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Nonlinear Dynamics in the Synthesis of Glucocorticoid Receptor in the Hpa Axis: an Explanation for Stress-Related Disease

Shakti Gupta, Eric Aslakson, Brian M. Gurbaxani, and Suzanne D. Vernon. National Center for Infectious Diseases, Centers for Disease Control, Atlanta, GA 30329

Every stress, either physiological or psychological, stimulates the hypothalamus- pituitary- adrenal (HPA) axis, the body's main stress management system. The HPA axis responds to maintain homeostasis or internal environmental balance of the body by controlling the body's cortisol level. Stress activates the hypothalamus part of the brain to release corticotrophin releasing hormone (CRH). CRH stimulates the secretion of adrenocorticotropic hormone (ACTH) in the pituitary. ACTH is released into the blood and induces the synthesis of cortisol in the adrenals. Cortisol diffuses back to brain, binds to glucocorticoid receptor (GR) in the hypothalamus and pituitary and inhibits the synthesis of CRH and ACTH. Dysregulation of the HPA axis is involved in numerous stress-related diseases including post-traumatic stress disorder and chronic fatigue syndrome.

We present a new structured model of HPA axis that includes GR. This model incorporates nonlinear kinetics of pituitary GR synthesis. This nonlinear effect arises from the fact that GR homodimerizes after cortisol activation and induces its own synthesis in the pituitary. This homodimerization makes possible two stable steady states (low and high) and one unstable steady state of GR expression in the pituitary thus producing bistability in the HPA axis steady state. In this model, the low GR concentration steady state represents normal or basal steady state, and high GR concentration steady state denotes a dysregulated steady state. A short stress from normal steady state produces a small perturbation in the GR concentration and comes back to its normal steady state, but a long stress produces a large perturbation in GR concentration and forces the HPA axis to an alternate steady state. This alternate high GR concentration steady state produces low cortisol (hypocortisolism), which is observed in these stress-related illnesses. The model also captures the transient responses of stress, CRH and dexamethasone tests used in clinical classification of patients verses healthy group.