Inclusion of the glucocorticoid receptor in a hypothalamic pituitary adrenal axis model reveals bistability.
Bottom Line:
The body's primary stress management system is the hypothalamic pituitary adrenal (HPA) axis.This model incorporates nonlinear kinetics of pituitary GR synthesis.In this model, low GR concentration represents the normal steady state, and high GR concentration represents a dysregulated steady state.
Affiliation: Division of Viral and Rickettsial Diseases, National Center for Zoonotic, Vector-Borne, and Enteric Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333, USA. shaktig@gmail.com
ABSTRACT
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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. Related in: MedlinePlus |
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Mentions: Equations (9)–(12) permit one or three positive steady states depending upon the parameter values. The three positive steady states exist because of homodimerization of the GR with cortisol. Figure 3 shows the variation of GR and cortisol steady state with respect to parameter krd. Variations in krd from person to person may be expected due to genetic differences in the details of GR production and degradation. For a high value of krd, there exists only a low GR concentration steady state. As the value of krd decreases, these equations produce two more steady states, one stable and another unstable in GR concentration. As krd decreases further, a low GR concentration state disappears and only a high GR concentration state exists (Figure 3a). In this model, we postulate that the low GR concentration represents the normal steady state, and high GR concentration denotes a dysregulated HPA axis steady state as it results in persistent low cortisol levels (hypocortisolism) (Figure 3b). Hypocortisolism results from the negative feedback between GR (i.e. the symbol "R" in Figure 1) and ACTH (A), and hence cortisol (O) produced downstream of it, as shown in Figure 1 and reflected by the inverse relationship between cortisol and GR in Figure 3. Thus individuals with very large values of krd would be constitutively healthy in this model, i.e. impervious to a dysregulated HPA-axis no matter how much they are stressed, and those with very low values of krd would be constitutively unhealthy. |
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Affiliation: Division of Viral and Rickettsial Diseases, National Center for Zoonotic, Vector-Borne, and Enteric Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333, USA. shaktig@gmail.com
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.