Glucocorticoid physiology, pharmacology and stress

Basal levels of glucocorticoids maintained by negative feedback regulation are known to modulate a wide range of physiological processes, through a variety of effects such as those on carbohydrate metabolism and "permissive" actions on effects of other hormones. Glucocorticoid levels increase sharply in response to the stress of any kind of threat to homeostasis. The increased levels have traditionally been ascribed the function of enhancing the organism's resistance to stress. How known physiological and pharmacological effects of high levels of glucocorticoids might accomplish this function, however, has been a mystery. A generalization that is beginning to emerge is that many of these effects may be secondary to modulation by glucocorticoids of the actions of numerous intercellular mediators, including established hormones, prostanoids, neutral proteinases, and cytokines such as interferon. These mediators participate in physiological mechanisms--endocrine, renal, immune, neural, etc.--that mount a first line of defense against such challenges to homeostasis as hemorrhage, metabolic disturbances, infection, anxiety, and others. Contrary to the traditional view that the role of glucocorticoids in stress is to enhance these defense mechanisms, it has become increasingly clear that glucocorticoids at moderate to high levels generally suppress them. This paradox first emerged when glucocorticoids were discovered to be antiinflammatory agents, and had remained a major obstacle to a unified picture of glucocorticoid function. We have suggested that stress-induced increases in glucocorticoid levels protect not against the source of stress itself but rather against the body's normal reactions to stress, preventing those reactions from overshooting and themselves threatening homeostasis. This hypothesis, the seeds of which are to be found in many earlier discussions of glucocorticoid effects, immediately accounts for the paradox noted above, and provides glucocorticoid physiology with a unified conceptual framework that can accommodate such apparently unrelated physiological and pharmacological effects as those on carbohydrate metabolism, inflammatory processes, shock and water balance. It also leads us to propose that some enzymes rapidly induced by glucocorticoids detoxify mediators released during stress-induced activation of primary defense mechanisms; those mediators could themselves cause damage if left unchecked.