Potential synergy between GLP-1 receptor agonists and follicle-stimulating hormone in improving spermatogenesis: biological rationale and future directions

Background Male infertility represents a significant global health burden, with obesity and metabolic dysfunction emerging as major contributors to impaired spermatogenesis and functional hypogonadism. Follicle-stimulating hormone (FSH) has been employed to stimulate spermatogenesis in selected patients, while glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated beneficial effects on male reproductive function beyond their metabolic actions. Understanding their potential synergistic mechanisms may open new therapeutic avenues. Methods We conducted a narrative review examining FSH signaling in spermatogenesis, GLP-1 receptor expression in testicular cells, the impact of obesity on male reproduction, and the molecular mechanisms underlying GLP-1RA–FSH synergistic interactions. Relevant studies were identified through a structured non-systematic search of PubMed/MEDLINE and Scopus (last searched September 2025), using search terms including ‘GLP-1 receptor agonists’, ‘semaglutide’, ‘liraglutide’, ‘follicle-stimulating hormone’, ‘FSH’, ‘spermatogenesis’, ‘male infertility’, ‘obesity’, and ‘functional hypogonadism’, supplemented by manual reference screening. No formal quality appraisal tool was applied, consistent with the narrative review format. Results FSH acts primarily through Sertoli cells via cAMP-dependent pathways, with clinical efficacy demonstrated in men with idiopathic oligozoospermia and hypogonadotropic hypogonadism. GLP-1 receptors are expressed in Leydig, Sertoli, and germ cells; GLP-1RAs improve testosterone, gonadotropin secretion, and sperm parameters predominantly in obese men with functional hypogonadism. Obesity impairs spermatogenesis through HPG axis suppression, insulin resistance, aromatase activity, oxidative stress, and chronic inflammation. GLP-1RAs may potentiate FSH action through shared signaling pathways (cAMP, PI3K/Akt, AMPK), enhanced Sertoli cell metabolism, and restoration of the HPG axis in metabolically impaired men. Conclusions The convergence of GLP-1 and FSH signaling in testicular cells, combined with GLP-1RA metabolic benefits in obese infertile men, provides a strong biological rationale for combination therapy. Preliminary clinical evidence supports GLP-1RA efficacy in improving reproductive outcomes in men with obesity-associated hypogonadism; this benefit appears conditional on pre-existing metabolic dysfunction, with negligible or mildly adverse effects in eugonadal metabolically healthy men. Prospective randomized controlled trials are urgently needed to evaluate combined GLP-1RA and FSH therapy, with particular attention to responder profiles and long-term reproductive outcomes.