A mechanistic model of ACTH-stimulated cortisol secretion

Model Status

This model has been edited to correct dimensional errors and checked for other problems. It runs in COR and OpenCell but whether it replicates experimental results is yet to be determined.

ValidateCellML confirms this model to be valid CellML but detects units inconsistencies.

Model Structure

Advances in the study of cortisol biosynthesis indicate that adrenocorticotropin (ACTH) stimulates steroid secretion by facilitating the delivery of free cholesterol to the side chain cleavage (scc) enzyme. ACTH binds to one or more specific receptors in the adrenocortical cell membrane (represented by A and B in the figure below) which has the effect of activating adenylate cyclase (ACase). The cytosolic concentration of adenosine 3,5-cyclic monophosphate (cAMP) increases, in turn a) activating cholesterol ester (CE) hydrolase, which catalyses the conversion of cholesterol ester into free cholesterol, and b) facilitating the transfer of cholesterol within the mitochondrion to a site accessible to the scc enzyme. Furthermore, low density lipoprotein receptor-mediated uptake of plasma cholesterol together with cytosolic cholesterol synthesis provide substrate for steroid synthesis, and both these processes can be controlled by an intracellular pool of cholesterol.

In their 1984 publication, Dempsher et al. describe all these physiological phenomena in a mathematical model of ACTH-stimulated cortisol secretion (the complete original paper reference is cited below). Steps in the biosynthetic pathway are described using first-order linear differential equations, and the results of the model simulations were compared, and were consistent with, experimental data. The corticotropin-releasing hormone (CRH) is synthesised in the hypothalamus and is carried to the anterior pituitary gland where it stimulates cells to produce adrenocorticotrophic hormone (ACTH). In turn, ACTH stimulates the synthesis and secretion of cortisol (F). Cortisol exerts a negative feedback effect on the ACTH secretion in the pituitary and also suppresses CRH synthesis in the hypothalamus. In addition, there is also a negative feedback effect of ACTH on the secretion of CRH. Therefore the entire process can be thought of as a self-regulating system, as summarised in the figure below).

A mechanistic model of ACTH-stimulated cortisol secretion, D.P. Dempsher, D.S. Gann, and R.D. Phair, 1984, American Journal of Physiology , 246, R587-R596. PubMed ID: 6326602

Schematic diagram of the model describing the effects of ACTH on cortisol secretion. (note that ECF represents the extracellular fluid).