GLP-1 Receptor Agonists and Male Reproductive Health: Mechanisms Underlying Endocrine, Testicular, and Spermatogenic Modifications

Panayiotis Michael Zavos, Carmen Teresa Navarro, Pedro Torrecillas Cabrera, Cesare Aragona, Maria Salomé Bezerra-Espínola, Shady Abdelsattar Saleem, Denisa Protopopescu.

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs)—including liraglutide, semaglutide, dulaglutide, and dual GLP-1/GIP receptor agonists such as tirzepatide—have transformed the clinical management of type 2 diabetes mellitus and clinical obesity [1-4]. Beyond metabolic and cardiovascular outcomes, accumulating preclinical models and human clinical evidence suggest that these agents exert profound, clinically relevant modifications across the male reproductive axis [1-3,5,6]. Obesity and metabolic dysfunction represent major drivers of male subfertility and secondary functional hypogonadism, impairing reproductive function through low-grade chronic inflammation, increased peripheral aromatization of testosterone to estradiol, testicular oxidative stress, altered metabolic signaling, and obesity-associated functional hypogonadism [7-11]. The reviewed evidence supports two broad explanatory pathways: indirect improvement through weight loss and metabolic restoration, and direct receptor-mediated
signaling within central hypothalamic-pituitary networks and testicular microenvironments [1,6,12,13]. Reported effects include substantial improvement in endogenous testosterone production, preservation or restoration of gonadotropin pulse signaling, and favorable changes in selected semen parameters (concentration, total count, progressive motility), particularly in men with obesity or metabolic dysfunction [5,6,12,14-16]. However, definitive fertility outcomes, including natural pregnancy and live birth, remain insufficiently studied [1,5,17,18].