This study compared safety reports for five long‑acting GnRH drugs, including triptorelin, and found that they all can cause serious side effects, especially reproductive and breast problems. Buserelin tends to cause stomach issues, while histrelin is linked to mental‑health problems, and adults face higher risks than kids. The findings help anyone thinking about using these drugs for hormone control to pick the safest option and watch for specific side effects.

Long-acting Gonadotropin-releasing hormone analogs(GnRHa), including leuprolide, goserelin, histrelin, buserelin, triptorelin, have been widely used for a variety of diseases including prostate cancer, breast cancer, endometriosis, uterine leiomyomas, and central precocious puberty (CPP). However, their real-world safety profile differences have not been adequately compared. We aimed to investigate the adverse event (AE) profile differences of long-acting GnRHa reported by the US Food and Drug Administration Adverse Event Reporting System (FAERS). All indications were searched long-acting GnRHa, as primary suspect drugs, from FAERS data (January 2004 to September 2023). We performed disproportionality analyses by reporting odds ratios (ROR) and conducted univariate and multivariate logistical regression analyses to determine the odds ratio (OR) of serious AEs associated with long-acting GnRHa under different exposure factors. Reproductive system and breast disorders accounted for the greatest proportion of adverse events among the five long-acting GnRHa formulations analyzed. Both buserelin and histrelin showed distinct adverse effect profiles, with buserelin demonstrating a higher incidence of gastrointestinal disorders and histrelin showing a greater propensity for psychiatric disorders. Logistic regression analysis revealed these five medications carried an elevated risk of significant medical events, and this risk was notably lower in pediatric patients (<18 years) compared to adult populations (≥18 years). Significant disparities exist between the adverse event profiles of long-acting GnRHa. The identification of high-risk factors and the enhancement of AEs monitoring are crucial during clinical application.