A COMPUTER-SIMULATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

This paper describes the construction of a computer model that simulat es the hypothalamic-pituitary-adrenal axis (HPA axis) regulation of co rtisol production. It is presented to illustrate the process of physio logical modeling using standard ''off the shelf'' technologies. The mo del simulates components of the HPA axis involved in the continuous se cretion and elimination of cortisol, adrenocorticotropin (ACTH), and c orticotropin releasing hormone (CRH). The physiological relations of t hese component pieces were modeled based on the current knowledge of t heir functioning. Rate constants, half lives, and receptor affinities were assigned values derived from the experimental literature. At its current level of development the model is able to accurately simulate the timing, magnitude and decay of the ACTH and cortisol concentration peaks resulting from the ovine-CRH stimulation test in normal and hyp ercortisolemic patients. The model will be used to predict the effects of lesions in different components of the HPA axis on the time course of cortisol and ACTH levels. We plan to use the model to explore the experimental conditions required to distinguish mechanisms underlying various disorders of the HPA axis, particularly depression. Efforts ar e currently underway to validate the model for a large variety of norm al and pathological perturbations of the HPA axis.