The Hepato-Hypothalamic-Pituitary-Adrenal-Renal Axis: Mathematical Modeling of Cortisol's Production, Metabolism, and Seasonal Variation.

Cortisol dynamics are governed by the integration of influences from the suprachiasmatic nucleus (SCN), the hypothalamic-pituitary-adrenal (HPA) axis, and metabolic enzymes, such as the 11β-hydroxysteroid dehydrogenase (HSD) family, which are highly expressed in hepatic and renal tissue. The coordinated regulation of cortisol dynamics is essential for the maintenance of a healthy state, and aberrant cortisol circadian rhythms are associated with various pathophysiological conditions. The duration of the light-dark cycle, or photoperiod, which regulates SCN activity, varies seasonally, and the shorter photoperiod winter season is associated with elevated cortisol levels, peak inflammatory disease incidence, and symptom exacerbation. Elevated expression and activity of 11β-HSD1 protein, assumed to also occur during the winter, have been allied with numerous inflammatory conditions. A comprehensive understanding of the communication between the underlying regulatory mechanisms of cortisol as well as how changes in their activity could lead to the development of disease is yet to be elucidated. In this work, we propose the use of a semimechanistic mathematical model to explore the impact of the hepato-hypothalamic-pituitary-adrenal-renal axis in modulating neuroendocrine-immune system dynamics. Our model predicts the predominance of a winter proinflammatory state and that genetic variations could alter 11β-HSD enzyme functionality, rendering certain subpopulations more susceptible to disease as a consequence of HPA axis dysregulation.