Pulse to catch a pulse: Transdermal pulsatile testosterone for feedback inhibition to achieve male contraception

摘要

Hormonal methods of male contraception have addressed feedback-inhbition of the cascade of hormones that has evolved to regulate sperm production but high concentrations of testosterone (T) in the blood have not worked satisfactorily. We hypothesized that an episodic event, such as degranulation of gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus, could be as well inhibited by episodic interference as by continuously-applied suppression. We used a computational model of hypothalamus-pituitary-gonad axis described by Veldhuis et al. to test the hypothesis that episodic administration of T would inhibit GnRH and/or luteinizing hormone (LH) secretion. A set of stochastic differential equations model feedback as well as feed-forward actions of GnRH, LH and T. The model predicted feedback-inhibition of GnRH pulses in a dose and frequency dependent manner when transdermal patches or injections delivering pulsatile T were applied. Pulsatile T delivered by real-life transdermal delivery system applied as per a parsimonious regimen inhibited spermatogenesis and reduced fertility.