Differentiation between genomic and non-genomic feedback controls yields an HPA axis model featuring hypercortisolism as an irreversible bistable switch.

[cushing syndrome]

The hypothalamic -pituitary -adrenal axis (HPA axis ) is a major part of the neuroendocrine system responsible for the regulation of the response to physical or mental stress and for the control of the synthesis of the stress hormone cortisol . Dysfunctions of the HPA axis characterized by either low (hypocortisolism ) or increased (hypercortisolism ) cortisol levels are implicated in various pathological conditions . Their understanding and therapeutic correction may be supported by mathematical modeling and simulation of the HPA axis .Mass action and Michaelis Menten enzyme kinetics were used to provide a mechanistic description of the feedback mechanisms within the pituitary gland cells by which cortisol inhibits its own production . A separation of the nucleus from the cytoplasm by compartments enabled a differentiation between slow genomic and fast non-genomic processes . The model in parts was trained against time resolved ACTH stress response data from an in vitro cell culture of murine AtT-20 pituitary tumor cells and analyzed by bifurcation discovery tools .A recently found pituitary gland cell membrane receptor that mediates rapid non-genomic actions of glucocorticoids has been incorporated into our model of the HPA axis . As a consequence of the distinction between genomic and non-genomic feedback processes our model possesses an extended dynamic repertoire in comparison to existing HPA models . In particular , our model exhibits limit cycle oscillations and bistable behavior associated to hypocortisolism but also features a (second ) bistable switch which captures irreversible transitions in hypercortisolism to elevated cortisol levels .Model predictive control and inverse bifurcation analysis have been previously applied in the simulation-based design of therapeutic strategies for the correction of hypocortisolism . Given the HPA model extension presented in this paper , these techniques may also be used in the study of hypercortisolism . As an example , we show how sparsity enforcing penalization may suggest network interventions that allow the return from elevated cortisol levels back to nominal ones .