Modeling robust oscillatory behavior of the hypothalamic-pituitary-adrenal axis

Model Structure

The hypothalamus-pituitary-adrenal (HPA) axis forms part of the endocrine system and it plays an essential role in the coordination of physiological processes in mammals. As its name suggests it comprises three glands; the hypothalamus, anterior pituitary and adrenal cortex. These glands function together by synthesising and secreting, or sensing and responding to, hormones such as corticotropin-releasing hormone (CRH), corticotropin (ACTH), and cortisol. Typically CRH is produced and secreted by the hypothalamus, stimulating the synthesis and secretion of ACTH by the anterior pituitary, in turn activating the adrenal cortex to produce and release cortisol. Cortisol has a negative feedback effect on CRH and ACTH production by the hypothalamus and anterior pituitary respectively (see figure below). The free cortisol in the plasma is bound by two proteins; corticosteroid-binding globulin (CBG) and albumin.

The hypothalamus effectively acts as an interface between the central nervous system (CNS) and the endocrine system. CNS activity affects the diurnal and circadian patterns of the HPA axis, and under conditions of stress the CNS increases its stimulation of the hypothalamus leading to a higher concentration of CRH and subsequently, significantly increased production of cortisol.

In the paper described here, Kyrylov et al. present a mathematical model of the HPA axis. Five system state variables were used to represent the circulatory concentrations of CRH, ACTH, free cortisol, CBG-bound cortisol and albumin-bound cortisol. Their model is based on the mathematical model published by Liu et al. in 1999 (which has also been described in CellML and can be found in the model repository), and further builds on this model by stabilising it and making it more robust to perturbations in certain parameter values. In addition, this new version of the model provides circadian rhythms, stress responses, and the ability to modulate gland size parameters, while retaining simplicity, and physiological relevance in terms of the hormone concentrations.

Schematic diagram of the hypothalamus-pituitary-adrenal (HPA) axis. Stimulatory and inhibitory paths are indicated by the arrows and + or - signs respectively. CRH represents corticotropin-releasing hormone, ACTH is corticotropin, and CBG represents corticosteroid-binding globulin.

The complete original paper reference is cited below:

Modeling robust oscillatory behavior of the hypothalamic-pituitary-adrenal axis, Vadim Kyrylov, Liudmila A. Severyanova, and Amandio Vieira, 2005, IEEE Transactions on Biomedical Engineering , 52, 1977-1983. (A PDF version of the article is available to journal subscribers on the IEEE Transactions on Biomedical Engineering website.) PubMed ID: 16366221