Emily Dorman; David Bishai

Disclosures

Expert Rev Pharmacoeconomics Outcomes Res. 2012;12(5):605-613. 

In This Article

Background: History & Current Pipeline of Male Methods

Evidence that spermatogenesis could be controlled via manipulation of the pituitary in rats was published in the 1920s[1] and successful suppression of spermatogenesis in humans was achieved via the administration of exogenous testosterone soon after.[2,3] Proof-of-concept for the effectiveness and reversibility of hormone-induced suppression of sperm production was demonstrated many years later through two landmark studies sponsored by the WHO.[4,5] These trials, in which 670 men in 10 countries participated, not only provided evidence that hormonal regulation of male fertility could be highly effective, reversible and well tolerated but established a safety monitoring strategy based on the analysis of monthly semen samples.[6]

The current landscape of potential male contraceptive products include a number of hormonal formulations that build on these early developments, as well as numerous nonhormonal methods. Both types of method aim to disrupt male fertility through the means of one or more of three basic mechanisms: suppression of sperm production, disruption of sperm maturation and/or function or disruption of sperm transport or motility.[7]

Hormonal methods were the first type of novel male method to be investigated and are therefore further along in development than nonhormonal methods. The primary approach for hormonal methods has been the suppression of spermatogenesis through disruption of the hypothalamic–pituitary–testicular axis through a progestogen or gonadotropin-releasing hormone analogue with androgen replacement. Current formulations (Table 1) include androgen-only therapies, androgen and progestin combinations, gonadotropin-releasing hormone antagonist, androgen combinations and selective androgen-and progestin-receptor modulators.[8] It is necessary to maintain physiological levels of testosterone in order to avoid androgen deprivation (which presents through symptoms such as fatigue, muscle loss, mood changes, low libido), or excess androgenic effects (which presents through symptoms such as acne, fluid retention and weight gain). As oral administration of testosterone is subject to high first-pass hepatic metabolism, maintenance of steady physiological androgen levels requires parenteral or transdermal drug delivery.[9]

Current nonhormonal approaches (Table 1) use various means to disrupt the production, function or motility of sperm by targeting cellular and physiological processes unique to the male reproductive system.[8] Two nonhormonal methods currently in development function as a temporary and reversible vasectomy. The intra-vas device, a set of tiny implants that block the flow of sperm, completed a randomized, Phase II trial in China.[10] Reversible inhibition of sperm under guidance, which involves injecting gel into the vas deferens to chemically inactivate sperm, has been shown to be effective in clinical tests and has been patented in the USA.[11] Genetic approaches target genes or gene products specific to the reproductive tract in order to selectively disrupt reproductive functions. The discovery that sperm tails contain calcium ion channels has led to work to develop a drug to disable these channels,[12] including further investigation into a Chinese herbal medicine that seems to incapacitate sperm using this mechanism.[101] Two drugs – an antihypertensive and an antipsychotic – have been found to keep men from ejaculating during orgasm.[13] However, these drugs would need modification to ameliorate their effects on blood pressure and mood. Finally, immunocontraception is a method that involves the use of antigens and antibodies to target different aspects of sperm production as a means of inducing infertility. This line of research has existed for several decades but results in this area are still preliminary.[14]

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