Assessing the Safety of Estro-Progestin and Progestin-only drugs: A Signal Detection Study of Meningioma Reports in EudraVigilance.
Manuzzi Alice A, Fazio Elena E, Nikitina Victoria V, Broccoli Massimiliano M et al.
Exogenous hormonal therapies are used for contraception and for several gynecologic and menopausal indications, frequently for prolonged periods. Previous epidemiological studies have reported an increased risk of meningioma with some progestins, particularly following prolonged exposure and high cumulative doses. It is a common intracranial tumor with marked female predominance, suggesting a potential role of hormones in its pathogenesis and growth. Most meningiomas are located in the anterior or middle skull base, where a higher prevalence of progesterone receptors has been observed. This evidence further underlines the relationship between hormonal factors and this type of intracranial tumor. Moreover, rapid and spontaneous tumor regression has been reported after cessation of treatment with exogenous hormones or when serum progestogen levels decrease due to physiological factors. This study aimed to investigate the presence of a safety signal for meningioma among users of estro-progestin and progestin-only therapies using pharmacovigilance data. Data from the EudraVigilance database were analyzed using both descriptive and statistical approaches. Three complementary disproportionality methods were applied to strengthen signal detection: Reporting Odds Ratio (ROR), Information Component (IC), and Empirical Bayes Geometric Mean (EBGM). The study period covered the last ten years, from January 1, 2016, to December 31, 2025. The drugs analyzed included: drospirenone-ethinylestradiol combination, dienogest-ethinylestradiol combination, drospirenone-only, desogestrel and levonorgestrel. We included all reports in which these drugs were recorded as suspected, excluding those in which they were reported only as concomitant drugs. A total of 21,091 reports, corresponding to 70,476 drug-ADR pairs, were identified. As expected, most reports concerned female patients, consistent with both the indication of these therapies and the known higher prevalence of meningioma in women. Disproportionality signals were identified for drospirenone and desogestrel-only formulations, suggesting a potential association with meningioma: A disproportionality signal was identified for desogestrel-only pills (110 reports; ROR 11.11, 95% CI 8.79-14.06; IC025 2.64; EB05 5.79). A novel exploratory signal also emerged for drospirenone-only pills (8 reports; ROR 2.41, 95% CI 1.19-4.89; IC025 0.54; EB05 1.17). No disproportionality signal was detected for the two combined formulations or levonorgestrel; absence of a signal should not be interpreted as absence of risk or evidence of comparative safety. In addition to meningioma, other serious adverse drug reactions - including known cardiovascular events and previously unreported reactions - were identified, warranting further investigation. These findings highlight the importance of ongoing pharmacovigilance activities and careful benefit-risk evaluation of hormonal therapies, particularly given their widespread and long-term use and the potential for rare but serious outcomes such as meningioma. This analysis identified new but exploratory safety signals that warrant confirmation in studies with valid exposure denominators, longitudinal treatment histories, latency assessment, and control of confounding. The findings should not be used alone to infer causality or guide comparative clinical decisions.