Timing feedback-inhibition by Testosterone: Disruption of spermatogenesis and induction of LH gonadotrope apoptosis

摘要

This report addresses the pulsatile approach to feedback-inhibition and tests the hypothesis of episodic interference in HPT axis in silico and in vivo. A computational model of HPG axis proposed by Keenan et al. 1998, has been used to study the interaction between endogenous T pulsatility and various profiles of exogenous T delivery. Stochastic differential equations are used to compute unobserved secretion rates of GnRH and LH from observed T concentrations and the model predicted concentrations of various hormones over one day or any desired span, retaining the dynamic nature of the axis. The model has been modified by incorporation of a function describing vitality of pituitary gonadotrophes to address the effect of chronic GnRH deprivation on the viability of pituitary gonadotrophes. The modified model simulates the kinetics of recovery of the HPT axis from T-induced suppression in a better way. The effects of pulsatile T delivered by real-life transdermal delivery system on spermatogenic status and reproductive capacity of rats have been assessed by studying hormone levels and testicular histology following external T administration and then withdrawal. Secretion of endogenous LH and T were reduced on applying T films over 11 weeks. Spermatogenesis was arrested at stages Ⅶ-Ⅷ. The vitality function was found to have in vivo correlation. Extensive apoptosis in the anterior pituitary supports the hypotheses that inhibition of GnRH leads to a reduction in numbers of LH-producing cells.