Use of progestins and risk of intracranial meningioma: national case-testimony study
EPI-PHARE study published in the BMJ
https://www.bmj.com/content/384/bmj-2023-078078
- Noémie Roland, general practitioner and epidemiologist;
2. Anke Neumann, senior statistician;
3. Léa Hoisnard, epidemiologist;
4. Lise Duranteau, endocrinologist and gynecologist;
5. Sébastien Froelich, professor of neurosurgery;
6. Mahmoud Zureik, professor of epidemiology and head of department;
7. Alain Weill, senior epidemiologist and deputy director
Authors' Affiliations
1. Correspondence to: N Roland noemie.roland@assurance-maladie.fr (@NoemieRoland11 @EPIPHARE on X)
- Accepted on February 22, 2024
ABSTRACT
Objective To evaluate the risk of intracranial meningioma associated with the use of certain progestins.
Design National case-control study.
Framework French National Health Data System (SNDS).
Participants: Out of a total of 108,366 women, 18,061 women living in France who underwent intracranial surgery for a meningioma between January 1, 2009, and December 31, 2018 (inclusion periods restricted for intrauterine systems) were considered part of the case group. Each case was matched with five controls for year of birth and region of residence (90,305 controls).
Main evaluation criteria: Selected progestins were used: progesterone, hydroxyprogesterone, dydrogesterone, medrogestone, medroxyprogesterone acetate, promegestone, dienogest, and levonorgestrel intrauterine system (IUS). For each progestin, use was defined as at least one dispensing within the year preceding the index date (within three years for 13.5 mg levonorgestrel IUS and within five years for 52 mg IUS). Conditional logistic regression was used to calculate the odds ratio for each progestin-related meningioma association.
Results The mean age was 57.6 years (standard deviation 12.8). Analyses showed an excess risk of meningioma with the use of medrogestone (42 exposed cases/18,061 cases (0.2%) vs 79 exposed controls/90,305 controls (0.1%), odds ratio 3.49 (95% confidence interval 2.38 to 5.10)), medroxyprogesterone acetate (injectable, 9/18,061 (0.05%) vs 11/90,305 (0.01%), 5.55 (2.27 to 13.56)), and promegestone (83/18,061 (0.5%) vs 225/90,305 (0.2%), 2.39 (1.85 to 3.09)). This increased risk was due to prolonged use (≥ one year). The results showed no increased risk of intracranial meningioma for intrauterine systems containing progesterone, dydrogesterone, or levonorgestrel. No conclusions could be drawn regarding dienogest or hydroxyprogesterone due to the small number of people who received these medications. A significantly increased risk of meningioma was observed for cyproterone acetate (891/18,061 (4.9%) vs 256/90,305 (0.3%), odds ratio 19.21 (95% confidence interval 16.61 to 22.22)), nomegestrol acetate (925/18,061 (5.1%) vs 1121/90,305 (1.2%), 4.93 (4.50 to 5.41)), and chlormadinone acetate (628/18,061 (3.5%) vs 946/90,305 (1.0%), 3.87 (3.48 to 4.30)), which were used as positive controls for use.
Conclusions:
Prolonged use of medrogestone, medroxyprogesterone acetate, and promegestone increases the risk of intracranial meningioma. The increased risk associated with the use of injectable medroxyprogesterone acetate, a widely used contraceptive, and the safety of levonorgestrel-releasing intrauterine systems are important new findings.
Introduction:
Meningiomas account for 40% of primary tumors of the central nervous system. The incidence of meningiomas in the United States is 9.5 per 100,000 person-years. Meningiomas are mostly histologically benign, slow-growing tumors, but they can nevertheless compress adjacent brain tissue, and patients may therefore require surgical decompression.
The incidence of meningiomas increases with age, with a sharp increase after the age of 65. Conversely, meningiomas are rare before the age of 35.
Other risk factors recognized for meningiomas are being a woman, intracranial exposure to ionizing radiation, type 2 neurofibromatosis and, as has only been demonstrated recently, the prolonged use (≥ a year) of high doses of three powerful progestins: cyproterone acetate, chlormainone acetate and Nomestrol acetate.
The link between female sex hormones, particularly progesterone, and intracranial meningiomas is biologically plausible. Progesterone receptors are present in more than 60% of meningiomas, and it has been observed that the volume of these tumors increases during pregnancy and decreases after delivery. However, a previous pregnancy does not appear to be a definitive risk factor for meningioma. Studies have also shown a link, albeit weak, between breast cancer and meningiomas.
No significant association between exogenous female hormones and the risk of meningioma has been demonstrated to date for hormonal contraceptives (combined or progestin pills). Furthermore, data concerning hormonal substitute for menopause is contradictory. Several studies have shown a slight excess risk of meningioma associated with the use of hormonal substitutive treatments for menopause, while others have not reported any deleterious effect of these molecules. On the other hand, the excess risk of meningioma observed with the use of high doses of cyproterone acetate in CIS women, men, and trans women has proven to be very high and slightly lower, but still substantial, for chlormadinone acetate and nomestrol acetate. The cessation of each of these three progestins generally leads to a reduction in the volume of meningioma, which makes it possible to avoid surgery and its risks of complications for most patients.
It is still unknown whether progestins other than these three high-dose oral progestins have a similar effect depending on their route of administration. Our study aimed to evaluate the real-world risk of intracranial meningioma associated with the use of progestins from an extensive list (progesterone, hydroxyprogesterone, dydrogesterone, medrogestone, medroxyprogesterone acetate, promegestone, dienogest, and levonorgestrel intrauterine systems) with different routes of administration (oral, transdermal, intravaginal, intramuscular, and intrauterine). While some of the progestins studied are used in France (promegestone) or in only a few countries (medrogestone), others are widely used worldwide at varying doses and for different indications (progesterone, levonorgestrel, hydroxyprogesterone, medroxyprogesterone) (Supplementary Table A). Some progestins may also pose a risk at certain doses when used over a long period, but not at lower doses or when used for a short period. Our secondary objectives were to describe the characteristics of the women in the case group (age, grade, and anatomical location of the meningiomas) and to estimate the number of surgically treated meningiomas attributable to the use of the progestins in question.
Methods of Study
: Study Design and Data Source
This population-based observational study used data from the French National Health Data System (SNDS). Given the analysis of multiple exposure situations (different definitions of exposure and follow-up periods) in our study, we opted for a case-control model rather than a cohort study, which allowed us to include long-term users of the drugs under consideration.
The SNDS database contains information on all health expense reimbursements for more than 99 % of the population residing in France and is linked to the French hospitals database. SNDS is currently one of the largest health care databases in the world and is widely used in pharmaco-epidemiological studies.
Case definition and control selection:
Eligible cases in this study were women of all ages residing in France who underwent surgery for an intracranial meningioma between January 1, 2009, and December 31, 2018. For each case, the corresponding hospital admission start date served as the index date. Women whose pregnancy had begun within the two years preceding the index date were excluded from the study (pregnancies were defined as those resulting in delivery or medical termination of pregnancy after 22 weeks of amenorrhea).
Intracranial meningiomal surgery was defined by the simultaneous combination of diagnostics and following acts recorded for the same hospital stay: a meningeal tumor (Codes D32, D42, or C70 according to the 10th revision of the International Classification of Diseases (CIM-10) coded as the main diagnosis of admission to the hospital and a surgery act intracranial (additional table B). These codes have already been used in our previous studies.
Five women of the control group were randomly paired with each woman in the case group for the year of birth and the region of residence ("department", a French geographic subdivision, n = 101). The traceability of the controls in the SNDS has been ensured by selecting only women who had at least one service reimbursed in the calendar year preceding the date of the index and in the two to three civil years preceding the date of the index. This criterion was also applied to the selection of cases.
For analyzes relating to intrauterine systems, subsets of these cases and paired witnesses have been taken into account to guarantee long enough time. For hormonal intrauterine systems containing 52 mg of Lévonorgestrel and intrauterine copper devices, cases and witnesses from 2011 to 2018 to been retained. For hormonal intrauterine systems containing 13.5 mg of Lévonorgestrel, the inclusion period was restricted at 2017-2018 (start of marketing in France in 2013).
Definition of exposure
Exposure to the progestin in question has been defined according to the WHO Anatomical Therapeutic Chemical (ATC) classification. The list included progesterone (oral and intravaginal: 100, 200 mg (ATC code G03DA04); percutaneous: 25 mg per bar (G03DA04)), dydrogesterone (10 mg, or in combination with estrogens: 5 or 10 mg (G03DB01, G03FA14, G03FB08)), hydroxyprogesterone (500 mg (G03DA03)), medrogestone (5 mg (G03DB03)), promegestone (0.125, 0.25, or 0.5 mg (G03DB07)), medroxyprogesterone acetate (injectable contraceptive, 150 mg/3 ml (G03AC06, L02AB02 partially)), dienogest (in combination with estrogen, 2 mg) (G03FA15)), levonorgestrel (52 mg intrauterine systems (G02BA03); 13.5 mg intrauterine systems (G02BA03)) (Supplementary Tables C and D). Since drospirenone, a derivative of spironolactone, is not reimbursed in France, we were unable to access data concerning its use. We therefore chose to study the use of spironolactone (25, 50, and 75 mg), even though its indications can be very different. The code used to identify spironolactone is C03DA01. The indications for these different progestins in France are available in Table 1 (see link to the study).
For oral, intravaginal, percutaneous or intramuscular progestins, the exposure was defined as at least a dispensation of the progestogen concerned during the 365 days preceding the index date. For intrauterine progestins, a dispensation has been sought in the three years preceding the index date for the Levonorgestrel 13.5 mg (the duration of efficiency of this intrauterine system being three years before any change or withdrawal of the system) and within the five years preceding the index date for intrauterine systems at the levonorgestrel 52 mg ( at six years according to the recommendations in force during the study period).
The exhibition has been described by three modes for each progestogen as follows: 1) Exhibition to the progestogen concerned, 2) Exhibition during the three years preceding the index date to at least one of the three high dose progestins known to increase the risk of meningioma (that is to say chlormadinone acetate, nomestrol acetate and cyproterone acetate), Progressive concerned or three high dose progestins (the reference for analyzes).
Definition of covariates
The description of sociodemographic and medical characteristics included age, region of residence, existence of neurofibromatosis type 2 (ICD-10 code Q85.1), and, for cases only, year of surgery, anatomical site (anterior, middle or posterior base of skull, convexity, falx and tentorium, other; Supplementary Table C), and degree of meningioma severity (according to WHO classification: benign, malignant, or atypical, Supplementary Table E).
Additional radiotherapy was also sought between three months before the index date and six months later (additional table F). In addition, the mortality of all causes combined two and five years after the date of the index was evaluated in cases, as well as the use of antiepileptic drugs during the third year after the date of the index (additional table G).
Statistical Analysis:
Conditioned pairwise logistic regression models were used to estimate odds ratios and their 95% confidence intervals (CIs) for the association between exposure to the studied progestins and meningioma (odds ratio of exposure versus no exposure). In addition, the effect of a history of neurofibromatosis type 2 on the risk of meningioma was estimated, as well as the effect of exposure to chlormadinone acetate, nomegestrol acetate, and cyproterone acetate, all of which served as positive controls for exposure to validate our results. Concurrently, exposure to a copper intrauterine device was used as a negative control for exposure (codes in Supplementary Table H).
The risk of meningioma associated with the use of progestins has also been estimated for each oral, percutaneous, intravaginal and intramuscular progestogen depending on the duration of use: in the short term (at least one exemption in the year preceding the date of the index but no exemption in the second year preceding the date of the index) and in the long term (at least one exemption in the year preceding the the index and at least one exemption in the second year preceding the date of the index).
The fraction attributable to the population has been approximated from the ODDS Ratio obtained for each progestogen. The formula used was as follows: Fraction attributable to the population = PC (1-1/Cost ratio), where PC is the prevalence of the use of the progestin concerned (isolated exposure) among the cases. Finally, sensitivity analyzes were carried out. The analyzes were laminated according to age (<35 years, 35-44 years, 45-54 years, 55-64 years and ≥65 years) and the location and the degree of severity of tumors each time a positive association was found between exposure to the progestogen considered and meningioma surgery.
The data was analyzed using the SAS version 9.4 (SAS Institute inc) software. A value P below 0.05 was considered to be statistically significant (two -sized tests).
Ethics:
This study was authorized by decree 2016-1871 of December 26, 2016. As an authorized permanent user of the SNDS (National Health Data System), the author's team was exempted from approval by the institutional review committee. This work was registered, prior to its implementation, in the EPI-PHARE scientific interest group's registry of studies under registry reference T-2023-01-437.
Patient and public participation
The list of progestins of interest (supplementary table B) was established in consultation with a temporary scientific council composed of representatives of the National Agency for the Safety of Medicines and Health Products, patient associations and health professionals (neurosurgery, endocrinology, gynecology and general medicine).
Results
Description of cases and controls
A total of 108,366 women were included in the study during the inclusion period from 2009 to 2018, of which 18,061 women in the case group were matched to 90,305 in the control group (see Table 1 in the link to the study).
Of these, 15,162 cases and 75,810 controls were included in the analyses of intrauterine systems and copper IUDs using 52 mg levonorgestrel (restricted inclusion period: 2011 to 2018) (Supplementary Table A), and 4,048 cases and their 20,240 controls were included in the analysis of 13.5 mg levonorgestrel IUDs (2017–18) (Supplementary Table B). Case and control descriptions for the IUD analyses are detailed in Supplementary Tables I and J.
The mean age of all women was 57.6 years (standard deviation 12.8 years). The most represented age groups were 45-54 years (26.7%), 55-64 years (26.4%) and 65-74 years (21.5%) (see table 2 in the link to the study).
The number of cases increased regularly, from 1329 in 2009 to 2069 in 2018. The meningiomas requiring surgical intervention were most often located at the base of the skull (10 046/18 061 cases in total (55.6 %); anterior skull base: 3979/18 061 (22.0 %), average: 3911/18 061 (21.7%), posterior: 2156/18 061 (11.9%)), followed by convexity (6468/18 061 (35.8%)). Regarding the rank of the tumor, most meningiomas were mild (16,662/18 061, 92.3 %), 1047/18 061 (5.8 %) were classified as atypical and 352/18 061 (1.9 %) as clever. Among the cases, 28.8% (5202/18 061) of women used antiepileptic drugs three years after the index date of surgery. Mortality was also higher in cases than in witnesses: 502 cases/18,061 (2.8 %) died within two years (compared to 1.2 % of witnesses) and 951/18 061 (5.3 %) within five years (against 3.4 % of witnesses). Mortality was higher for cases with malignant tumors, 12.5 % of which died within two years and 20.7 % within five years.
Comparison of cases and witnesses in the subsets used to analyze hormone intrauterine systems is included in additional data (additional tables I and J).
Progestins (other than intrauterine)
Exposure among cases
Among the 18,061 women admitted to hospital for meningioma surgery between 2009 and 2018, 329 (1.8%) had used oral or intravaginal progesterone, 90 (0.5%) percutaneous progesterone, zero hydroxyprogesterone, 156 (0.9%) dydrogesterone, 42 (0.2%) medrogestone, nine (
Effect on the risk of meningioma:
No significant association with an increased risk of surgically treated intracranial meningioma was observed with exposure to oral or intravaginal progesterone (odds ratio 0.88 (95% CI 0.78 to 0.99)) or percutaneous progesterone (1.11 (0.89 to 1.40)), dydrogesterone (0.96 (0.81 to 1.14)) or spironolactone (0.95 (0.84 to 1.09)) (Table 3, Supplementary Table C). Exposure to dienogest was rare, with only 14 women exposed (3/18,061 among cases and 11/90,305 among controls), and therefore the estimated odds ratio had a very wide confidence interval (1.48 (0.41 to 5.35)). Furthermore, we were unable to assess the odds ratio for hydroxyprogesterone because no exposed cases were found (Table 2).
On the other hand, an excessive risk of meningioma was associated with the use of the Medrogestone (3.49 (2,38 to 5.10)), the medroxyprogesterone acetate (5.55 (2.27 to 13.56)) and the promisegestone (2,39 (1.85 to 3.09)). As expected, an excessive risk of meningioma has been observed in women exposed to type 2 neurofibromatosis (18.93 (10.50 to 34.11)), as well as in those exposed to chlormadinone acetate (3.87 (3.48 to 4.30)), nomigestrol acetate (4.93 (4.93 (4.50 to 5.41)) and Cyproterone acetate (19.21 (16.61 to 22.22)) (Table 2).
The duration of exposure to Medrogestone, MédroxyProgesterone Acetate, Promegestone, ChlormaDinone, Nomestrol and Cyproterone Acetate for Exposed cases and witnesses are presented in the additional table L. The results show that three -quarters of the women in the group of cases which had been exposed for more than three years. With regard to medrogestone, MédroxyProgesterone acetate and Promergestone, excess risk associated with prolonged use was higher than that measured for short -term exposure and combined prolonged. More specifically, the prolonged use of the Promegestone had a rating of dimension of 2.74 (2.04 to 3.67) (against 2.39 for all exposure durations) and short -term use of a dimension ratio of 1.62 (0.95 to 2.76). For the prolonged use of Médrogestone, the rating ratio was 4.08 (2.72 to 6.10) (compared to 3.49 for all the exposure durations combined), and for MédroxyProgesterone acetate, the rating ratio was 5.62 (2,19 to 14.42). No significant association has been reported for short or prolonged periods of use of other progestins studied.
The meningiomas before the age of 45 were rare in the cases of exposure to the Medrogestone (n = 3/42), to medroxyprogesterone acetate (n = 3/9) or to the Promegestone (n = 10/83), and only one (medroxyprogesterone) was observed before the age of 35 years.
With regard to medrogestone, the most frequent locations of meningiomas in the cases exposed were the base of the skull (n = 21/42; 13 in the middle) and convexity (n = 19/42) (additional tables M, N and O). The excess risk of meningioma for the midfielder of the skull was particularly high (ODDS Ratio 8.30 (95 % CI 3.70 to 18.63)). In addition, the excess risk estimated in women aged 45 to 54 was slightly higher than in the main analysis (4.53 (2.73 to 7.53) against 3.49 (2.38 to 5.10)).
Among the women of the group of cases exposed to the Promegestone, meningiomas were preferentially located at the front of the base of the skull (n = 25/83), on convexity (n = 25/83) and in the middle of the skull base (n = 22/83). The excess risk of meningioma linked to the use of the Promegestone was slightly higher in the group of over 65 years (ODDS Ratio 3.21 (95% CI 1.39 to 7.43)) and for the meningiomas located at the front or in the middle of the skull base (3.15 (1.95 to 5.10) and 3.03 (1.82 to 5.02), respectively).
We did not find any clever grade tumor among the cases exposed to Medrogestone, medroxyprogesterone acetate or promotestone (for information, the same analyzes were carried out for chlormadinone acetate, nomestrol acetate and cyproterone acetate in the additional table).
Levonorgestrel-containing intrauterine systems:
Exposure among cases
. A total of 566/15,162 users of 52 mg levonorgestrel were among those who underwent surgery for meningioma between 2011 and 2018 (3.7%) (Table 3). For intrauterine systems containing 13.5 mg levonorgestrel, 10 users out of 4,048 were reported among cases in 2017 and 2018 (0.2% of all cases). Again, women who had been exposed to cyproterone acetate, nomegestrol acetate or cyproterone acetate, or a combination thereof, in the previous three years were not counted (among them, 95 were exposed to 52 mg levonorgestrel intrauterine systems and three to 13.5 mg levonorgestrel intrauterine systems).
Effect on the risk of meningioma
No excess risk of meningioma has been reported with the use of hormonal intrauterine systems containing 52 mg (odds ratio 0.94 (95% CI 0.86 to 1.04)) or 13.5 mg (1.39 (0.70 to 2.77)) of levonorgestrel (Table 2).
Exposure to copper intrauterine devices, used as a negative exposure control in this study, presented an ODDS ratio of 1.13 (1.01 to 1.25).
Attributable Cases
: The population attributable fractions, which are relative to the total number of surgically treated intracranial meningiomas observed, were 0.17% for medrogestone exposure, 0.04% for medroxyprogesterone acetate, and 0.27% for promegestone. For comparison, they were calculated at 2.58% for chlormadinone acetate, 4.08% for nomegestrol acetate, and 4.68% for cyproterone acetate. The figures for attributable cases are presented in Supplementary Table D.
Discussion
Main results
Although the risk of meningioma was already known for three progestins, this study is the first to assess the risk associated with progestins that are much more widely used for multiple indications, such as contraception.
This study based on the population shows an association between the prolonged use of Medrogestone (5 mg), injectable medroxyprogesterone acetate (150 mg) and Promegestone (0.125, 0.25, 0.5 mg) and a risk of intracranial meningioma requiring surgical intervention. No risk of this type has been reported for using less than a year of these progestins. On the other hand, we did not find excess risk of meningioma with the use of progesterone (25, 100, 200 mg; oral, intravaginal, percutaneous), Dydrogesterone (10 mg, combined with estrogens: 5, 10 mg), or Spironolactone (25, 50, 75 mg), neither in the short term nor in the long term The use of intrauterine systems in Levonorgestrel (13.5, 52 mg). A small number of women have been exposed to Diénogest (2 mg, in combination with estrogens) and hydroxyprogesterone (500 mg), and we cannot therefore draw conclusions concerning the association between the use of these progestins and the risk of meningioma.
No malignant meningioma was observed in women exposed to Medrogestone, medroxyprogesterone acetate or the Promegestone. In addition, the number of cases of intracranial meningiomas treated surgically attributable to the use of these progestins was much lower than the number of cases attributable to the taking of chlormadinone acetate, nomigestrol acetate and, in particular, of cyproterone acetate. This result is explained both by an excess risk of lower meningioma (for medrogestone and prominegestone) and by lower rates of use in France (particularly low for medroxyprogesterone acetate, with less than 5,000 women exposed each quarter during the period of inclusion of the 2009-18 study).
Specific Considerations Regarding Meningiomas:
Meningiomas are essentially benign tumors. Between 2011 and 2015, 80.5% of meningiomas diagnosed in the United States were grade 1, 17.7% grade 2, and 1.7% grade 3.<sup>1</sup> Even in the absence of malignancy, meningiomas can cause potentially debilitating symptoms. In such cases, the first-line treatment is surgery, even for the oldest patients, which carries a risk of complications and morbidity.
Age is an important factor both for the indication of progestins and to consider intracranial surgery. In our study, the average age of women in the group of cases was 57.6 years. Medrogestone, medroxyprogesterone acetate and prominegestone can be used by women of childbearing, premenopausal and postmenopausal age. In our study, only one user of these progestins who underwent meningioma surgery was under the age of 35 (medroxyprogesterone).
Postoperative complications are not uncommon in the case of meningiomas. Depending on the exact location of meningiomas, the surgical risk varies, but the operation can have serious neurological consequences due to the immediate proximity of a highly functional cortical area and critical neurovascular structures. Cognitive functions tend to improve after the operation of a meningioma, but several studies have suggested a risk of postoperative anxiety and depression and high consumption of antidepressants and sedatives in the medium term, although other studies have reported contradictory results concerning depression. Epilepsy attacks are also a possible short -term complication of the operation, resulting in the need to take antiepileptic drugs in the years following the operation. In our study, almost three in ten women (28.8 % of cases) used antiepileptic drugs three years after the operation, which corresponds to the results previously published. In addition, the results have shown that progesterone -related meningiomas tend to occur more frequently at the base of the skull and that lesions surgery at this place is much more difficult. The recent evidence of stabilization or the regression of meningiomas after stopping chlormadinone acetate, nomestrol acetate and acetate Cyproterone have reduced surgical indications for these patients, thus avoiding potential complications. A recent report has shown that, although the tissue of meningioma most often regresses in size, hyperostosis associated with meningiomas is still increasing, which may require surgery, not for oncological purposes, but only for the decompression of nervous structures and for the relief of symptoms.
Use of Progestins Studied in France and Worldwide:
Medrogestone is indicated in France for the treatment of menstrual cycle disorders and luteal insufficiency (dysmenorrhea, functional or fibroid-related menorrhagia, premenstrual syndrome, and irregular cycles), endometriosis, mastodynia, and hormone replacement therapy for menopause. In the United States, medrogestone has never been approved by the Food and Drug Administration (FDA). Outside of France, this molecule is also used in Germany, in combination with estrogens (0.3 mg/5 mg, 0.6 mg/2 mg, 0.6 mg/5 mg). The use of medrogestone increased significantly in France in 2019, notably due to the postponement of prescriptions for chlormadinone acetate, nomegestrol acetate, and cyproterone acetate, following French and European recommendations in 2018 and 2019 to reduce the risk of meningioma attributable to these progestins. As therapeutic alternatives have not shown an increased risk of meningioma, switching from products known to increase this risk to medrogestone should be reconsidered.
Worldwide, in 2019, 3.9 % of women of prosecuted age used injectable contraception (medroxyprogesterone), or 74 million users, but figures vary strongly between the world regions (from 1.8 % in high -income countries to 8.7 % in low -income countries). This method of contraception is the most used in Indonesia (13 million women), Ethiopia (4. 6 million women) and South Africa (3.6 million women). In the United States, MédroxyProgesterone acetate is used in more than 2 million prescriptions in 2020 and more than one in five sexually active American declares that she used injectable medroxyprogesterone acetate (150 mg/3 ml) during his life. Injectable contraceptives are much less used in Europe (3.1 % of women of childbearing age in the United Kingdom and 0.2 % in France). Our results confirm the preliminary conclusions of studies relating to cases of meningiomas exposed to chronic use of a acetate of medroxyprogesterone or on cases of administration of high doses. In particular, our results have similarities with those of a retrospective journal of 25 patients diagnosed with meningioma with antecedents of chronic use of chronic acetate Medroxyprogesterone and treated at the medical center of the University of Pittsburgh between 2014 and 2021 concerning the characteristics of cases exposed to medroxyprogesterone acetate (women (average age of 46 years) with meningiomas commonly located at the base of the skull). In addition, medroxyprogesterone acetate used as injectable contraceptives is known to be prescribed to specific populations, especially people with mental illnesses. The protection of these vulnerable populations against additional drug risks is particularly important. Médroxyprogesterone acetate in deposit (150 mg) is approved as a means of contraception in more than 100 countries around the world. In countries where the number of people using medroxyprogesterone acetate is high, the number of meningiomas attributable to this progestogen can be potentially important. In addition, medroxyprogesterone (non-acetate) is also used orally, in lower doses, in certain countries other than France (especially in the United States), for which there are no data on the risk of meningioma to date.
Promegestone was only available in France (not marketed in other countries) and was withdrawn from the market in 2020. This medication was indicated for the relief of perimenopausal symptoms and for hormone replacement therapy during menopause. With its discontinuation, some users may have switched to medrogestone in 2020, a molecule also implicated in the risk of meningioma in our findings. Clinicians must therefore remain vigilant, as the risk of meningioma could persist beyond the market withdrawal and any potential switch to another progestin.
The FDA defines a therapeutic class like "all the products (...) supposed to be closely linked in terms of chemical structure, pharmacology, therapeutic activity and undesirable effects". There are different subtypes of progestins as a function of the molecule whose progestin is derived (ex: progesterone, testosterone and spironolactone) (additional table B). Their chemical structures and pharmacological properties differ according to this classification, which explains why no class effect is reported for certain benefits and risks associated with their use (for example, breast cancer and cardiovascular risk). The progestins have distinct affinities for the different steroidal receptors of the target organs, which can vary even within a subclass, which determines their activity.
Our study suggests that the 17-OH-Hydroprogesterone and the derivatives of 19-Norprogesterone, both derived from progesterone, have a class effect on the risk of meningioma. Four of the five progestins belonging to the group of 17-OH-Hydroprogesterone showed an increase in the risk of meningioma (additional table R). However, the fact that we have found different risk sizes seems to be more a question of cumulative duration and dose than belonging to a class of progestins. We were unable to draw conclusions on hydroxyprogesterone (due to lack of power), the fifth progestogen of the subclass, but its main indication (assisted procreation technique) corresponded to fewer exposed women and a very short exposure (about 15 days), which could explain that this drug is different from the others. Finally, to date, in the doses considered in the study, no excess risk of meningioma associated with testosterone derivatives has been highlighted. However, the risk of meningioma associated with the use of these derivatives in other doses and in other patterns must be studied.
Strengths and limitations:
To our knowledge, this meningioma risk study is the first to expand the list of progestins of interest beyond chlormadinone acetate, nomegestrol acetate, and cyproterone acetate, detailing the risk associated with each progestin and its various routes of administration. This nationwide study included women of all ages, both in the case and control groups. The SNDS database allowed for the use of comprehensive data over a 12-year period (2006–2018; postoperative information was retrieved up to 2022), thus avoiding recall bias.
The exclusion of women whose pregnancy began in the two years preceding the date of the index made it possible to guarantee the reliability of the risk estimates associated with the use of progestins. Pregnancy is a single state, which affects exposure to progestins (of endogenous or exogenous origin), the probability of appearance or increase in the volume of meningioma, and the probability of admission to the hospital for surgery (with possibly a lower intervention rate, depending on symptoms, maternal and fetal health, and characteristics of the tumor).
Another potentially important factor of confusion, the use of chlormadinone acetate, nomigestrol acetate or cyproterone acetate has been taken into account in analyzes by modeling exposure to each progestogen of interest with a separate or simultaneous exposure mode to these drugs. In addition, the results obtained for exposure to negative and positive control, including exposure to chlormadinone acetate, nomestrol acetate and cyproterone acetate, confirm the merits of the method chosen for this study.
However, this study also has several limitations. Due to the scarcity of historical data in the SNDS (which began in 2006 and lacked information for some reimbursement schemes in its early years), we only have three years of follow-up for the oldest meningioma cases (2009-2006) and 12 years for the most recent. The SNDS does not provide information on non-reimbursed medications, which forced us to study dienogest in combination with estrogens rather than dienogest alone. Further studies will therefore be necessary. Similarly, we were unable to study other progestins, such as norgestimate, gestodene, and norethisterone, which are contained in non-reimbursed products (Supplementary Table B). In contrast, desogestrel is available and reimbursed in France. Because its dosage is much lower, we chose not to study it. Further study to evaluate the dose-response relationship with prolonged use would be necessary. Progestin implants (etonogestrel) are also rarely used in France and are primarily used by young women, for whom the risk of meningioma is likely very low. We also did not study the risk associated with the use of hormonal intrauterine systems containing 19.5 mg of levonorgestrel because their marketing in France is too recent (2018). However, an increased risk associated with the use of 19.5 mg levonorgestrel intrauterine systems is unlikely because this dose of levonorgestrel is lower than that of 52 mg levonorgestrel intrauterine systems, for which we observed no risk.
Furthermore, the SNDS does not provide information on all the clinical details and medical indications for which progestins are prescribed. This missing data makes it impossible to assess the benefit-risk ratio of prescriptions, which could be favorable in the absence of an effective alternative, for example, in the case of relieving endometriosis symptoms. We only have an indirect idea of the indication, based on the user's age and the molecule used (progesterone is not indicated for endometriosis, for example, and dydrogesterone is indicated for endometriosis but is rarely used for this purpose). Nevertheless, assessing the benefit-risk ratio was not the objective of our study and will require further studies using other data sources to evaluate product efficacy. Moreover, no data suggest that the increased risk of meningioma depends on the medical indication for prescribing the progestin. In the 2021 study by Weill and colleagues, the excess risk of meningioma associated with the use of cyproterone acetate was equivalent for men and women, who nevertheless use cyproterone acetate for radically different indications.
In this study, only hospital admission for meningioma surgery was used as an outcome of interest. However, meningiomas can also be treated with radiotherapy (in rare cases) or simply monitored. Therefore, it is highly likely that this study underestimated the prevalence of meningiomas attributable to progestin use by limiting itself to symptomatic tumors requiring surgical intervention. Nevertheless, using hospital admission for surgery as an outcome ensured diagnostic specificity and thus limited classification bias. The SNDS (French National Health Data System) does not specify the histological characteristics of meningiomas or whether the tumor is solitary or multiple, two important criteria for determining severity and choosing the appropriate treatment. However, for the cases selected for this study, the WHO meningioma severity grade is coded via the primary diagnosis, which is entered using the ICD-10 code at the end of the hospital stay after reviewing the pathology report. We therefore have indirect information on the histology of tumors.
Our study has several confusion factors. The two main risk factors identified for meningioma, in addition to age (taken into account in this study) and being a woman (only women were included in this study), are genetic predisposition, attributed in particular to hereditary mutations in the gene of type 2 neurofibromatosis, and medical or environmental exposure to high doses of ionizing radiation. Radiation therapy for brain cancer (especially during childhood) is probably the most important medical reason for exposure to intracranial radiation, but only a small proportion of individuals in the general population has undergone brain radiotherapy or malignant cerebral tumor during childhood.
The progestins studied in our study which have not led to an increase in the risk of meningioma should be considered under the specific conditions of use in France. These results cannot be generalized to the use of these progestins in other indications, at higher doses or longer durations of use. Likewise, the use of one or more of these progestins could increase the risk of meningioma, when the patient has already received another type of progestogen.
The prescribers must be aware of the previous use of progestins, whatever they may be, and any change in the type of prescribed progestogen, and must take into account the cumulative dose of progestogen for each patient. The list of progestins that we have studied is very wide, covering a variety of indications (summarized in Table 1) for women of all ages (of prosecutor, premenopausal and menopausal). As in the hormonal treatment of menopause, progestins can be easily substituted for each other, and progesterone therefore seems to be the safest alternative. For endometriosis, however, the therapeutic alternatives are much more limited and each indication must be discussed on the basis of the personal benefit/risk ratio. If a high risk progestin should be continued, clinical and radiological monitoring and compliance with the recommendations are essential.
Finally, we did not estimate the effect of concomitant use of estrogen on the risk of meningioma. In a previous report, the concomitant prescription of estrogen was weakly but significantly associated with the risk of meningioma, with an adjusted risk ratio on the age of 1.6 (95 % CI: 1.1 to 2.4) for the use of cyproterone acetate. In our previous studies, the simultaneous prescription of estrogen with chlormadinone acetate (risk ratio 0.8 (0.5 to 1.3)) and nomestrol acetate (1.0 (0.7 to 1.7)) was not significantly associated with a risk of meningioma. In addition, in these two studies, which were cohort studies of women starting treatment with the progestogen considered, the proportion of women with a simultaneous prescription of estrogen at the start of progestin treatment was relatively low (6.8 % and 5.0 %, respectively, per study).
Conclusions:
Prolonged use of medrogestone, medroxyprogesterone acetate, and promegestone has been shown to be associated with an increased risk of meningioma. Future studies should further clarify the association between duration of use and risk for the progestins studied, and extend the discussion on meningioma risk to dienogest and hydroxyprogesterone. Finally, no increased risk of meningioma has been associated with the use of progesterone, dydrogesterone, spironolactone, or hormonal intrauterine systems used worldwide, regardless of the levonorgestrel dose they contain.
Other studies are also necessary to assess the risk of meningioma linked to the use of medroxyprogesterone acetate, which, in this study, was considered at a dose of 150 mg and corresponded to a second -intention injectable contraceptive rarely used in France. Studies in countries where the use of this product is wider and, moreover, often administered to vulnerable populations, are urgent to better understand its association dose-response.
What we already know about this subject
– Known risk factors for intracranial meningioma include age, female sex, neurofibromatosis type 2, exposure to ionizing radiation and the use of high-dose progestins: nomegestrol, chlormadinone and cyproterone acetate
– Many other progestins are widely used for multiple indications for which the risk of meningioma associated with their use has not been individually estimated.
What this study adds
– Prolonged use of medrogestone (5 mg, oral), medroxyprogesterone acetate (150 mg, injectable), and promegestone (0.125/0.5 mg, oral) has been shown to be associated with an increased risk of intracranial meningioma.
– In countries where medroxyprogesterone acetate is commonly used for birth control (74 million users worldwide), the number of attributable meningiomas may be potentially high.
– The results concerning oral, intravaginal, and transdermal progesterone, as well as dydrogesterone and levonorgestrel intrauterine systems, are reassuring and confirm the absence of an increased risk of meningioma.
Ethical Statements
Ethical Approval
This study was authorized by Decree 2016-1871 of December 26, 2016.27 As a permanent user of the SNDS, the author's team was exempted from approval by the institutional review committee. This work was registered, prior to its implementation, in the registry of studies of the EPI-PHARE scientific interest group requiring the use of the SNDS (register reference: EP-0437).
Data Availability Statement:
According to the terms of the SNDS data use agreement, the complete study data cannot be shared with other researchers (https://www.snds.gouv.fr). However, the authors strive to share as much of the publication-related data as possible: algorithms and other additional information are provided in the supplementary data; aggregated data can be provided upon request by contacting the corresponding author at noemie.roland@assurance-maladie.fr.
Acknowledgements
We thank Bérangère Baricault and Pauline Dayani for their assistance in responding to the reviewers, as well as Sylvie Fontanel and Emmanuelle Mignaton for proofreading the manuscript. We also thank Alex Edelman and Associates for proofreading the English version.
Footnotes
– Contributors: AW conceived the study. NR, AN, LH, and AW designed and planned the study. NR and AN wrote the manuscript. AN and LH managed the data. AN, LH, and NR performed the statistical analyses. AW and MZ managed the project and the study. All authors approved the final manuscript. The corresponding author (NR) attests that all cited authors meet the criteria for authorship and that no other eligible authors have been omitted. AW is the guarantor.
