A new model for the HPA axis explains dysregulation of stress hormones on the timescale of weeks

• Published in: Molecular systems biology Vol. 16; no. 7; pp. e9510 - n/a
• Main Authors: Karin, Omer, Raz, Moriya, Tendler, Avichai, Bar, Alon, Korem Kohanim, Yael, Milo, Tomer, Alon, Uri
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-07-2020; EMBO Press; John Wiley and Sons Inc; Springer Nature
• Subjects: Adrenocorticotropic hormone; Adrenocorticotropic Hormone - metabolism; Alcohol; Alcoholism; Alcoholism - metabolism; Animals; Anorexia; Anorexia - metabolism; Cortisol; Disorders; Drug abuse; dynamical compensation; EMBO10; EMBO37; endocrine circuits; Endocrine Glands - growth & development; Endocrine Glands - metabolism; Epigenetics; exact adaptation; Feedback; Feedback, Physiological; Glucocorticoids; Growth factors; Hormones; Humans; Hydrocortisone - metabolism; Hypothalamic-pituitary-adrenal axis; Hypothalamo-Hypophyseal System - metabolism; Hypothalamo-Hypophyseal System - physiopathology; Hypothalamus; Mathematical models; mathematical models of disease; Mental depression; Mental disorders; Models, Theoretical; Mood; Mood Disorders - metabolism; Parameters; Physiology; Pituitary; Pituitary-Adrenal System - metabolism; Pituitary-Adrenal System - physiopathology; Postpartum; Postpartum Period - metabolism; Receptors, Glucocorticoid - metabolism; Software; Stress; Stress, Physiological; systems medicine; endocrine circuits; systems medicine; dynamical compensation; mathematical models of disease; exact adaptation
• ISSN: 1744-4292; 1744-4292
• DOI: 10.15252/msb.20209510

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.
Synopsis
Prolonged activation of the HPA axis leads to dysregulation and has clinical consequences. This study presents a mechanism for HPA dysregulation based on the effect of HPA hormones acting as growth factors for their downstream glands.
A mathematical model that includes gland functional mass dynamics introduces a new slow timescale of weeks to the HPA axis.
The gland masses grow during prolonged activation, providing dynamical compensation, and recover with overshoots over weeks after withdrawal of activation.
These overshoots explain the observed HPA dysregulation in pathological conditions, and clarify the role of glucocorticoid receptors in resilience to prolonged stress.
Graphical Abstract
Prolonged activation of the HPA axis leads to dysregulation and has clinical consequences. This study presents a mechanism for HPA dysregulation based on the effect of HPA hormones acting as growth factors for their downstream glands.