Context
Prolonged (≥ 1 year) and high dose use of six progestins – cyproterone acetates (≥ 25 mg/day), chlormadinone (5-10 mg/day), nomegestrol (3.75-5 mg/day), medroxyprogesterone (150 mg/1 ml), medrogestone (5 mg) and promegestone (0.5 mg) – greatly increases the risk of intracranial meningioma. This risk has not been evaluated specifically with the use of oral contraception containing the progestins desogestrel (75 μg alone) and levonorgestrel (30 μg alone or at 50, 100, 125, 150 μg in combination with ethinyl estradiol). These two oral contraceptive progestins are very widely used in France with more than 3.6 million women affected in January 2022.
Objective
Evaluate in real life the risk of intracranial meningioma linked to the use of progestin-only oral contraceptives: desogestrel (75 μg, progestin-only pill) and levonorgestrel (progestin-only pill at 30 μg, or contained in a pill combined with ethinyl estradiol at 50 -150 μg).
Method
A case-control study was conducted using information from the National Health Data System (SNDS). We analyzed all cases of women who underwent surgery for an intracranial meningioma between January 1, 2020 and December 31, 2023.
For each case, the index date was the date of entry into the hospital stay relating to the neurosurgical intervention. Furthermore, women who had an onset of pregnancy within three years before the index date were excluded from the study. Ten control women who had not been operated on for meningioma until the index date were randomly associated with each case, matching on year of birth and department of residence, using the risk set sampling approach.
Exposure was defined by at least one delivery in the rolling year before the index date (“current exposure”) of desogestrel 75μg (progestin-only pill), levonorgestrel 30 μg alone (progestin-only pill) or in combined form. (50 to 150 μg, estrogen-progestin pill).
Using conditional logistic regression models, we calculated, for each progestin of interest, the odds ratio (OR) estimating the association between previous exposure to the progestin and the risk of intracranial meningioma. We separated, in a separate modality, any previous exposure (up to six years before) and/or simultaneous exposure to medrogestone, promegestone, cyproterone acetate, chlormadinone, nomegestrol and/or medroxyprogesterone, to avoid a confounding bias linked to the use of a progestogen with a known and demonstrated risk of meningioma. We also calculated the fraction of attributable cases of meningiomas operated on in the population for each progestogen, estimated from the OR obtained in case of significance. We estimated the necessary number of patients treated to observe one case of operated meningioma.
Finally, sensitivity analyzes were carried out: stratification by age (5 age classes: <35 years, 35-44 years, 45-54 years and ≥55 years), by location of the meningioma (anterior, middle or posterior level). of the base of the skull, convexity, falx cerebri and tent of the cerebellum, others), by single or multiple character of the meningioma(s), and by grade of severity of the tumor (benign, atypical, malignant).
Results
A total of 8,391 women who underwent meningioma surgery were included in the study, matched with 83,910 control women.
Among the 8,391 cases, 287 (3.4%) used desogestrel 75 μg during the previous year, 157 (1.9%) used levonorgestrel in combined form (50, 100, 125 or 150 μg combined with ethinylestradiol), and 17 (0.2%) levonorgestrel alone (30 μg).
An increased risk of intracranial meningioma was observed for current exposure to desogestrel 75μg (OR of 1.25 [intervalle de confiance à 95% 1,10-1,42]). The risk appears after five years of use (OR of 1.70 [1,39-2,08]) and increases with duration. From 5 to 6 years of use, the OR is 1.51 [1,17-1,94] and beyond 7 years of use, it is 2.09 [1,51-2,90]). If desogestrel 75 μg is stopped for more than a year, the increased risk of meningioma disappears (OR = 0.83 [0,63-1,09].
On the other hand, exposure to levonorgestrel, whether in combined form or alone, was not significantly associated with an increased risk of intracranial meningioma surgery (respectively: combined OR of 0.92 [0,77-1,09]ORonly 1.44 [0,87-2,40]), regardless of the exposure times.
For desogestrel, there was a greater excess risk of operated meningioma in the event of multiple meningiomatous localization (OR of 1.89 [1,13-3,16]), location in the middle level of the base of the skull (OR of 1.90 [1,47-2,46]), and location in the anterior level of the skull base (OR of 1.50 [1,17-1,93]). The increased risk of meningioma in cases exposed to desogestrel was found from the age of 45 (45-54 years, OR of 1.42 [1,20-1,69]) ; ≥ 55 years, OR of 1.54 [0,73-3,24]).
Furthermore, the risk of meningioma associated with exposure to desogestrel 75 μg in the previous year was increased in the event of exposure to at least one of the six known progestins with a risk of meningioma (cyproterone acetates, chlormadinone, nomegestrol, medroxyprogesterone, and medrogestone and promegestone) in the previous 6 years (OR = 3.30 [2,64-4,11]). The excess risk also persisted in the event of exposure to desogestrel in the previous rolling year (A-1) and to at least one of the six progestins at risk between A-2 and A-6 before the index date and without exposure in year A-1 (OR = 2.47 [1,88-3,25]).
The fraction of cases attributable to meningiomas exposed to desogestrel in the population was 0.7% of all cases, i.e. 59 cases of operated meningiomas attributable to exposure to desogestrel during the period 2020-2023 (for 1.3 million users of desogestrel in a given month approximately). We estimated that it would be necessary to treat 67,287 women with desogestrel 75μg to observe one case of a woman operated on for a meningioma. In the event of exposure to desogestrel for more than 5 years, 17,331 treated women are necessary to observe one case of operated meningioma.
Conclusions
This national study found a risk of operated intracranial meningioma associated with prolonged, continuous and ongoing use of the progestogen pill desogestrel 75 μg beyond five years. This significant risk remains very low (i.e. 67,000 female users for one case of operated meningioma) compared to that observed for the six progestins already known to be at risk of meningioma. This risk particularly concerns women over 45 and increases with the duration of use of desogestrel. A risk is also observed in the event of use of desogestrel 75 μg following the use of another risky progestogen, in particular nomegestrol and chlormadinone acetates. On the other hand, the results concerning oral levonorgestrel alone 30 μg or combined with estrogens (50-150 μg) are reassuring and in favor of the absence of risk of meningioma.
