TY - JOUR
T1 - Noninvasive analytical estimation of endogenous GnRH drive
T2 - Analysis using graded competitive GnRH-receptor antagonism and a calibrating pulse of exogenous GnRH
AU - Keenan, Daniel M.
AU - Clarke, Iain J.
AU - Veldhuis, Johannes D.
PY - 2011/12
Y1 - 2011/12
N2 - 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).
AB - 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).
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U2 - 10.1210/en.2011-1461
DO - 10.1210/en.2011-1461
M3 - Article
C2 - 22028450
AN - SCOPUS:82355165077
SN - 0013-7227
VL - 152
SP - 4882
EP - 4893
JO - Endocrinology
JF - Endocrinology
IS - 12
ER -