 8.4% [8.0-8.8%]. The corresponding number of attributable meningiomas was 2,124 [2008-2020] (212 per year, on average) , assuming the hypothesis of a causal association between exposure to powerful progestins and meningioma.

The FAP des Méningiomes was 11.0% [10.5-11.5%] for women and 0.8% [0.5-1.0%] for men, with a corresponding number of attributable cases of 2072 [1978-2165] and 48 [33-63].

The meningioma FAP for the NF2 was 0.4% [0.3-0.5%] and the estimated number of attributable meningiomas was 111 [90-132].

Discussion

This study revealed a strong association between intracranial meningiomas requiring surgery and prolonged exposure to powerful progestins, with an increasing AMC gradient to nomac and ACP.

This increase in risk concerned all the grades and all anatomical sites but was the highest for the base of the previous and average skull for each progestogen. The estimated number of cases attributable to powerful progestins was greater than 2,000 in France between 2009 and 2018, about 20 times that of the cases attributable to the NF2 .

Our results showing a strong association between long exposure to ACP and the risk of operated meningioma (or = 22.7 [19.5-26.4]) are in accordance with those of other studies. A strong dose-answer relationship between ACP and intracranial meningiomas has already been reported in women in France (HR = 21.7 [10.8-43.5] for cumulative doses> 60g) 13, in men in Denmark (HR = 18.5 [9,2-37,1] for cumulative doses> 10g) 28, and in transsexuals standardized incidence: 11.9 [5.5-22.7]) 12.

On the other hand, no epidemiological study published to date has shown an association between exposure to the CMA or the nomac and the meningiomas. Meningioma cases have been published for the Nomac18,19 and the CMA16 or included in larger series including ACP20,29. Several years long exposure, locations at the base of the skull (frequently with ophthalmological symptoms), and non -systematic regression when you stop treatment in the absence of surgery have been reported.

In a recent review, Hage et al. have shown that the current evidence of the association between HRT and meningioma are contradictory , but seem to promote an increased risk10. Two cohort studies not published on AMC and Nomac are being discussed at the European Agency of the Medicmen T30.

In our study, we found a significant association between the prolonged use of the AMC and the nomac, although the gold are lower than those of the ACP. Results as diverse for the association between meningioma and progestins probably reflect the use of different types of progestins and prolonged use and the high dose seeming to contribute to the association with meningioma. In particular, the use of these three progestins (ACP, CMA and Nomac) in France has been higher in terms of frequency and dose than in other countries of Western Europe. ACP, CMA and Nomac are not currently marketed in the United States. Such an association between powerful progestins and meningiomas could therefore not be demonstrated in the past in the United States.

We have found that the risk of operated meningioma was highest in the previous and average part of the skull base in patients exposed to progestogen . This result is consistent with those of previous observational studies and with known biological mechanisms.

In a study on 300 patients who have undergone surgery for meningioma, a higher rate of expression of progesterone receptors> 50% was observed for meningiomas of the median skull base than for other sites 7.

In addition, the meningiomas associated with progesterone had significantly higher levels of expression of progesterone receptors and were more frequently located at the base of the skull than other meningiomas 8

Another specific characteristic of meningiomas associated with progestins are mutations affecting the PIK3CA/AKT1 track, which have been more frequently observed in the ACP meningiomas than in a control group8,21.

Such a preferential mutational landscape of meningiomas induced by the ACP seems to have been confirmed by an observational study showing the coexistence of meningiomas in regression bearing a PIK3CA mutation and growing meningiomas carrying NF2 mutations in the same patient after stopping the drug in four women exposed to ACP21.

An independent clonal origin, associated with a predisposition of certain meningeal cells (mainly located in the anterior and average skull) to develop meningiomas, could explain the pathogenesis of these meningiomas linked to progestins21.

A French epidemiological study also reported that the risk of meningioma from the anterior base of the skull was 47 times higher in patients exposed to ACP13. Interestingly, we have highlighted a strong association with the meningiomas of the base of the median skull involving the spheno-orbital angle (gold = 12.0 [10,2-14,1]). A single previous study was interested in this specific site and found that a high proportion of women with such tumors had been exposed to high doses of ACP, Nomac or CMA for at least two years29. In addition, our results have shown that the increased risk concerns the meningomes made of all grades . Although case reports and series of Méningiomes de Grade 2 associated with ACP, Nomac or CMA have been published, no epidemiological evidence of an increased risk was available so far23.

Strengths of this study

The main strength of the study was the design based on the registers and the size of the population (more than 25,000 surgeries for meningioma over 10 years and 125,000 checks). The use of prospective recordings of drugs issued in the SNDS has made it possible to avoid the recall bias, a major limit of case-control studies . In addition, we can highlight the accuracy of data on exposure to progestins and the location of meningiomas operated according to the surgical procedure. We have also calculated the fractions attributable to the population, which supports the evaluation of the burden of the morbidity of a causal factor in a population.

Our short -term approach (<1 year) vs long term (> 1 year) highlighted the absence of risk or a very small risk with short -term use for each of the three powerful progestins. The risk of meningioma is mainly linked to very long -term use (> 5 years), which has not been assessed in previous studies.

Limits of this study

First, we included patients who have undergone surgery for intracranial meningioma , while exclusive radiotherapy is also indicated. However, surgery is the first option for managing meningiomas of all grade 31. In a French study, only 4 % of patients who developed meningioma after exposure to ACP were treated with radiotherapy 13.

We have included patients who have undergone surgery, regardless of the grade of the tumor. The classification of tumors did not precisely follow the last classification of the grades of WHO 32 due to the source of the data, but the CIM-10 codes were reliable because they were recorded by the surgeons. As expected, mortality and radiotherapy rates associated with surgery increased with the rank of the tumor in our study.

Anatomical sites have been classified according to information available using the French medical classification of clinical acts. Different classifications have been used in previous studies, no consensual surgical anatomical classification being currently available. Our classification made it possible to consider a large number of sites (16 groups). In addition to diagnostic codes, clinical procedures are recorded by surgeons and can therefore be considered reliable.

In terms of exposure, the indication of progestin treatment was not available . However, the three progestins have, in part, different indications and have all been associated with an increased risk of meningioma. All age groups were affected by this increased risk and there was no differential ACP risk for men, women or transsexuals. The indication is therefore not likely to be a factor of confusion in the assessment of the risk of meningioma associated with progestins. With regard to the duration of exposure, we have considered current use, even if meningioma is generally a slow growth tumor. Despite this limitation, we show a significant association, in particular for prolonged use (> 1 year). We have hypothesized that prolonged use reflects a longer period of exposure to progestins, with the prescription, administration and repeated taking of drugs. The description of the prolonged exposure for the period 2013-2018 tends to confirm this hypothesis: 80% of the prolonged use corresponded to an exposure each year for at least the six years preceding the index date. We have not assessed the effect of stopping progestin treatment. Several studies have concluded that stopping the ACP, the Nomac or the AMC caused a reduction in the risk of meningioma or a tumor regression13-19. We have not taken into account ionizing radiation, because this risk factor only applies a few cases33,34 and it is unlikely that it confuses exposure to progestins.

Finally, we cannot formally exclude the possibility that the indication of surgery for exposed patients has changed over time . ACP labeling was modified in 2011 and 2013 to provide information on reported meningiom cases associated with the use of the drug. However, these updates have had little impact on clinical care 13 and we assumed that the choice of neurosurgical management was based on current European directives for most cases and that asymptomatic patients were supported by observation. The labeling of the AMC and the Nomac was modified in 2018, that is to say during the last year of the study period.

Clinical implications and future research

In France, the screening of meningiomas by magnetic resonance imaging in patients receiving progestogen for long -term treatment has already been set up for ACP and will soon be recommended for AMC and Nomac 35.36. People who have used powerful progestins for many years could benefit from such screening. Future research could explore the association between very long -term exposure to low -dose progestoges contained in oral contraceptives and the risk of meningioma.

Conclusion

In this case-control study at the national level, we observed a strong and significant association between exposure to three progestins and meningioma surgically treated. The risk was high for patients with prolonged use and for meningiomas operated on the previous base and average of the skull.

The surgical removal of these tumors is one of the most difficult forms of intracranial surgery and is associated with a much higher risk. Our data should encourage information from people using powerful progestins during prolonged periods on this risk and assessment of the individual benefit/risk ratio.

Regulatory and ethical aspects

The French public establishment carrying out this study, the EPI-Phare scientific interest group, has permanent access to the SNDS database in accordance with the provisions of articles R.1461-12 and following of the Code of Public Health and the Decision of the National Commission for Data Protection CNIL-2016-316. This study was recorded in the study register of the EPI-Phare scientific interest group. No informed consent was therefore required. This research did not benefit from any specific funding.

Data availability

Data sharing is not applicable. In accordance with French laws governing data protection and French regulations, the authors cannot publicly disseminate data from the National Health Data System (SNDS). However, any person or structure, public or private, for profit or not, can access SNDS data on authorization from the National Commission for Computer Science and Liberties (CNIL) to carry out a study, research or evaluation of public interest (https://www.snds.gouv.fr/snds/procus-d-acces-aux-donnees and https://www.snds.gouv.fr).

Funding

No funding was received for this work.

Competing interests

The authors do not report any competitive interest.

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Figures

Figure 1 Organization chart

Figure 2 Incidence of meningiomas treated surgically depending on the age group and sex at birth

Paintings

Table 1. Characteristics of case and control groups

CIM-10: International classification of diseases, tenth revision; Sex, woman: individuals born women

† Northeast: Grand Est, Bourgogne Franche-Comté, Hauts-de-France; Paris region (Ile-de-France): City of Paris and Île-de-France region; North-West: Brittany, Val de Loire center, Normandy, Pays de la Loire; South-East: Auvergne-Rhône-Alpes, Provence-Alpes-Côte d'Azur, Corsica; Sud-Ouest: Nouvelle-Aquitaine, Occitanie; Overseas zone: Guadeloupe, Martinique, Guyana, meeting

‡ Death within 2 years: for the whole cohort, the deaths all causes have been identified from the date of indexing up to 2 years after this date.

• Death within 5 years: The deaths of all causes were identified from the index date up to 5 years later for all cases having undergone meningioma surgery before January 1, 2016.

Table 2. Nudes and proportions of cases and witnesses exposed and estimated, taking into account the match variables, with confidence intervals

However: Odds Ratio, by controlling the pairing factors (sex at birth, year of birth and area of ​​residence).

Current use: Exhibition at least once within 365 days preceding the date of the index, regardless of previous exposure; Short -term use: exposure within 365 days of the date of the index, excluding the period between 365 and 730 days before the date of the index; Prolonged use: Exhibition both within 365 days and between 365 and 730 days before the index date

Table 3. Association between meningioma surgically treated and exposure to progestins depending on age, sex at birth, grade and the site of the tumor; Estimated and 95%IC.

However: Odds Ratio, by controlling the pairing factors (sex at birth, year of birth and region of residence)

CIM-10: International classification of diseases, tenth revision; Sex, feminine: individuals born of female sex

 

Table 1. Characteristics of case and control groups

Characteristics Case controls

N = 25.216 n = 126.080

n (%) n (%)

Sex (birth)/Woman 18.892 (74.9) 94,460 (74.9)

Age, average (sd) 57.5 (13.5) 57.5 (13.5)

Age group

0-19                                                    128 (0.5)                     640 (0.5)

20-34                                                  1,021 (4.1)                  5,105 (4.1)

35-44                                                  3,132 (12.4)                15,660 (12.4)

45-54                                                  6,132 (24.3)                30,660 (24.3)

55-64                                                  6,552 (26.0)               32,760 (26.0)

65-74                                                  5,570 (22.1)               27,850 (22.1)

75-84                                                  2,421 (9.6)                  12,105 (9.6)

≥ 85                                                    260 (1.0)                     1,300 (1.0)

Zone of residence †

Paris region 4,331 (17.2) 21.655 (17.2)

Northeast 4,842 (19.2) 24,210 (19.2)

North West 5,000 (19.8) 25,000 (19.8)

South-East 5.755 (22.8) 28,775 (22.8)

South West 4,802 (19.0) 24.010 (19.0)

Overseas 486 (1.9) 2.430 (1.9)

Year of operation

2009                                                   2,070 (8.2)

2010                                                   2,220 (8.8)

2011                                                   2,299 (9.1)

2012                                                   2,464 (9.8)

2013                                                   2,469 (9.8)

2014                                                   2,639 (10.5)

2015                                                   2,628 (10.4)

2016                                                   2,762 (10.9)

2017                                                   2,742 (10.9)

2018                                                   2,923 (11.6)

Anatomical location of meningioma

Anterior skull base 5.285 (20.9) -

Average skull base 4.790 (19.0)

Posterior base of the skull 2.770 (11.0)

Convexity 9.554 (37.9)

Falx and Tentorium 2.608 (10.3)

Other places 209 (0.8)

Grade of the ICD-10 tumor

Benin (D32) 23.010 (91.3)

Sex, woman 17,429 (75.7)

Atypical (D42) 1.587 (6.3)

Sex, woman 1.101 (69.4)

Malin (C70) 619 (2.4)

Sex, woman 362 (58.5)

Adjuvant radiotherapy

All grades 2.274 (9.0)

Benin (D32) 1,917 (8.3)

Atypical (D42) 145 (9.1)

Malin (C70) 212 (34.2)

Death, according to the rank of the tumor, in

2 years ( n = 25216) ‡

All grades 854 (3.4)

Benin (D32) 692 (3.0)

Atypical (D42) 70 (4.4)

Malin (C70) 92 (14.8)

5 years ( n = 16789) §

All grades 1,152 (6.8)

Benin (D32) 971 (6.3)

Atypical (D42) 91 (8.5)

Malin (C70) 90 (25.5)

 

CIM-10: International classification of diseases, tenth revision; Sex, woman: individuals born of female sex.

† North East: Grand Est, Bourgogne Franche-Comté, Hauts-de-France; Paris region (Ile-de-France): Paris and Ile-de-France region; North-West: Brittany, Val de Loire center, Normandy, Pays de la Loire; South-East: Auvergne-Rhône-Alpes, Provence-Alpes-Côte d'Azur, Corsica; Sud-Ouest: Nouvelle-Aquitaine, Occitanie; Overseas: Guadeloupe, Martinique, Guyana, Reunion

 

‡ Death within 2 years: for the entire cohort, the deaths all causes were identified for the date of index up to 2 years after this date.

• Death within 5 years: deaths, all causes, were identified from the date of indexing up to 5 years later for all cases having undergone meningioma surgery before January 1, ²⁰¹⁶ .

 

 

 

 

 

 

 

Table 2. Nudes and proportions of exposed cases and estimated gold, by controlling the matching variables, with confidence intervals

Exhibition boxes controls or [95% CI]

N = 25.216 n = 126.080

 

Neurofibromatosis Type II 117 (0.5) 30 (0.02) 19.5 [13.1-29.1]

Exposure to at least one of the progestins

Current use 2.497 (9.9) 2.382 (1.9) 6.7 [6.3-7.1]

Short term <1 year 206 (0.8) 861 (0.7) 1.2 [1.0 - 1.4]

Prolonged ≥ 1 year 2,291 (9.1) 1.521 (1.2) 9.5 [8.8 - 10.2]

Cyproterone acetate

Current use 961 (3.8) 290 (0.2) 18.3 [16.0-21.1]

Short term <1 year 30 (0.1) 63 (0.05) 2.4 [1.5-3.7]

Prolonged ≥ 1 year 931 (3.7) 227 (0.2) 22.7 [19.5-26.4]

Nomestrol acetate

Current use 969 (3.8) 1.149 (0.9) 4.7 [4.3-5.1]

Short term <1 year 105 (0.4) 421 (0.3) 1.3 [1.0-1.6]

Prolonged ≥ 1 year 864 (3.4) 728 (0.6) 6.5 [5.8-7.2]

Chlormadinone acetate

Current use 683 (2.7) 1.096 (0.9) 3.3 [3.0-3.6]

Short term <1 year 80 (0.3) 416 (0.3) 0.9 [0.8-1.2]

Prolonged ≥ 1 year 603 (2.4) 680 (0.5) 4.7 [4.5-5.3]

 

However: Odds Ratio, by controlling the pairing factor (sex at birth, birth year and area of ​​residence)

Current use: exposure at least once within 365 days preceding the index date, regardless of previous exposure; Short -term use: exposure within 365 days preceding the index date, excluding the period between 365 and 730 days before the index date; Prolonged use: Exhibition both within 365 days and between 365 and 730 days before the index date

 

Table 3. Association between meningioma surgically treated and exposure to progestins depending on age, sex at birth, grade and the site of the tumor; Estimated but 95% IC

Exhibition one of 3 acetate of acetate of acetate of

Cyproterone Progestatives Nomegestrol Chlormadinone

 

Sex, woman

Global 6.6 [6.3-7.1] 19.7 [17.0-22.7] 4.7 [4.3-5.1] 3.3 [3.0-3.6]

0-19                5.0 [0.3-79.9] 5.0 [0.3-79.9]             –                      –

20-34              5.4 [4.0-7.2]   12.6 [8.0-19.8] 3.1 [1.8-5.5] 2.0 [1.1-3.5]

35-44              6.0 [5.2-6.8]   21.9 [16.4-29.2] 3.5 [2.9-4.3] 2.6 [2.1-3.3]

45-54              6.3 [5.8-6.9]   18.7 [15.0-23.4] 4.6 [4.1-5.2] 3.6 [3.2-4.0]

55-64              8.9 [7.5-10.6] 21.8 [14.8-32.0] 7.1 [5.5-9.0] 4.1 [3.0-5.7]

≥ 65 years 10.6 [7.7-14.6] 27.9 [15.1-51.6] 7.7 [4.8-12.3] 1.8 [0.7-4.5]

Sex, man

Global 8.0 [5.2-12.3] 8.0 [5.2-12.3]

<65 years 12.5 [5.5-28.4] 12.5 [5.5-28.4]---

≥ 65 years 6.6 [4.0-11.0] 6.6 [4.0-11.0]---

ICD-10 grade tumor

Benin (D32) 6.7 [6.2-7.1] 18.4 [15.9-21.2] 4.7 [4.3-5.1] 3.3 [3.0-3.6]

Sex, woman 6.6 [6.2-7.1] 19.5 [16.7-22.7] 4.7 [4.3-5.1] 3.3 [3.0-3.6]

Sex, man 9.1 [5.7-14.6] 9.1 [5.7-14.6]---

Atypical (D42) 7.1 [5.5-9.2] 21.6 [12.1-38.6] 4.6 [3.2-6.7] 3.3 [2.2-4.9]

Sex, woman 7.0 [5.4-9.1] 21.7 [11.9-39.7] 4.6 [3.2-6.7] 3.3 [2.2-4.9]

Sex, man 20.0 [2.2-178.9] 20.0 [2.2-178.9]---

Malin (C70) 6.1 [3.8-9.8] 14.3 [6.0-33.8] 4.9 [2.2-10.8] 2.8 [1.3-5.9]

Sex, woman 6.6 [4.0-10.8] 23.7 [8.1-69.8] 4.9 [2.2-10.8] 2.8 [1.3-5.9]

Sex, man 1.7 [0.2-16.0] 1.7 [0.2-16.0]---

Anatomical location

Anterior skull base 10.2 [8.9-11.6] 35.7 [26.5-48.2] 6.2 [5.2-7.4] 3.5 [2.9-4.4]

Average skull base 9.7 [8.6-11.1] 23.9 [17.8-32.2] 6.8 [5.7-8.1] 4.7 [3.9-5.7]

Posterior base of the skull 2.9 [2.4-3.6] 6.4 [3.9-10.4] 2.6 [1.9-3.5] 2.1 [1.5-2.9]

Convexity 5.1 [4.6-5.7] 12.4 [9.9-15.5] 3.5 [3.0-4.2] 2.9 [2.4-3.4]

Falx and Tentorium 3.5 [2.8-4.5] 10.4 [6.2-17.4] 2.8 [1.9-3.9] 2.0 [1.3-3.0]

However: Odds Ratio, by controlling the pairing factors (sex at birth, year of birth and area of ​​residence)

CIM-10: International classification of diseases, tenth revision; Female sex: people born of female sex

 

See diagram in the original document