Abstract
In recent years, novel antidiabetic drugs, particularly sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA), have attracted increasing interest for their effects beyond glycemic control, including potential actions on male reproductive function. This review critically summarizes current evidence regarding the impact of antidiabetic therapies on spermatogenesis, testicular metabolic homeostasis, and male gonadal function, focusing on the underlying molecular and pathophysiological mechanisms. Experimental evidence suggests that metabolic dysfunction, oxidative stress, inflammation, apoptosis, and impaired Sertoli cell metabolism play a central role in diabetes- and obesity-associated male reproductive dysfunction. In this context, SGLT2i and GLP-1 RA appear capable of modulating several of these pathways, improving sperm parameters, preserving testicular architecture, and attenuating oxidative and inflammatory damage in preclinical models. Emerging data also suggest possible direct gonadal effects mediated through intracellular signaling pathways involved in steroidogenesis, autophagy, and cellular energy regulation. However, clinical evidence remains limited and partly conflicting, and it is still unclear whether these findings translate into clinically meaningful reproductive benefits in humans. Preliminary evidence suggests that dual GIP/GLP-1 receptor agonists, such as tirzepatide, may exert beneficial effects on male reproductive health. However, direct evidence regarding their impact on spermatogenesis and fertility remains limited. Overall, well-designed prospective clinical studies incorporating reproductive and hormonal outcomes are warranted to better define the role of these therapies within an integrated andro-metabolic approach to the management of obesity- and diabetes-associated male reproductive dysfunction.