Cortisol feedback state governs adrenocorticotropin secretory-burst shape, frequency, and mass in a dual-waveform construct: time of day-dependent regulation

Abstract

Keenan, Daniel M., and Johannes D. Veldhuis. Cortisol feedback state governs adrenocorticotropin secretory-burst shape, frequency, and mass in a dual-waveform construct: time of day-dependent regulation. Am J Physiol Regul Integr Comp Physiol 285: R950-R961, 2003. First published July 3, 2003 10.1152/ajpregu.00299.2003.-Quantification of in vivo pituitary hormone secretion requires simultaneous appraisal of implicit 1) secretory-burst waveform, mass, and stochastic pulse timing; 2) basal secretion; 3) biexponential elimination kinetics; and 4) random experimental error (Keenan DM, Licinio J, and Veldhuis JD. Proc Natl Acad Sci USA 98: 4028-4033, 2001). The present study extends this analytic formalism to allow for time of day-dependent waveform adaptation (burstshape change) at statistically determinable boundary times. Thereby, we test the hypothesis that diurnal mechanisms and glucocorticoid negative feedback jointly govern distinctive facets of the burstlike secretion of ACTH. To this end, we reanalyzed intensively (10 min) sampled 24-h plasma ACTH concentration profiles collected previously under feedback-intact and drug-induced cortisol depletion in nine healthy adults. Akaiki information criterion-based model comparison favored dual (rather than single) secretory-burst representation of 24-h ACTH release in both the intact and low-cortisol setting in eight of nine subjects. Under feedback-intact conditions, analytically predicted waveform changepoints (median clock times 0611 and 1739) flanked an interval of elevated ACTH secretory-burst mass (P Ͻ 10 Ϫ3 ). Experimental hypocortisolemia did not alter day/night boundaries, but 1) stimulated day ACTH secretoryburst mass (P Ͻ 10 Ϫ3 ); 2) accelerated day ACTH secretoryburst frequency (P Ͻ 10 Ϫ3 ); and 3) forced skewness of day ACTH secretory bursts toward more rapid initial release (P Ͻ 0.05). In contrast, the basal ACTH secretion rate and regularity of interpulse-interval lengths were invariant of day/night segmentation and cortisol availability. In conclusion, unknown diurnal factors and systemic cortisol concentrations codetermine ACTH secretory-burst waveform, frequency, and mass, whereas neither mechanism regulates basal ACTH release or regularity of the burst-renewal process.insert key words not found in either title here THE STRESS-RESPONSIVE CORTICOTROPIC AXIS comprises (minimally) circadian inputs, hypothalamic peptides, pituitary corticotropes, sympathetic pathways, the adrenal gland, and glucocorticoid receptors (7, 23). Central regulation unfolds via paraventricular nuclear release of corticotropin-releasing hormone (CRH) and AVP into hypophysial portal blood in discrete bursts (1,30). Intermittent neuronal outflow of CRH and AVP putatively constitutes the primary pulse renewal process. These secretagogues stimulate exocytotic release and de novo synthesis of ACTH by the anterior pituitary gland (1,5,9,24,25,32,40). Secreted ACTH drives the production of aldosterone and glucocorticoids by the adrenal zona glomerulosa and fasciculata (9). Glucocort...

Sex defines the age dependence of endogenous ACTH-cortisol dose responsiveness

“…The core model equations provide a representation of admixed basal and pulsatile secretion, cortisol subject-specific slow-phase half-lives with a fixed rapid-phase half-life of 2.4 min comprising 37% of the decay amplitude, allowable random effects on successive cortisol secretory-burst mass values, and experimental uncertainty due to sample withdrawal, processing, and assay (35,36). Key features are highlighted below.…”

“…"concentration due to basal secretion" ϩ "concentration due to pulsatile secretion," where a is the proportion of rapid to total elimination (0.37), ␣ 1 and ␣2 are the respective rate constants of the rapid (0.298) and slow (estimated) elimination phases, X(0) is the starting hormone concentration, ␤ 0 is the basal secretion rate, t time and P(r)dr are the instantaneous pulsatile secretion rate over the infinitesimal time interval (r, r ϩ dr) (35,36). The function defining pulsatile cortisol secretion was given by…”

“…Primary analytical outcomes include 1) basal (nonpulsatile) cortisol secretion (mol/l/24 h); 2) reconstructed (reconvolved) cortisol-concentration time series; 3) slowphase half-life (min) of cortisol; 4) the mass of cortisol (mol/l) secreted per burst; 5) cortisol secretory-event frequency (per 24 h), and 6) specific dose-response properties defined by efficacy (asymptotically projected maximal ACTH-stimulated cortisol secretion rate, nmol⅐l Ϫ1 ⅐min Ϫ1 ); and ED50 or potency (ACTH concentration in pmol/l driving half-maximal cortisol secretion). Secondary measures were basal (nonpulsatile) cortisol secretion and adrenal sensitivity (maximal positive slope of the ACTH concentration-cortisol secretion relationship) (13,35,36). Random effects on mean dose-response efficacy (averaged across all ACTH pulses in each subject) were permitted, but not required, on a pulse-by-pulse basis over 24 h in each subject (34).…”

Predictive modeling of the hypothalamic-pituitary-adrenal (HPA) axis response to acute and chronic stress

“…Bifurcation analysis was used to predict the response of the HPA axis to chronic stress. Model predictions were compared with experimental findings reported in the literature and relevance for pharmacotherapy with glucocorticoids was discussed.Key words: HPA axis, Stress, Cortisol, Predictive modeling, Circadian and ultradian rhythmicity acteristic frequencies: ultradian oscillations, with a period of 20-120 min [4-6] superimposed on circadian oscillations, with a period of about 24 h. The importance of circadian rhythms for adequate functioning of the HPA axis has been recognized for years [7, 8]; in addition, new experimental [9-15] and theoretical [16][17][18][19][20][21][22][23][24][25][26][27] results offer enough evidence to support the indispensable roles of ultradian oscillatory dynamics of HPA hormones levels for normal physiology. Since ultradian and circadian oscillations operate on different time scales, their effects are manifested in different biological realms.…”

“…acteristic frequencies: ultradian oscillations, with a period of 20-120 min [4][5][6] superimposed on circadian oscillations, with a period of about 24 h. The importance of circadian rhythms for adequate functioning of the HPA axis has been recognized for years [7,8]; in addition, new experimental [9][10][11][12][13][14][15] and theoretical [16][17][18][19][20][21][22][23][24][25][26][27] results offer enough evidence to support the indispensable roles of ultradian oscillatory dynamics of HPA hormones levels for normal physiology. Since ultradian and circadian oscillations operate on different time scales, their effects are manifested in different biological realms.…”