Sperm redox biology challenges the role of antioxidants as a treatment for male factor infertility

In spite of inconclusive or negative outcomes from clinical studies, oral antioxidants are still largely prescribed to infertile men to improve sperm motility and/or reduce sperm DNA damage, on the basis of the assumption that it is an oxidative damage and it will be corrected by antioxidants. We aimed to challenge this view by examining the available experimental evidence. The regulation of sperm motility may suffer several pathologic derangements, including alterations of the flagellum, impaired function of the activating phosphatases and kinases, impaired function of the extracellular vesicles of either epididymal or prostatic origin, deranged Ca²⁺ trafficking, and infection/inflammation of the male accessory glands. None of the aforementioned issues seem to be directly dependent on the redox balance and to indicate a direct role for oral antioxidants treatment. Indeed, antioxidants may generate reductive imbalances resulting in an increase in the nicotinamide adenine dinucleotide reduced/nicotinamide adenine dinucleotide oxidized ratio, which sustains reactive oxygen species generation in mitochondria, potentially leading to increased sperm DNA damage, whereas a shortage of nicotinamide adenine dinucleotide oxidized may jeopardize the pol(ADP-ribose) polymerase-based DNA repair mechanisms at the time of histone to protamine transition, resulting in unresolved double-strand breaks and defective protamination, which further increases DNA vulnerability. The occurrence of reactive oxygen species and oxidative damages does not necessarily imply a shortage of antioxidant defenses, and the possibility that a different problem is in place should be considered. On this base, the current attitude to prescribe oral antioxidants to infertile men without demonstration of antioxidant shortage or true oxidative imbalance should be reconsidered.