Use of progestins and risk of intracranial meningioma: national case-testimony study
Study of Epi-Phare published at BMJ
https://www.bmj.com/content/384/bmj-2023-078078
- Noémie Roland, general practitioner and epidemiologist,
2. Anke Neumann, Main 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 Service,
7. and deputy director
Affiliations of the authors
1. Correspondence to: n Roland Noemie.roland@assurance-maladie.fr (@noemierland11 @epiphare on x)
- Accepted on February 22, 2024
Summary
Objective Evaluating the risk of intracranial meningioma associated with the use of certain progestins.
CAS-TESTIMENT NATIONAL STUDY
design system of French health data (SNDS).
Participants: out of a total of 108,366 women, 18,061 women living in France and having undergone intracranial surgery for meningioma between January 1, 2009 and December 31, 2018 (periods of restricted inclusion for intrauterine systems) were considered to be part of the case group. Each case was paid to five witnesses for the year of birth and the region of residence (90,305 witnesses).
Main evaluation criteria: selected progestins have been used: progesterone, hydroxyprogesterone, dydrogesterone, medrogestone, medroxyprogesterone, promotestone, dienogestone and intrauterine levonorgestrel. For each progestogen, the use was defined by at least one dispensation in the year preceding the index date (within three years for intrauterine systems at the Lévonorgestrel of 13.5 mg and within five years for those of 52 mg). Conditional logistics regression has been used to calculate the rating report for each progestin meningioma association.
Results The average age was 57.6 years (standard deviation 12.8). The analyzes showed an excess risk of meningioma with the use of medrogestone (42 cases exposed/18,061 cases (0.2 %) against 79 witnesses exposed/90,305 witnesses (0.1 %), Odds Ratio 3.49 (95 %confidence interval 2. 38 to 5.10)), MédroxyProgesterone Acetate 9/18 061 (0.05 %) V 11/90 305 (0.01 %), 5.55 (2.27 to 13.56)), and Promestone (83/18 061 (0.5 %) V 225/90 305 (0.2 %), 2.39 (1.85 to 3.09)). This excess risk was due to prolonged use (≥ one year). The results have shown no excess risk of intracranial meningioma for intrauterine progesterone systems, dydrogesterone or levonorgestrel. No conclusion could be drawn concerning dienogest or hydroxyprogesterone due to the small number of people who have received these drugs. A strongly increased risk of meningioma was observed for cyproterone acetate (891/18 061 (4.9%) V 256/90 305 (0.3%), ODDS Ratio 19.21 (confidence interval at 95%16.61 to 22.22)), Nomestrol acetate (925/18 061 1121/90 305 (1.2%), 4.93 (4.50 to 5.41)), and chlormadinone acetate (628/18 061 (3.5%) V 946/90 305 (1.0%), 3.87 (3.48 to 4.30)), which were used as positive controls for use.
Conclusions
The prolonged use of medrogestone, acetate of medroxyprogesterone and prominegestone 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 intrauterine systems in levonorgestrel are new important discoveries.
Introduction
Méningiomes represent 40 % of primary tumors in the central nervous system. The incidence of meningiomas in the United States is 9.5 per 100,000 people-years. Meningiomas are mostly histologically benign tumors with slow growth, but they can nevertheless compress adjacent cerebral tissues and patients may therefore need 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, in particular progesterone, and intracranial meningiomas is biologically plausible. Progress receptors are present in more than 60 % of meningiomas and it was observed that the volume of these tumors increased during pregnancy and decreased after childbirth. However, an earlier pregnancy does not seem to be a unequivocal risk factor of meningioma. Studies have also shown a link, although 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.
We still do not know if progestinas other than these three oral progestins in high doses have a similar effect according to their path of administration. Our study aimed at assessing the risk of intracranial meningioma in real life associated with the use of progestins of an extensive list (progesterone, hydroxyprogesterone, dydrogesterone, medrogestone, acetate of medroxyprogesterone, promotestone, dienogest and intrauterine systems in the levonorgestrel) Tracks (oral, percutaneous, intravaginal, intramuscular and intrauterine). While some of the progestins studied are used in France (Promestone) or in only a few countries (Medrogestone), others are widely used in the world in doses and for various indications (progesterone, levonorgestrel, hydroxyprogesterone, medroxyprogesterone) (additional table A). Some progestins may also present a risk in certain doses when used over a long period, but not in lower doses or when used over a short period. Our secondary objectives were to describe the characteristics of the women of the case group (age, grade and anatomical location of meningiomas) and to estimate the number of meningiomas treated surgically attributable to the use of the progestins concerned.
Working methods
Design of the study and data source This observational study based on the population used data from the National Health Data System (SNDS). Given the analysis of multiple exposure situations (different definitions of exposure and reversing periods) in our study, we have opted for a case-control model rather than for a cohort study, which allowed us to include long-term users of the drugs considered.
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.
Definition of cases and selection of witnesses
The eligible cases in this study are women residing in France, of all ages, operated with an intracranial meningiom between January 1, 2009 and December 31, 2018. For each case, the date of start of admission to the corresponding hospital marked the date of indexing. Women whose pregnancy had started in the two years preceding the index date were excluded from the study (pregnancies were defined as those that led to childbirth or medical interruption 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 in 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 progestogen considered was defined according to the anatomical, therapeutic and chemical classification (ATC) of the WHO. 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)), Promestone (0.125, 0.25, or 0. 5 mg (G03DB07)), MédroxyProgesterone acetate (injectable contraceptive, 150 mg/3 ml (G03AC06, L02AB02 partially))), Diénogest (in combination with estrogen, 2 mg (G03FA15)), Lévonorgestrel (intrauterine systems of 52 mg (G02BA03); intrauterine systems of 13.5 mg (G02BA03)) (additional tables C and D). The Drospirenone, which is a derivative of the Spironolactone, not being reimbursed in France, we could not access the data concerning its use. We have therefore chosen to study the use of the Spironolactone (25, 50 and 75 mg), even if its indications can be very different. The code used to identify the Spironolactone is C03DA01. The indications of these different progestins in France are available in Table 1 (see the 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 covariables
The description of the socio-demographic and medical characteristics included age, the region of residence, the existence of a type 2 neurofibromatosis (ICD-10 Q85.1), and, for cases only, the year of surgery, the anatomical site (anterior, medium or posterior base, convex, Falx and Tentorium, degree of severity of meningioma (according to the classification of the WHO: Benin, clever, or atypical, additional 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
of logistical regression models packaged on paired pairs were used to estimate the rating reports and their confidence intervals (CI) at 95 % for the association between exposure to the progestins studied and meningioma (rating report of exposure compared to non-exposition). In addition, the effect of type 2 neurofibromatosis history on the risk of meningioma has been estimated, as well as the effect of exposure to chlormadinone acetate, nomigestrol acetate and cyproterone acetate, which are all used as positive controls for exposure in order to validate our results. At the same time, exposure to an intrauterine copper device has been used as a negative exposure control (codes in the additional 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 the 2016-1871 decree of December 26, 2016. As an authorized permanent user of the SNDS, the author's team was exempt from the approval of the institutional examination committee. This work was declared, before its implementation, on the study register of the Scientific Interest Grouping Epi-Phare with the reference of the register T-2023-01-437.
Participation of patients and the public
The list of progestins of interest (Complementary table B) was established in consultation with a temporary scientific council made up of representatives of the national drug safety agency and health products, associations of patients and health professionals (neurosurgery, endocrinology, gynecology and general medicine).
Results
Description of cases and witnesses
in total, 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 appeared at 90,305 in the witnesses group (see Table 1 in the link to the study).
Among them, 15,162 cases and 75,810 witnesses were retained for the analyzes of intrauterine systems and intrauterine copper devices using 52 mg of levonorgestrel (restricted inclusion period: 2011 to 2018) (additional table A) and 4048 cases and their 20,240 witnesses for the analysis of intrauterine systems of 13.5 mg (2017-18) (Additional table B). The descriptions of cases and witnesses for the analyzes of intrauterine devices are detailed in additional tables I and J.
The average age of all women was 57.6 years (standard deviation of 12.8 years). The most represented age groups were 45-54 year olds (26.7 %), 55-64 year olds (26.4 %) and 65-74 year olds (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)
Exhibition among the cases
among the 18,061 women admitted to the hospital for meningiomal surgery between 2009 and 2018, 329 (1.8%) had used oral or intravaginal progesterone, 90 (0.5%) of percutaneous progesterone, zero hydroxyprogesteron, 156 (0. 9%) Dydrogesterone, 42 (0.2%) of Médrogestone, new (<0.1%) of medroxyprogesterone acetate, 83 (0.5%) of Promestone, three (<0.1%) of Diénogest and 264 (1.5%) of Spironolactone (Table 3 of the study, additional table C). These figures exclude 2,999 women who had been exposed to cyproterone acetate, nomestrol acetate or chlormadinone acetate, or a combination, in the previous three years (among these 2,999 women, 68 had also been exposed to oral progesterone or chlormadinon acetate), 68 Oral progesterone, 47 with percutaneous progesterone, 0 at hydroxyprogesterone, 43 at Dydrogesterone, 10 at Médrogestone, 0 with MédroxyProgesterone acetate, 17 at La Promestone, 1 in Diénogest and 56 at the Spironolactone). The cumulative median doses of progestogen for cases and witnesses exposed are indicated in the additional table K.
Effect on the risk of meningioma
No significant association with an increased risk of intracranial meningioma surgically treated has been observed with exposure to oral or intravaginal progesterone (rating ratio of 0.88 (95 % CI from 0.78 to 0.99)) or percutaneous progesterone (1.11 (0.89 to 1.40)), to the Dydrogesterone (0.96 (0.81 to 1.14)) or to the Spironolactone (0.95 (0.84 to 1.09)) (Table 3, additional table C). Exposure to Diénogest was rare, with only 14 exposed women (3/18 061 among the cases and 11/30 305 among witnesses) and, consequently, the estimated rating report had a very large confidence interval (1.48 (0.41 to 5.35)). In addition, we were unable to assess the rating report on hydroxyprogesterone because no exposed case was 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).
Intrauterine systems at the Lévonorgestrel
Exhibition among cases in total, 566/15 162 users of Levonorgestrel Hormonal 52 mg were among the cases operated by meningiom between 2011 and 2018 (3.7%) (Table 3). For intrauterine systems containing 13.5 mg of Lévonorgestrel, 10 users out of 4048 were reported among cases of 2017 and 2018 (0.2 % of all cases). Again, the women who had been exposed to cyproterone acetate, nomestrol acetate or cyproterone acetate, or a combination, during the previous three years have not been counted (among them, 95 were exposed to the intrauterine systems of 52 mg of Lévonorgesrel and three to the intrauterine systems of 13.5 mg Lévonorgestrel).
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 Lévonorgestrel (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).
Cases attributable
The fractions attributable to the population, which relate to the overall observed number of intracranial meningiomes surgically treated, were 0.17 % for exposure to Medrogestone, 0.04 % for medroxyprogesterone acetate and 0.27 % for the prominegestone. For comparison, they were calculated at 2.58 % for chlormaudinone acetate, 4.08 % for nomestrol acetate and 4.68 % for cyproterone acetate. The figures for the attributable cases are presented in the additional table D.
discussion
results although the risk of meningioma was already known for three progestins, this study is the first to assess the risk associated with progestins which 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 on meningiomas
meningioma is an essentially benign tumor. Between 2011 and 2015, 80.5 % of meningiomas diagnosed in the United States were grade 1, 17.7 % grade 2 and 1.7 % grade 3.1 even in the absence of malignancy, meningiomas can cause potentially disabling symptoms. In this case, the first -line treatment is surgery, even for older patients, which implies 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 the progestins studied in France and in the world
Médrogestone is indicated in France in the treatment of menstrual cycle disorders and luteal insufficiency (dysmenorrhea, functional menorrhagia or linked to fibroma, premenstrual syndrome and irregular cycles), endometriosis, mastodynia and the substitute hormonal treatment. In the United States, the Medrogestone has never been approved by the Food and Drug Administration (FDA). Outside 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, in particular due to the prescription postponement of chlormadinone acetate, nomigestrol acetate and cyproterone acetate, following the French and European recommendations for reducing the risk of meningioma attributable to these progestins in 2018 and 2019. The therapeutic alternatives Risk of meningioma, the transition from products notoriously increasing 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.
Promestone was only available in France (not marketed in other countries) and was withdrawn from the market in 2020. This medication was indicated in the relief of premenopause symptoms and in hormonal substitute for menopause. With the cessation of its marketing, some users could have switched to the Medrogestone in 2020, a molecule also involved in the risk of meningioma in our results. Clinicians must therefore remain vigilant because the risk of meningioma could last beyond the withdrawal of the market and from a possible transition to another progestogen.
The FDA defines a therapeutic class as "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 limits
to our knowledge, this study on the risk of meningioma is the first to widen the list of progestins of interest beyond chlormadinone acetate, nomigestrol acetate and cyproterone acetate, by detailing the risk associated with each progestin, with different administration methods. This study was conducted nationally with women of all ages, both for cases and for witnesses. The SNDS database made it possible to use exhaustive data over a period of 12 years (2006-18; postoperative information was sought until 2022), which made it possible to avoid memorization biases.
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 limits. Due to the scarcity of historical data in the SNDS (which started in 2006, and had no information for certain reimbursement plans in the first years) , we only have three years of decline for the oldest (2009-06), and 12 years for the most recent meningiomas . The SNDS does not provide information on non -reimbursed drugs, which forced us to study Diénogest in association with estrogens rather than dienoest alone. Additional studies will therefore be necessary. Likewise, we were unable to study other progestins, such as norgestimate, gestodene and norethisterone, content in non -refunded products (additional table B). On the other hand, the Déogestrel is available and reimbursed in France. Its dosage being much lower, we have chosen not to study it. An additional study to assess a dose-response association in the event of prolonged use would be necessary. Progestative implants (Stonogestrel) are also little used in France, and concern young women, for whom the risk of meningioma is probably very low. We have not studied the risk associated with the use of hormonal intrauterine systems containing 19.5 mg of Lévonorgestrel because its marketing in France is too recent (2018). However, an excess risk linked to the use of intrauterine systems at the 19.5 mg levonorgestrel is unlikely because this dose of levonorgestrel is lower than that of intrauterine systems with levonorgestrel 52 mg, for which we have not observed a risk.
In addition, SNDS does not provide information on all clinical details and medical indications for which progestins are prescribed. These missing data do not make it possible 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 the relief of the symptoms of endometriosis. We have only an indirect idea of the indication, depending on the age of the user, and the molecule used (progesterone is not indicated in endometriosis, for example, and dydrogesterone is indicated in endometriosis but is rarely used in this indication). However, assessment of the benefit/risk ratio was not the objective of our study and will require additional studies using other data sources for product efficiency. In addition, no data suggests that the increase in the risk of meningioma depend on the medical indication of the prescription of the progestogen. In the study of Weill and his colleagues in 2021, the excess risk of meningioma associated with the use of cyproterone acetate was equivalent to men and women, who nevertheless use cyproterone acetate for radically different indications.
In this study, only admission to the hospital for meningioma surgery was used as a result of interest. However, meningiomas can also be treated with radiotherapy (in rare cases) or simply monitored. It is therefore very likely that this study underestimated the prevalence of meningiomas attributable to the use of progestins by limiting itself only to symptomatic tumors requiring surgery. However, the use of admission to the hospital for surgery as a result made it possible to guarantee the specificity of the diagnosis and therefore to limit the classification bias. The SNDS does not specify the histological characteristics of meningiomas or the isolated or multiple nature of the tumor, two important criteria to determine the severity and the choice of the appropriate treatment. However, for cases selected for this study, the gravity of severity of meningioma according to the WHO is coded via the main diagnosis, which is seized according to the CIM-10 code at the end of the hospital stay after reading the anatomopathology 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
The prolonged use of medrogestone, acetate of medroxyprogesterone and prominegestone has proven to be associated with an increased risk of meningioma. Future studies should further clarify the association between the duration of use and the risk for the progestins studied, and extend the discussion on the risk of meningioma to dienogest and hydroxyprogesterone. Finally, no excessive risk of meningioma has been associated with the use of progesterone, dydrogesterone, spironolactone or hormonal intrauterine systems used worldwide, regardless of the dose of levonorgestrel 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
- the known risk factors of intracranial meningioma are age, female sex, type 2 neurofibromatosis, exposure to ionizing radiation and the use of high dose progestins: Nomestrol, Chlormadinone and Cyproterone Acetate
- many other progestins are widely used for multiple indications for multiple indications for multiple indications for multiple indications for multiple indications for multiple indications Which the risk of meningioma associated with their use has not been estimated individually.
What this study adds
- the prolonged use of Medrogestone (5 mg, oral), a acetate of MédroxyProgesterone (150 mg, injectable) and Promestone (0.125/0.5 mg, oral) proved associated with an excessive risk of intracranial meningioma.
- In countries where the use of medroxyprogesterone acetate for birth control is frequent (74 million users worldwide), the number of attributable meningiomas can be potentially high.
-The results concerning oral, intravaginal and percutaneous progesterone, as well as dydrogesterone and intrauterine systems in levonorgestrel, are reassuring and confirm the lack of excessive meningioma risk.
Ethics declarations
Ethical approval This study was authorized by the 2016-1871 decree of December 26, 2016.27 As permanent SNDS user, the author's team was exempt from the approval of the institutional assessment committee. This work was declared, before its implementation, on the study register of the Scientific Interest Grouping Epi-Phare requiring the use of the SNDS (Reference of the Registry: EP-0437).
Data availability declaration
In the words of the SNDS data use agreement, full study data cannot be shared with other researchers (https://www.snds.gouv.fr). However, the authors strive to share publication data as much as possible: algorithms and other additional information is provided in additional data; The aggregated data can be provided on request by contacting the author corresponding to the address naemie.roland@assurance-maladie.fr .
Acknowledgments
We thank Bérangère Baricault and Pauline Dayani for helping them respond to assessors, as well as Sylvie Fontanel and Emmanuelle Mignaton for the rereading of the manuscript. We also thank Alex Edelman and Associates for the rereading of the English version.
Folder notes
- Employees: AW had the idea of the study. NR, AN, LH and AW designed and planned the study. NR and An have written the manuscript. An and LH ensured data management. An, LH and NR carried out statistical analyzes. AW and MZ have managed the project and the study. All the authors approved the final manuscript. The corresponding author (NR) attests that all the authors mentioned meet the criteria of paternity and that no other meeting the criteria has been omitted. AW is the guarantor.
