Inclusion of the glucocorticoid receptor in a hypothalamic pituitary adrenal axis model reveals bistability: where a pulsatile stress is applied to the model

Model Status

This particular version of the model has a pulsatile stress and recreates the shapes of the graphs in figure 5 of the paper. This CellML model runs in both COR and OpenCell. The units have been checked and they are consistent. The equations are based on the scaled set in the paper (9-12) and the concentrations of the hormones are therefore dimensionless. For this reason the CellML model doesn't quite recreate the graphs in figure 5 (where the hormones are assigned units of picomolar and nanomolar).

Model Structure

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.

The original paper reference is cited below:

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, 2007,Theoretical Biology and Medical Modelling, volume 4, issue 8. PubMed ID: 17300722

The HPA axis model has three compartments, namely the hypothalamus, pituitary and adrenals. F is an external stress that triggers CRH (C) secretion by the hypothalamus. In turn, this signals to the pituitary to release ACTH (A) which stimulates the adrenal gland to release cortisol (O). Cortisol binds to the glucocorticoid receptor (R) in the pituitary and has a negative feedback effect on the release of CRH and ACTH. In addition, the cortisol-receptor complex has a positive feedback effect, promoting further receptor synthesis.