Abstract
Stress activates a complex network of hormones known as the hypothalamic–pituitary–adrenal (HPA) axis. The HPA axis is dysregulated in chronic stress and psychiatric disorders, but the origin of this dysregulation is unclear and cannot be explained by current HPA models. To address this, we developed a mathematical model for the HPA axis that incorporates changes in the total functional mass of the HPA hormone‐secreting glands. The mass changes are caused by HPA hormones which act as growth factors for the glands in the axis. We find that the HPA axis shows the property of dynamical compensation, where gland masses adjust over weeks to buffer variation in physiological parameters. These mass changes explain the experimental findings on dysregulation of cortisol and ACTH dynamics in alcoholism, anorexia, and postpartum. Dysregulation occurs for a wide range of parameters and is exacerbated by impaired glucocorticoid receptor (GR) feedback, providing an explanation for the implication of GR in mood disorders. These findings suggest that gland‐mass dynamics may play an important role in the pathophysiology of stress‐related disorders.
Highlights
A major hormone system that responds to stress is the HPA axis (Tsigos & Chrousos, 2002; Hosseinichimeh et al, 2015; Melmed et al, 2015; Zavala et al, 2019)
Elevated cortisol and blunted ACTH responses are observed in other conditions that involve prolonged HPA axis activation (Fig 1D), including anorexia nervosa (Gold et al, 1986a), alcohol abuse disorder, and pregnancy (Magiakou et al, 1996)
We provide a mechanism to explain HPA axis dysregulation, based on the effects of the hormones on the gland masses
Summary
A major hormone system that responds to stress is the HPA axis (Tsigos & Chrousos, 2002; Hosseinichimeh et al, 2015; Melmed et al, 2015; Zavala et al, 2019). In the CRH test, CRH is administered and cortisol and ACTH dynamics are measured for a few hours (Fig 1B). Major depression is associated with a blunted (reduced) ACTH response (Holsboer et al, 1984; Gold et al, 1986b; von Bardeleben & Holsboer, 1989) in the CRH test (Fig 1C), as well as with elevated baseline cortisol (Murphy, 1991). Elevated cortisol and blunted ACTH responses are observed in other conditions that involve prolonged HPA axis activation (Fig 1D), including anorexia nervosa (Gold et al, 1986a), alcohol abuse disorder (von Bardeleben et al, 1989), and pregnancy (Magiakou et al, 1996)
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