Capacitation‐Induced Changes in Sperm Motility, AMPK Phosphorylation, and Tyrosine Phosphorylation Are Diminished by Therapeutically Relevant Concentrations of Metformin

Type 2 diabetes mellitus (T2DM), the predominant form of diabetes mellitus (DM), has been established as a key etiological factor in male infertility. The incidence of T2DM among reproductive-aged males has shown a progressive annual increase, potentially contributing to the observed decline in fertility rates. As a primary oral hypoglycemic medication in the management of T2DM, metformin requires comprehensive investigation into its impacts on male reproductive function. The effects of metformin, at concentrations within the therapeutic range, on the functional competence of capacitated human sperm were assessed in vitro to elucidate the involved mechanisms. Following exposure in capacitation medium, sperm functions critical for fertilization, such as motility, penetration ability, capacitation, acrosome reaction, and hyperactivation were systematically evaluated. The potential mechanisms such as 5'-AMP-activated protein kinase phosphorylation and tyrosine phosphorylation of sperm in capacitated state were also measured by western blot. The results indicate that metformin, at 40 and 80 μM, markedly reduced the enhancement of sperm parameters induced by HTF++ buffer. This detrimental effect is attributable to the inhibition of both AMP-activated protein kinase (AMPK) activation and tyrosine phosphorylation signaling pathways. Our findings indicate that as a commonly used medicine for T2DM in clinic, the potential negative impact of metformin on fertility should be considered, especially for men of reproductive age who are undergoing glucose management and diabetes treatment.