Milo, T.; Nir Halber, S.; Raz, M.; Mayo, A.; Alon, U.

Elevated cortisol causes morbidity in chronic stress and mood disorders, including metabolic and cardiovascular diseases. There is therefore interest in developing drugs that lower cortisol by targeting its endocrine pathway, the hypothalamic-pituitary-adrenal (HPA) axis. Several promising HPA-modulating drugs have, however, failed to lower long-term cortisol in mood disorders such as major depressive disorder despite their effectiveness in situations where high cortisol is caused by a tumor (Cushing's syndrome). Why these drugs failed is not well understood. Here we use a mathematical model of the HPA axis to show that the pituitary and the adrenal glands compensate for the effect of drugs by adjusting their functional mass, a feedback compensation that is absent in Cushing tumors. To find potential drug targets, we carried out a systematic in silico analysis of points of intervention in the HPA axis. We find that only two interventions that target corticotropin-releasing hormone (CRH) can lower long-term cortisol. Other drug targets either fail to lower cortisol due to gland-mass compensation or lower cortisol but harm other aspects of the HPA axis. Thus, we identify potential drug targets, including CRH-neutralizing antibodies and CRH-synthesis inhibitors, for lowering long-term cortisol in mood disorders and in those suffering from chronic stress. More generally, this study indicates that understanding the slow compensatory mechanisms in endocrine axes can be crucial in order to prioritize drug targets.