Model-Based Therapeutic Correction of Hypothalamic-Pituitary-Adrenal Axis Dysfunction

Abstract

The hypothalamic-pituitary-adrenal (HPA) axis is a major system maintaining body homeostasis by regulating the neuroendocrine and sympathetic nervous systems as well modulating immune function. Recent work has shown that the complex dynamics of this system accommodate several stable steady states, one of which corresponds to the hypocortisol state observed in patients with chronic fatigue syndrome (CFS). At present these dynamics are not formally considered in the development of treatment strategies. Here we use model-based predictive control (MPC) methodology to estimate robust treatment courses for displacing the HPA axis from an abnormal hypocortisol steady state back to a healthy cortisol level. This approach was applied to a recent model of HPA axis dynamics incorporating glucocorticoid receptor kinetics. A candidate treatment that displays robust properties in the face of significant biological variability and measurement uncertainty requires that cortisol be further suppressed for a short period until adrenocorticotropic hormone levels exceed 30% of baseline. Treatment may then be discontinued, and the HPA axis will naturally progress to a stable attractor defined by normal hormone levels. Suppression of biologically available cortisol may be achieved through the use of binding proteins such as CBG and certain metabolizing enzymes, thus offering possible avenues for deployment in a clinical setting. Treatment strategies can therefore be designed that maximally exploit system dynamics to provide a robust response to treatment and ensure a positive outcome over a wide range of conditions. Perhaps most importantly, a treatment course involving further reduction in cortisol, even transient, is quite counterintuitive and challenges the conventional strategy of supplementing cortisol levels, an approach based on steady-state reasoning.

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“…This is also consistent with the ordinary differential equation based models used by Gupta et al [27] and Ben Zvi et al [16]. Interestingly, when the GR-GRD feedback loop is added to the HPA axis in the HPA-HPG models, the original low CORT state found by Gupta et al [27] disappears.…”

“…These states are consistent with the ordinary differential equation models of the HPA-GR system used by Gupta et al [27] and Ben Zvi et al [16].…”

“…This is a direct result of the state transition logic applied to the system. When multiple inputs determine the level of CORT all inputs must be low for CORT to drop, not just the level of ACTH as prescribed by Gupta et al [27] and Ben Zvi et al [16]. The hypocortisolic condition can be regained when neighboring regulatory systems are included, such as the female HPG axis.…”

“…Previously we investigated the possibility that some of these pathological states may coincide with naturally occurring states of the regulatory system in question [16]. These backup regimes would offer alternate homeostatic control in crisis situations but at the cost of reduced function.…”

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“…ACTH in turn stimulates the production of glucocorticoids in the zona fasciculata of the adrenal cortex. 7 The rate-limiting step in cortisol synthesis is the transfer of cholesterol into the mitochondria. 8 The subsequent metabolism of cholesterol relies on a number of adrenal enzymes.…”