The Physiological and Pharmacological Significance of the Circadian Timing of the HPA Axis: A Mathematical Modeling Approach

As a potent endogenous regulator of homeostasis, the circadian time-keeping system synchronizes internal physiology to periodic changes in the external environment to enhance survival. Adapting endogenous rhythms to the external time is accomplished hierarchically with the central pacemaker located in the supra-chiasmatic nucleus (SCN) signaling the hypothalamus-pituitary-adrenal (HPA) axis to release hormones, notably cortisol, which help maintain the body's circadian rhythm. Given the essential role of HPA-releasing hormones in regulating physiological functions, including immune response, cell cycle, and energy metabo-lism, their daily variation is critical for the proper function of the circadian timing system. In this review, we focus on cortisol and key fundamental properties of the HPA axis and highlight their importance in control-ling circadian dynamics. We demonstrate how systems-driven, mathematical modeling of the HPA axis com-plements experimental findings, enhances our understanding of complex physiological systems, helps predict potential mechanisms of action, and elucidates the consequences of circadian disruption. Finally, we outline the implications of circadian regulation in the context of personalized chronotherapy. Focusing on the chrono-pharmacology of synthetic glucocorticoids, we review the challenges and opportunities associ-ated with moving toward personalized therapies that capitalize on circadian rhythms. (c) 2023 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.