Adverse event profile differences among long-acting gonadotropin-releasing hormone analogs: A real-world, pharmacovigilance study

Abstract

Background: 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.

Objective: 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).

Methods: 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.

Results: 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).

Conclusions: 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.

Fig 1. Adverse reactions reported of Long-Acting GnRH Agonists on Human Organs.

Long-acting GnRHa have been reported corresponding adverse reactions in various organ systems of the human body for different indications. The main affected organs include the pituitary gland, bones, cardiovascular system and reproductive organs, etc.

Fig 2. The process of data processing and analysis, including the source of data acquisition, the reporting time and the cleaning.

Fig 3. Clinical characteristics of patients treated with long-acting GnRHa in the FAERS database.

(A) Date received, p < 0.001^a; (B) Age in report, p < 0.001^b; (C) Role code, p > 0.05^a; (D) Top 10 indication, p < 0.001^a; (E) Top ten reporter country, p < 0.001^a; (F) Gender, p < 0.001^c; (G) Outcome, p > 0.05^a. a: Fisher’s exact test; b: One-way ANOVA; c: Pearson Chi-Square. We have highlighted statistically significant values in boldface for emphasis. The numbers in Fig 3A and 3D represent signal number. The numbers in Fig 3B, 3C, 3E, 3F and 3G represent signal number percent.

Fig 4. Union of the top 20 signals with the highest frequency or ROR value for long-acting GnRHa, including leuprolide, goserelin, triptorelin, histrelin, buserelin.

The x-axis displays the normalized AE frequency (original values divided by 50) for leuprolide, goserelin, and triptorelin, while the y-axis represents the different AEs. The bubble size reflects the ROR value with log2 (ROR). We have presented the top twenty AEs with the highest frequency using bubbles, where each bubble corresponds to an AE, appearing on the far right of the x-axis, and the top twenty AEs with the highest signal strength are shown in the biggest bubbles. And AEs that display both high frequency and strong intensity are shown in big blue bubbles appearing to the right side of the x-axis.

Fig 5. The signal number of long-acting GnRHa-related significant Adverse Events (AEs) at the System Organ Class (SOC) level.