The rate of secretion follows a circadian rhythm (Figure 39–2) governed by pulses of ACTH that peak in the early morning hours and after meals. In plasma, cortisol is bound to circulating proteins. Corticosteroid-binding globulin (CBG), an α2 globulin synthesized by the liver, binds about 90% of the circulating hormone under normal circumstances. The remainder is free (about
FIGURE 39–2 Circadian variation in plasma cortisol throughout the 24-hour day (upper panel). The sensitivity of tissues to glucocorticoids is also circadian but inverse to that of cortisol, with low sensitivity in the late morning and high sensitivity in the evening and early night (lower panel). The sensitivity of tissues to glucocorticoids is inversely related to that of glucocorticoid receptor (GR) acetylation by the transcription factor CLOCK; the acetylated receptor has decreased transcriptional activity. (Adapted, with permission, from Nader N, Chrousos GP, Kino T: Interactions of the circadian CLOCK system and the HPA axis. Trends Endocrinol Metab 2010;21:277. Copyright Elsevier.) 5–10%) or loosely bound to albumin (about 5%) and is available to exert its effect on target cells. When plasma cortisol levels exceed 20–30 mcg/dL, CBG is saturated, and the concentration of free cortisol rises rapidly. CBG is increased in pregnancy, with estrogen administration, and in hyperthyroidism. It is decreased by hypothyroidism, genetic defects in synthesis, and protein deficiency states. Albumin has a large capacity but low affinity for cortisol, and for practical purposes albumin-bound cortisol should be considered free. Synthetic corticosteroids such as dexamethasone are largely bound to albumin rather than CBG.
The half-life of cortisol in the circulation is normally about 60–90 minutes; it may be increased when hydrocortisone (the pharmaceutical preparation of cortisol) is administered in large amounts or when stress, hypothyroidism, or liver disease is present. Only 1% of cortisol is excreted unchanged in the urine as free cortisol; about 20% of cortisol is converted to cortisone by 11-hydroxysteroid dehydrogenase in the kidney and other tissues with mineralocorticoid receptors (see below) before reaching the liver. Most cortisol is metabolized in the liver. About one-third of the cortisol produced daily is excreted in the urine as dihydroxy ketone metabolites and is measured as 17-hydroxysteroids (see Figure 39–3 for carbon numbering). Many cortisol metabolites are conjugated with glucuronic acid or sulfate at the C3 and C21 hydroxyls, respectively, in the liver; they are then excreted in the urine.
In some species (eg, the rat), corticosterone is the major glucocorticoid. It is less firmly bound to protein and therefore metabolized more rapidly. The pathways of its degradation are similar to those of cortisol.
A. Mechanism of Action