until cortisol levels increase; high levels of cortisol inhibit ACTH secretion.

One feature of this hypothalamic-pituitary-adrenal (HPA) axis is the presence of a diurnal rhythm, so that the ACTH nadir occurs in the early morning hours, followed by increasing levels during the night that stimulate cortisol to peak levels in the morning (around 8:00 a.m.). Both ACTH and cortisol values decline to very low levels in the evening between 10:00 p.m. and 2:00 a.m.

Glucocorticoids, like other steroid hormones, are thought to exert their biologic effects by binding to an intracellular receptor specific to each class of steroid. The steroid-receptor complex can bind specifically to sites on DNA called response elements and thereby alter rates of transcription of genes. This type of genomic response involves subsequent protein synthesis and is usually detected within hours of exposure to steroids. Importantly, the outcome may be to either increase or decrease an end point. Full expression of the expected effect is deemed a full "agonist" effect. A reduction in the observed effect after the addition of another steroid can be considered "antagonism." When given alone, the second steroid may have a suboptimal agonist effect (partial agonist) or have only antagonist effects.

A number of factors influence glucocorticoid effects on a given tissue. These include the type and amount of the glucocorticoid available and the number of intracellular glucocorticoid receptors. About 95 percent of the circulating cortisol in man is bound to corticosteroid-binding protein (CBG). Since only the free, or unbound, cortisol is available for entry into the cells, conditions that alter CBG levels may alter transiently the availability of glucocorticoids to the cells, until a new steady state is achieved by alteration in ACTH, and hence cortisol production and the free cortisol fraction. Studies in man involving agents that compete with cortisol for CBG sites, or agents that do not bind to CBG, and studies in rats, which have no corticosteroid-binding protein, must be interpreted with this in mind.

The diurnal rhythm of circulating cortisol already mentioned illustrates the concept that the plasma glucocorticoid concentration may not reflect accurately the physiologic status: circulating levels vary up to 30-fold over a day in normal individuals. For this reason, daily urine free cortisol excretion is a better index of the integrated exposure of the body to cortisol, because it derives from unbound plasma cortisol. Finally, the number of glucocorticoid receptors in a given cell population may be regulated, usually inversely, by glucocorticoid exposure, so that exposure to glucocorticoids may induce a decrease of up to 50 percent in receptor number (Hoeck et al., 1989). Also, the number of glucocorticoid receptors may vary in relation to the cell cycle in in vitro systems. Whether these observations hold in vivo is not known. For these



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