Timing feedback-inhibition of the male reproductive hormone axis

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. Since the published model did not address the effect of chronic GnRH deprivation on the viability of pituitary gonadotrophes, we introduced a function to address this issue. Incorporation of this function in the model allowed the prediction of a “holiday period” in the contraceptive regimen, during which exogenous T would not be needed to protect from conception. Pulsatile T delivered by real-life transdermal delivery system applied as per a parsimonious regimen reduced secretion of LH and T and fertility. The vitality function, proposed to account for survival and proliferation of pituitary gonadotrophes correlated with in vivo observations as extensive apoptosis in the anterior pituitary was observed after application of transdermal T