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1Department of Statistics, University of Virginia, Charlottesville, Virginia 22904; 2Department of Internal Medicine, Leiden University, 2333 2A Leiden, The Netherlands; and 3Division of Endocrinology and Metabolism, Department of Internal Medicine, Endocrine Research Unit, Mayo Medical and Graduate Schools of Medicine, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905
Submitted 13 April 2004 ; accepted in final form 4 June 2004
According to current regulatory concepts, pulsatile ACTH concentrations (CON) stimulate time-lagged cortisol secretion rates (SEC) via an implicit CON-SEC dose-response relationship. The present analyses reconstruct nonlinear properties of this in vivo agonist-response interface noninvasively in order to investigate pulse-by-pulse coupling consistency and to obviate the need to infuse isotopes or exogenous effectors, which may disrupt pathway interactions. This approach required an ensemble strategy of 1) measuring ACTH and cortisol CON in plasma sampled every 10 min for 24 h in 32 healthy adults, and 2) estimating simultaneously a) variable-waveform ACTH and cortisol SEC bursts superimposed upon fixed basal SEC; b) biexponential kinetics of ACTH and cortisol disappearance; c) nonequilibrium exchange of cortisol among free and cortisol-binding globulin (CBG)- and albumin-bound moieties; d) two SEC-burst shapes demarcated by a statistically defined day/night boundary; e) feedforward efficacy, potency, and sensitivity; and f) stochastic variability in feedforward measures over time. Thereby, we estimate 1) ACTH SEC (µg·l–1·day–1) of 0.27 ± 0.04 basal and 0.87 ± 0.07 pulsatile (means ± SE); 2) cortisol SEC (µmol·l–1·day–1) of 0.10 ± 0.01 basal and 3.5 ± 0.20 pulsatile; 3) free cortisol half-lives (min) of 1.8 ± 0.20 (diffusion/advection) and 4.1 ± 0.30 (elimination) and a half-life of total cortisol of 49 ± 2.4 and of ACTH of 20 ± 1.3; 4) ACTH potency (EC50, ng/l) of 26 ± 2.4, efficacy (nmol·l–1·min–1) 10 ± 1.8, and sensitivity (slope units) 0.65 ± 0.09; 5) night/day augmentation of ACTH and cortisol SEC-burst mass by 2.1- and 1.7-fold (median); 6) abbreviation of the modal time to maximal ACTH and cortisol SEC rates by 4.4- and 4.3-fold, respectively, after a change point clock time of 0205 (median); 7) in vivo percentage distribution of cortisol as 6% free, 14% albumin bound, and 80% CBG bound with an absolute free cortisol CON (nmol/l) 11.5 ± 0.54; and 8) significant (mean CV) stochastic variability in feedforward efficacy (140%), potency (38%), and sensitivity (56%) within the succession of paired ACTH/cortisol pulses of any given subject. In conclusion, the present composite formulation illustrates a platform for dissecting mechanisms of in vivo regulation of effector-response properties noninvasively in the corticotropic axis of the uninfused individual.
adrenal; feedback; pituitary; stress; diurnal; signaling
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