Noninvasive Analytical Estimation of Endogenous GnRH Drive: Analysis Using Graded Competitive GnRH-receptor Antagonism and a Calibrating Pulse of Exogenous GnRH

Homeostatic control of endocrine systems proceeds via feedforward (agonistic, stimulatory) and feedback (antagonistic, inhibitory) interactions mediated via implicit dose-response functions. However, neither the feedback/feedforward pathways nor the dose-response interfaces are directly observed in vivo. Thus, the goal was to formulate and estimate an ensemble construct of time-varying feedback/feedforward interactions among GnRH, LH, and testosterone (T) in the male gonadal axis. The new analytical model revises and extends an earlier construct by: 1) allowing systemic T concentrations to inhibit hypothalamic GnRH output; 2) estimating GnRH outflow after injection of a calibrating pulse of biosynthetic GnRH; 3) framing the pituitary response to GnRH as a secretory burst, rather than continuous LH release; and 4) regressing feedback and feedforward ensemble parameters on age, rather than evaluating age dichotomously. Application of this methodology in 21 men aged 23-72 yr unveiled age-related 1) diminution of GnRH efficacy normalized for the decline in free T with age (P = 0.016), 2) potentiation of maximal T feedback onto (inhibition of) GnRH secretion (P = 0.006), and 3) accentuation of hypothalamic GnRH's sensitivity to T repression (P = 0.003). Outcomes were specific, because injected GnRH agonist and antagonist concentrations were invariant of age. We conclude that combining experimental and analytical strategies may provide a noninvasive means to investigate and decipher feedback determinants of unobserved endocrine signal(s).