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

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

Dysfunction

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http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000273

Journal: PLoS Comput Biol. 2009 Jan;5(1):e1000273. Epub 2009 Jan 23.

Authors: Ben-Zvi A, Vernon SD, Broderick G.

Affiliations:

[1] Department of Chemical and Materials Engineering, University of

Alberta, Edmonton, Alberta, Canada,

[2] The CFIDS Association of America, Charlotte, North Carolina,

United States of America,

[3] Department of Medicine, University of Alberta, Edmonton, Alberta, Canada

NLM Citation: PMID: 19165314

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.