Inclusion of the glucocorticoid receptor in a hypothalamic pituitary adrenal axis model reveals bistability
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Inclusion of the glucocorticoid receptor in a hypothalamic pituitary adrenal axis model reveals bistability Shakti Gupta, Eric Aslakson*, Brian M Gurbaxani and Suzanne D Vernon Address: Division of Viral and Rickettsial Diseases, National Center for Zoonotic, Vector-Borne, and Enteric Diseases, Centers for Disease Control and Prevention, 600 Clifton Rd, MS-A15, Atlanta, Georgia 30333, USA Email: Shakti Gupta - [email protected]; Eric Aslakson* - [email protected]; Brian M Gurbaxani - [email protected]; Suzanne D Vernon - [email protected] * Corresponding author
Published: 14 February 2007 Theoretical Biology and Medical Modelling 2007, 4:8
doi:10.1186/1742-4682-4-8
Received: 27 August 2006 Accepted: 14 February 2007
This article is available from: http://www.tbiomed.com/content/4/1/8 © 2007 Gupta et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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). Conclusion: 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.
Background The hypothalamic pituitary adrenal (HPA) axis represents a self-regulated dynamic feedback neuroendocrine system that is essential for maintai
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