Effects of GnRH agonists and antagonists on cardiovascular and metabolic systems in adults: Mechanistic pathways and risk management

Gonadotropin-releasing hormone (GnRH) therapy, widely used in the management of reproductive and oncological disorders in adult humans, has been increasingly linked to metabolic and cardiovascular complications. This review focuses on the human clinical evidence, highlighting the interplay between GnRH-induced metabolic dysregulation and cardiotoxicity, particularly through mechanisms involving insulin resistance, dyslipidemia, and adipose tissue dysfunction. Suppression of sex steroid hormones by GnRH agonists and antagonists disrupts glucose and lipid metabolism, leading to heightened risks of type 2 diabetes, atherosclerosis, and cardiovascular disease (CVD). Long-term therapy promotes visceral adiposity-a metabolically active depot that amplifies systemic inflammation and endothelial dysfunction-further accelerating vascular injury. While substantial data exist in adult populations, evidence in youth remains extremely limited. The use of GnRH agonists in conditions such as central precocious puberty and gender dysphoria raises critical unanswered questions regarding whether early-life suppression of sex steroids produces similar or distinct cardiometabolic effects compared with adults. Given this uncertainty, extrapolation from adult data must be approached with caution. This review underscores the urgent need for proactive cardiovascular risk management in adults undergoing long-term GnRH therapy and highlights the importance of future longitudinal studies in younger populations. Integrating pharmacologic interventions (e.g., insulin sensitizers, statins, antihypertensives) with lifestyle strategies and precision-medicine approaches will be key to optimizing long-term metabolic and cardiovascular outcomes.