The Cardiovascular Burden of Gonadotropin-Releasing Hormone (GnRH) Therapy: Mechanisms, Risks, and Interventions

Gonadotropin-releasing hormone (GnRH) therapy, a cornerstone in the treatment of various oncological and reproductive conditions, has been increasingly associated with significant cardiovascular risks, particularly when administered long-term. This review examines the complex relationship between GnRH therapy, metabolic dysregulation, and cardiotoxicity, with a focus on the mechanisms driving these cardiovascular outcomes. Prolonged GnRH suppression induces a spectrum of metabolic disturbances, including insulin resistance, dyslipidemia, and obesity, all of which elevate the risk of cardiovascular events such as hypertension, myocardial infarction, and stroke. These risks are further influenced by sex-specific differences and pre-existing cardiovascular conditions, necessitating tailored therapeutic strategies. The review highlights the urgent need for comprehensive monitoring and early intervention in patients undergoing GnRH treatment, with a particular emphasis on personalized care approaches. Additionally, we explore both pharmacological and non-pharmacological interventions aimed at mitigating these risks, including the potential of next-generation GnRH modulators and combination therapies. The need for future research is underscored, particularly in understanding the molecular and cellular mechanisms underlying cardiovascular toxicity, identifying predictive biomarkers, and developing safer therapeutic alternatives. This review provides a comprehensive framework for clinicians and researchers working to optimize the benefits of GnRH therapy while minimizing its cardiovascular burden, ultimately improving patient outcomes across various clinical settings.