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Joint synchrony of reciprocal hormonal signaling in human paradigms of both ACTH excess and cortisol depletion

¹Division of Endocrinology, Department of Internal Medicine, Endocrine Research Unit and General Clinical Research Center, Mayo Clinic, Mayo Medical and Graduate Schools of Medicine, Rochester, Minnesota; ²990 Moose Hill Road, Guilford, Connecticut; ³Department of Statistics, University of Virginia, Charlottesville, Virginia; and ⁴Department of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands

Submitted 7 January 2005 ; accepted in final form 20 February 2005

The hypothalamo-pituitary-adrenal axis is a stress-adaptive neuroendocrine ensemble, in which adrenocorticotropin (ACTH) drives cortisol secretion (feedforward) and cortisol restrains ACTH outflow (feedback). Quantifying direction- and pathway-specific adjustments within this and other interlinked systems by noninvasive means remains difficult. The present study tests the hypothesis that forward and reverse cross-approximate entropy (X-ApEn), a lag-, scale-, and model-independent measure of two-signal synchrony, would allow quantifiable discrimination of feedforward (ACTH cortisol) and feedback (cortisol ACTH) control. To this end, forward X-ApEn was defined by employing serial ACTH concentrations as a template to appraise pair-wise synchrony with cortisol secretion rates and vice versa for reverse X-ApEn. Coupled hormone profiles included normal ACTH-normal cortisol, high ACTH-high cortisol, and high ACTH-low cortisol concentrations in 35 healthy subjects, 21 patients with tumoral ACTH secretion, and 9 volunteers given placebo and a steroidogenic inhibitor, respectively. We used forward and reverse X-ApEn analyses to identify marked and equivalent losses of feedforward and feedback linkages (both P < 0.001) in patients with tumoral ACTH secretion. An identical analytical strategy revealed that ACTH cortisol feedforward synchrony decreases (P < 0.001), whereas cortisol ACTH feedback synchrony increases (P < 0.001), in response to hypocortisolemia. The collective outcomes establish precedence for pathway-specific adaptations in a major neurohormonal system. Thus quantification of directionally defined joint synchrony of biologically coupled signals offers a noninvasive strategy to dissect feedforward- and feedback-selective adaptations in an interactive axis.

adrenocorticotropin; regulation; statistic; cross-approximate entropy; neuroendocrine stress

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