Antidiabetic agents and male fertility: unraveling the impact of glucose-lowering therapies on sperm quality in diabetic males-a narrative review.

Background and Objective: Diabetes mellitus imposes a substantial burden on male fertility, adversely affecting sperm quality through structural damage in the reproductive tract, endocrine disruption, and dysregulation of cellular metabolism. While glucose-lowering agents help achieve glycemic control, they may also ameliorate diabetes-induced impairment of sperm quality. However, these drugs exert heterogeneous effects on male reproduction via divergent mechanisms, with outcomes often varying between in vivo and in vitro settings. This review aims to systematically evaluate the impacts of different antihyperglycemic therapies on semen quality and elucidate their mechanistic bases, to guide therapy selection for improving fertility in diabetic men. Methods: A comprehensive search of the PubMed and Embase databases was conducted, covering the period from their inception to 2025. Key Content and Findings: Insulin enhances sperm DNA integrity via Hsp70-2/TP-1/TP-2 upregulation and acts as a cryoprotectant. Metformin activates AMPK-mediated autophagy and synergizes with zinc to preserve fertility. SGLT-2 inhibitors suppress testicular apoptosis via Nrf2/HO-1 antioxidant pathways. Critically, sulfonylureas improve in vivo sperm quality but exert spermicidal effects in vitro by disrupting calcium homeostasis. Conclusions: Current evidence supports the potential of certain antihyperglycemic agents in mitigating diabetes-related male infertility, though drug-specific and context-dependent effects must be considered. Further phenotype-targeted studies are needed to optimize clinical treatment strategies.