Molecular Determinants of Glucocorticoid Receptor Function and Tissue Sensitivity to Glucocorticoids

I. Introduction STEROID hormones are essential constituents of the intercellular communication system that maintains homeostasis in higher organisms. Glucocorticoids, a major subclass of steroid hormones, modulate a large number of metabolic, cardiovascular, immune, and behavioral functions (for a review see Refs. 1 and 2). Glucocorticoids are produced by the adrenal cortex under the regulatory influence of ACTH. The latter is produced by corticotrophs of the anterior pituitary, in turn, under the regulatory influence of hypothalamic CRH and arginine vasopressin (AVP). The hypothalamic-pituitary-adrenal (HPA) axis is kept in balance by the negative feedback effects of cortisol on the secretion of ACTH, CRH, and usually, to a lesser extent, AVP. In the resting state, basal levels of CRH, AVP, ACTH, and cortisol are released in a pulsatile and circadian fashion. At these baseline levels, the main function of cortisol is to sustain normoglycemia and to prevent arterial hypotension. Whether and to what extent the immunosuppressive effects of cortisol are relevant at resting state levels in humans is still a matter of dispute (3). Activation of the HPA axis during physical and/or emotional stress and the resulting increase in plasma cortisol levels are probably required for central nervous system (CNS) activation, higher blood glucose concentrations, and an elevated mean blood pressure in the stress state. Cortisol also restrains a potential concurrent inflammatory/immune reaction, which might otherwise lead to tissue damage.