Toward Development of the Male Pill: A Decade of Potential Non-hormonal Contraceptive Targets

With the continued steep rise of the global human population, and the paucity of safe and practical contraceptive options available to men, the need for development of effective and reversible non-hormonal methods of male fertility control is widely recognized. Currently there are several contraceptive options available to men, however, none of the non-hormonal alternatives have been clinically approved. To advance progress in the development of a safe and reversible contraceptive for men, further identification of novel reproductive tract-specific druggable protein targets is required. Here we provide an overview of genes/proteins identified in the last decade as specific or highly expressed in the male reproductive tract, with deletion phenotypes leading to complete male infertility in mice. These phenotypes include arrest of spermatogenesis and/or spermiogenesis, abnormal spermiation, abnormal spermatid morphology, abnormal sperm motility, azoospermia, globozoospermia, asthenozoospermia, and/or teratozoospermia, which are all desirable outcomes for a novel male contraceptive. We also consider other associated deletion phenotypes that could impact the desirability of a potential contraceptive. We further discuss novel contraceptive targets underscoring promising leads with the objective of presenting data for potential druggability and whether collateral effects may exist from paralogs with close sequence similarity.