Abstract
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.
Highlights
Fertility control approaches for men fall into one of two categories: hormonal and nonhormonal
Claims of total reversibility and full recovery to fertility have been made with hormonal contraception in males (Pasztor et al, 2017), prolonged use of exogenous hormones is associated with off-target effects, such as decreased high density lipoprotein cholesterol levels and potential cardiovascular risk in otherwise healthy men (Meriggiola et al, 1995)
The most promising candidates— BTBD18, CCDC63, CCDC155, HFM1, MCMDC2, and TDRD5— encode proteins that show sequence similarity below 40% to their respective, non-reproductive tract expressed paralogs, and within the conserved domains of their paralogs, KLHL26, SSH2, CCDC114, SNRNP200, MCM3, and TDRD1; these potential targets have a reasonable potential for drug specificity with a low risk of collateral effects
Summary
Fertility control approaches for men fall into one of two categories: hormonal and nonhormonal. Targeting genes involved in early sperm development, for instance, could potentially be more effective, as suggested by several previous reviews identifying groups of male reproductive tract-expressed genes as promising drug targets (Schultz et al, 2003; Archambeault and Matzuk, 2014; Payne and Goldberg, 2014; O’Rand et al, 2016).
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