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Quantifying Nonlinear Interactions within the Hypothalamo-Pituitary-Adrenal Axis in the Conscious Horse

Department of Statistics (D.M.K.), University of Virginia, Charlottesville, Virginia 22904; Equine Research Unit (S.A., C.I.), Lincoln University, Christchurch 8150, New Zealand; and Endocrine Research Unit (J.D.V.), Department of Internal Medicine, Clinical Translational Science Unit, Mayo Medical and Graduate Schools of Medicine, Mayo Clinic, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: Johannes D. Veldhuis, Endocrine Research Unit, Department of Internal Medicine, Clinical Translational Science Unit, Mayo Medical and Graduate Schools of Medicine, Mayo Clinic, Rochester, Minnesota 55905. E-mail: veldhuis.johannes{at}mayo.edu.

Cortisol is an important mediator of physiological stress responses. Hypothalamic CRH and arginine vasopressin (AVP) and pituitary ACTH, in addition to hypothalamic and pituitary cortisol feedback, regulate cortisol secretion. Importantly, joint interactions among the four, rather than the signal of any one hormone, govern this life-preserving axis. Quantifying in vivo strength of such joint interactions has been difficult, especially without direct injection of cortisol, CRH, AVP, or ACTH. The goal of the present research was to estimate these joint feedback and feedforward interactions in vivo in the conscious horse during low-cortisol and hypoglycemic stress. Pituitary venous sampling of ACTH, CRH, and AVP was performed every 0.5–1 min and jugular venous sampling of cortisol every 15–20 min. Estimation of hypothalamic dynamics revealed that: 1) hypocortisolemia amplifies CRH and AVP secretion, when mean (slow) and rate-adjusted (rapid) cortisol feedback concentrations decrease by 0–25%; and 2) reduced peptide feedback augments CRH and AVP secretion, when CRH and AVP secretion each decreases by 0–25 and 50% of its respective maximum. Thus, low-cortisol feedback enhances CRH outflow in part by relieving CRH’s autoinhibition. Estimation of pituitary dynamics disclosed that: 1) endogenous CRH and AVP synergize in evoking ACTH secretion, and 2) hypocortisolemia potentiates individual and conjoint stimulation of ACTH secretion by CRH and AVP. Formulations such as the present one should have application to evaluating other complex endocrine dynamics.

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