Inhibition of human sperm respiration by 4-hydroperoxycyclophosphamide and protection by mesna and WR-1065

Objective: To determine the effect of 4-hydroperoxycyclophosphamide (4OOH-CP) on the respiration of human sperm, and investigate the protective properties of mesna and WR-1065. Setting: SUNY Upstate Medical University, Syracuse, NY. Patient(s): Men (n = 12) visited the Andrology Department for fertility evaluation. Intervention(s): None. Main Outcome Measure(s): Sperm respiration. Result(s): Immediate decline in the rate of respiration was observed when 4OOH-CP was added to washed sperm or semen. The inhibition was concentration dependent. The respiration was less affected when 4OOH-CP was added to semen, suggesting the presence of protective factors in the seminal plasma. Excess of mesna or WR-1065 ameliorated the effect of 4OOH-CP. Mesna was the more potent of the two compounds. 4OOH-CP also inhibited the respiration of mitochondria from beef heart. Conclusion(s): These findings emphasize the adverse effects of alkylating agents on sperm function. The results also provide a framework for thiol drug administration with high-dose alkylating agents to protect male fertility. The protective capacity of seminal plasma deserves further testing.