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Figure 1 Structures of the natural glucocorticoids, Cortisol and corticosterone, and of cortisone, an inactive metabolite derived from Cortisol by oxidation of the 11 -hydroxyl group.

ized in pursuit of compounds with reduced salt retention and other unwanted side-effects, a quest that yielded prednisolone, dexamethasone and other important steroids in current use (Figure 2).

The discovery of the anti-inflammatory effects also caused turmoil among adrenal physiologists, who were unable to reconcile the suppressive effects on inflammation with their assumption that stress-induced glucocorticoids stimulated defense mechanisms. Consequently they stigmatized the antiinflammatory effects as pharmacological artifacts without physiological significance, leaving the major therapeutic applications of the glucocorticoids with no apparent physiological foundation. That paradoxical situation prevailed for over three decadcs. In recent years an alternative view of the protective role of glucocorticoids in stress that reconciles glucocorticoid physiology with therapy has gained strong experimental support. It proposes that in many circumstances high, stress-induced levels of glucocorticoids actually protect the organism from its own stress-activated defense mechanisms, suppressing those mechanisms to prevent them from overshooting and causing damage. This view places immunosuppressive, anti-inflammatory and other such actions at the center of glucocorticoid physiology.

Glucocorticoids can therefore be viewed as sustaining life through two different but related mechanisms: they 'permissively' activate some homeo-static defense mechanisms and, generally at higher levels, they prevent such mechanisms from overshooting. In the course of normal diurnal variation they probably exert both these influences to varying degrees; under stress, the second may predominate. Figure 3 illustrates qualitatively how activity of a defense mechanism might be influenced at various Cortisol concentrations. Levels of free Cortisol in humans vary diurnally over the lower range of the bell-shaped curve, rising in the morning to roughly the concentration for peak activity. Stress-induced levels can go well into the suppressive range.

Regulation of glucocorticoid secretion via the hypothalamo-pituitary-adrenal (HPA) axis began to be understood in the 1930s. ACTH (adrenocorticotropic hormone) was identified as the anterior pituitary peptide that stimulates glucocorticoid secretion as well as growth of the inner zones of the adrenal cortex. Its secretion was eventually shown to be stimulated by the hypothalamic hormone CRH (corticotropin-releasing hormone) in conjunction with VP (vasopressin, also a hypothalamic hormone). Glucocorticoids in turn exert negative feedback on production of CRH, VP and ACTH, thus

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