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Inclusion of the glucocorticoid receptor in a hypothalamic pituitary adrenal axis model reveals bistability

Gupta S, Aslakson E, Gurbaxani BM, Vernon SD
Theoretical Biology and Medical Modeling 2007;4:8.

The complete electronic version of this article is available at: http://www. tbiomed.com/content/4/1/8

Summary

Evidence from clinical studies increasingly implicates dysfunction of the hypothalamic pituitary adrenal (HPA) axis as central to the pathophysiology of CFS. The HPA axis is a self-regulated dynamic feedback system linking the brain and body. HPA axis function involves the immune, autonomic nervous, musculoskeletal, and endocrine systems. In addition to our various clinical studies, our research group is developing mathematical models of HPA axis function. These models are extremely important because they identify potential perturbations in the system that can be directly evaluated in clinical studies, because they can help to identify the source of differences observed in clinical studies between persons with CFS and controls, and because they may identify targets for pharmacologic intervention. The model described in this manuscript includes the dynamic effects of corticotropic releasing hormone, ACTH, cortisol, and expression of the glucocorticoid receptor in the pituitary. This model predicts that repeated stress and glucocorticoid receptor expression will lead to a bistable state; this has profound implications concerning risk factors and the pathophysiology of CFS.

Abstract

Background The body’s primary stress management system is the hypothalamic pituitary adrenal (HPA) axis. The HPA axis responds to physical and mental challenge to maintain homeostasis in part by controlling the body’s cortisol level. Dysregulation of the HPA axis is implicated in numerous stress-related diseases.

Results We developed a structured model of the HPA axis that includes the glucocorticoid receptor (GR). This model incorporates nonlinear kinetics of pituitary GR synthesis. The 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 state of cortisol production resulting in bistability of the HPA axis. In this model, low GR concentration represents the normal steady state, and high GR concentration represents a dysregulated steady state. A short stress in the normal steady state produces a small perturbation in the GR concentration that quickly returns to normal levels. Long, repeated stress produces persistent and high GR concentration that does not return to baseline forcing the HPA axis to an alternate steady state. One consequence of increased steady state GR is reduced steady state cortisol, which has been observed in some stress related disorders such as Chronic Fatigue Syndrome (CFS).

Conclusions Inclusion of pituitary GR expression resulted in a biologically plausible model of HPA axis bistability and hypocortisolism. High GR concentration enhanced cortisol negative feedback on the hypothalamus and forced the HPA axis into an alternative, low cortisol state. This model can be used to explore mechanisms underlying disorders of the HPA axis.

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