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-, scaleand 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 pairwise synchrony with cortisol secretion rates, and vice versa for reverse X-ApEn. Coupled hormone profiles comprised 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. Forward and reverse X-ApEn analyses identified marked and equivalent loss 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.