Hormonal dysregulation after prolonged HPA axis activation can be explained by changes of adrenal and corticotroph masses

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 new 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 the 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. Author SummaryThe HPA axis is a neuroendocrine axis that is activated in response to stressors. The classical description of this axis includes three hormones that act in a cascade, with the final hormone cortisol inhibiting the two upstream hormones, ACTH and CRH. This classical picture has timescales of hours due to hormone half-lives, and cannot explain phenomena on the scale of weeks to months associated with this axis, such as the dysregulation observed in depression, alcohol addiction, postpartum, and other conditions. Here, we use a minimal-model approach to add to the classical model two known interactions in which CRH and ACTH not only regulate downstream hormones, but also act as growth factors for the cells that secrete these hormones. This creates a physiological circuit that can maintain total cell mass and buffer parameter changes. It has a fragility in which after prolonged stress, the total cell functional masses grow and take weeks to return to baseline. This is sufficient to explain the specific dynamics of hormone dysregulation found in several contexts. It also quantifies the effect of the cortisol (glucocorticoid) receptor on resilience to prolonged stress. Our findings suggest that interactions between hormones and cell functional mass may play an important role in HPA axis regulation on the timescale of weeks to months. Synopsis O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY The HPA axis helps the body adapt to stress, but becomes dysregulated after prolonged activation, with clinical consequences. The origin of this dysregulation is unclear. We provide a mechanism for dysregulation based on the effect of the HPA hormones as growth factors for their downstream glands. O_LIA mathematical model that includes gland functional mass dynamics, introduces a new slow timescale of weeks to the HPA axis; previous models had only fast timescales of hours. C_LIO_LIThe gland masses grow during prolonged activation, providing dynamical compensation, and recover with overshoots over weeks after withdrawal of activation. C_LIO_LIThese overshoots are sufficient to explain the observed HPA dysregulation in pathological conditions, and clarify the role of glucocorticoid receptors in resilience to prolonged stress. C_LI