Progestogen use and the risk of intracranial meningioma: a systematic review and meta-analysis

Meningiomas are the most common primary brain tumours in adults. Concerns have emerged about a possible link between progestogen use and intracranial meningioma; we assessed this association.

In this systematic review and meta-analysis, we searched PubMed/MEDLINE, Embase, Cochrane Library, EPI-PHARE database (from inception up to November 01, 2025), pharmacovigilance reports, and backward snowballing. Eligible publications were English or French epidemiological studies, reporting associations between progestogens and intracranial meningiomas. We excluded non-original reports, abstracts-only, and studies without eligible progestogen exposure or meningioma outcomes. We extracted summary data from published reports. Risk of bias was assessed with the Newcastle-Ottawa Scale, and certainty of evidence with GRADE. The primary outcome was intracranial meningioma. Secondary outcomes were malignancy, location, and regression. Random-effects models were used, and heterogeneity was assessed with I²; a narrative synthesis was also performed.

Of 542 records screened, 78 studies were included in the review, and 14 high-quality observational studies in meta-analysis; all 14 were NOS high quality, although residual confounding and potential outcome misclassification cannot be excluded. Cyproterone acetate (CPA) was associated with increased meningioma risk (5 studies; 1047 exposed; pooled-OR 12.36 (95% CI: 7.47-20.45); I²: 73.8%; GRADE: moderate). Depot medroxyprogesterone acetate was also associated (6 studies; 842 exposed; pooled-OR 2.68 (95% CI: 1.72-4.19); I²: 92.7%; GRADE: low). Chlormadinone acetate (CMA), nomegestrol acetate (NOMAC), promegestone, medrogestone, and desogestrel showed signals of increased risk (CMA 3 studies, 164-683 exposed; NOMAC 3, 171-969; promegestone 1, 83; medrogestone 1, 42; desogestrel 2, 115-287). We did not pool these estimates due to sparse, heterogeneous evidence. No signal was found for norgestrel, levonorgestrel, progesterone, dydrogesterone, or spironolactone; evidence for dienogest and hydroxyprogesterone was insufficient. Regression after withdrawal was reported for CPA and NOMAC. Tumours were predominantly anterior/middle skull base, and malignant meningiomas were more frequent with CPA, CMA, and NOMAC.

The certainty of evidence was limited by the observational design, residual confounding, heterogeneity, and imprecision for some exposures. Use of specific progestogens, particularly high dose macroprogestogens may be associated with an increased risk of intracranial meningioma. Transparent patient information and careful clinical and, where appropriate, imaging follow-up are essential.

None.