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

Peter Y. Liu, Steven M. Pincus, Daniel M. Keenan, Ferdinand Roelfsema, Johannes D. Veldhuis

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


The hypothaiamo-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.

Original languageEnglish (US)
Pages (from-to)E160-E165
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Issue number1 52-1
StatePublished - Jul 2005


  • Adrenocorticotropin
  • Cross-approximate entropy
  • Neuroendocrine stress
  • Regulation
  • Statistic

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)


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