A biomathematical model of time-delayed feedback in the human male hypothalamic-pituitary-Leydig cell axis

Am J Physiol. 1998 Jul;275(1):E157-76. doi: 10.1152/ajpendo.1998.275.1.E157.

Abstract

We develop, implement, and test a feedback and feedforward biomathematical construct of the male hypothalamic [gonadotropin-releasing hormone (GnRH)]-pituitary [luteinizing hormone (LH)]-gonadal [testosterone (Te)] axis. This stochastic differential equation formulation consists of a nonstationary stochastic point process responsible for generating episodic release of GnRH, which is modulated negatively by short-loop (GnRH) and long-loop (Te) feedback. Pulsatile GnRH release in turn drives bursts of LH secretion via an agonistic dose-response curve that is partially damped by Te negative feedback. Circulating LH stimulates (feedforward) Te synthesis and release by a second dose response. Te acts via negative dose-responsive feedback on GnRH and LH output, thus fulfilling conditions of a closed-loop control system. Four computer simulations document expected feedback performance, as published earlier for the human male GnRH-LH-Te axis. Six other simulations test distinct within-model coupling mechanisms to link a circadian modulatory input to a pulsatile control node so as to explicate the known 24-h variations in Te and, to a lesser extent, LH. We conclude that relevant dynamic function, internodal dose-dependent regulatory connections, and within-system time-delayed coupling together provide a biomathematical basis for a nonlinear feedback-feedforward control model with combined pulsatile and circadian features that closely emulate the measurable output activities of the male hypothalamic-pituitary-Leydig cell axis.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Circadian Rhythm
  • Feedback
  • Gonadotropin-Releasing Hormone / physiology
  • Humans
  • Hypothalamo-Hypophyseal System / physiology*
  • Leydig Cells / physiology*
  • Luteinizing Hormone / physiology
  • Male
  • Mathematics
  • Models, Biological*
  • Poisson Distribution
  • Stochastic Processes
  • Testosterone / physiology
  • Time Factors

Substances

  • Gonadotropin-Releasing Hormone
  • Testosterone
  • Luteinizing Hormone