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

Stress activates a complex network of hormones known as the Hypothalamic-Pituitary-Adrenal (HPA) axis. The HPA axis regulates multiple metabolic, immune, and behavioral end-points. Dysregulation of the HPA axis is a hallmark of several psychiatric conditions, including depression and substance-abuse disorders. However, little is known about the origin of this dysregulation, and we currently lack mathematical models that can explain its dynamics on the timescale of weeks. Specifically, accumulated experimental evidence indicates that after prolonged activation of the HPA axis, ACTH responses become blunted, and this blunting persists for weeks even after normalization of cortisol levels and responses. Here, we use mathematical modelling to show that this dysregulation can be explained by changes in the functional masses of the glands (total mass of the cells) that secrete ACTH and cortisol. These mass changes occur because the hormones CRH and ACTH regulate the growth of corticotroph and adrenal cortex cells, respectively. Furthermore, we show that impaired glucocorticoid receptor (GR) feedback exacerbates this dysregulation, providing a rationale for the role of GR in depression. We propose that this dysregulation is a side-effect of a circuit with a physiological function, in which gland-mass changes provide dynamical compensation to physiological variation. These findings suggest that gland-mass dynamics may play a role in the pathophysiology of stress-related disorders.