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1 Department of Statistics, University of Virginia, Charlottesville, VA, USA
2 Division of Endocrinology and Metabolism, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
* To whom correspondence should be addressed. E-mail: veldhuis.johannes{at}mayo.edu.
Quantification of in vivo pituitary-hormone secretion requires simultaneous appraisal of implicit: (a) secretory-burst waveform, mass and stochastic pulse timing; (b) basal secretion; (c)biexponential elimination kinetics; and (d) random experimental error (Proc Natl Acad Sci 98: 4028-4033, 2001). The present study extends this analytical formalism to allow for time of day-dependent waveform adaptation (burst-shape change) at statistically determinable boundary times. Thereby, we test the hypothesis that diurnal mechanisms and glucocorticoid negative feedback jointly govern distinctive facets of the burst-like secretion of adrenocorticotropin (ACTH). To this end, we reanalyzed intensively (10-min) sampled 24-hr 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-hr ACTH release in both the intact and low-cortisol setting in 8 of 9 subjects. Under feedback-intact conditions, analytically predicted waveform changepoints (median clock times 0611 h and 1739 h) flanked an interval of elevated ACTH secretory-burst mass (P < 10-3). Experimental hypocortisolemia did not alter day/night boundaries, but: (a) stimulated day ACTH secretory-burst mass (P < 10-3); (b) accelerated day ACTH secretory-burst frequency (P < 10-3); and (c) forced skewness of day ACTH secretory bursts toward more rapid initial release (P < 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.
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