Rate of Secretion
Cortisol, the major glucocorticoid in humans, is secreted at a rate of 15 to 20 mg/day in men and at an approximately 10% lower rate in women,25 while corticosterone is secreted at a rate of 4 mg/day. ACTH stimulation can increase corticosterone secretion 40 mg/d. The two main mineralocorticoids, aldosterone and deoxycorticosterone, are secreted at the rates of 50 to 200 and 16 to 40 mg/d, respectively.
Metabolism
Corticosteroids are metabolized through enzymatic transformations that diminish their physiologic activity and increase water solubility to enhance their urinary excretion.26 The majority of serum cortisol is reduced to dihydrocortisol and then to tetrahydrocortisol, which is then conjugated to glucuronic acid. Approximately 10% of cortisol is converted to the 17-ketosteroid, which is then conjugated to sulfate. Circulating aldosterone is converted to the tetrahydroglucuronide derivative. Corticosteroid metabolism occurs primarily in the liver. Certain diseases of the liver result in elevated free hormone due to decreased corticosteroid metabolism, and a reduction in serum steroid-binding proteins.
Plasma Clearance
The plasma clearance of cortisol is rapid, with a half-life of 66 min at normal hormone levels16. With large steroid loads, however, the half-life increases to 120 min. The volume of distribution (VD) changes in a similar fashion, with a VD of 10 L under normal conditions and a VD that can be greater than total body water with large steroid loads. Corticosterone turns over even more rapidly than cortisol, and the clearance rates of both steroids are unaffected by acute stress or adrenal insufficiency. The plasma half-life of aldosterone is less than 20 min.
Excretion
Cortisol excretion in urine is relatively low, 100 μg/d, primarily because 80 to 90% of filtered cortisol is reabsorbed, mostly from the distal tubule of the kidney.27 In contrast, conjugated metabolites are filtered and excreted with no reabsorption. More than 90% of secreted glucocorticoid is ultimately excreted in urine. Less than 10% of secreted aldosterone appears in the urine in the free form. The majority is excreted as glucuronide derivatives.
Transport in Blood
In circulation, cortisol can be found in free form, but the majority is bound to either liver-derived corticosteroid-binding globulin (CBG) or albumin due to its lipophilic nature. The normal plasma level of CBG is a relatively constant 40 mg/L (0.8 μmol), which binds about 70% of plasma cortisol(14 μg/dL). However, plasma CBG levels are dynamically regulated. During pregnancy, plasma levels of CBG rise dramatically, while acute stresses, such as burn injury or sepsis, can lead to dramatic decreases in plasma CBG. Cortisol binds to CBG with high affinity (kDa = 2.4 × 10-7 M; half-life of steroid binding = 5 days). Other steroids, including progesterone, prednisolone, and aldosterone, compete for binding sites on CBG, and high levels of one steroid will displace the others. For example, therapeutic levels of prednisone displace 35% of CBG-bound cortisol. In contrast, many synthetic glucocorticoids, including dexamethasone, fail to bind CBG. Albumin circulates in plasma at a concentration of 40 g/L (0.5 to 0.6 mmol) and has low affinity for cortisol (kDa 5 × 10-5 M). Only 20% of plasma cortisol is bound to albumin. At low serum cortisol levels, most of the cortisol is bound to CBG. However, the binding capacity of CBG is saturated at a cortisol concentration of 28 μg/dL, a level that is frequently exceeded in stressed patients. With elevations in plasma cortisol, there is an increased proportion of albumin-bound and free cortisol, whereas the amount of CBG-bound cortisol remains the same. The concentration of free cortisol is 1 μg/dL at a normal total plasma cortisol of 20 μg/dL, although this value can rise to as high as 15 to 50 μg/dL after ACTH stimulation. Free cortisol is considered to be the active form because protein-bound cortisol cannot easily pass through cell membranes. As a result of rapid equilibration between the bound and free fractions of cortisol, the bound fraction acts as a reservoir. Thus, increases in plasma CBG such as occur during pregnancy can greatly increase the amount of cortisol reserves available at a constant rate of synthesis, whereas short-term decreases in plasma CBG during acute stress can significantly increase the pool of free cortisol. That total plasma cortisol falls below 5 μg/dL at night exemplifies how rapidly cortisol can leave the plasma. Aldosterone does not have a specific binding protein, but binds weakly to albumin. A normal plasma aldosterone level is 0.006 μg/dL (0.17 nmol). Other steroids with mineralocorticoid activity, such as corticosterone and 11-deoxycorticosterone, do bind CBG. CBG-bound corticosteroids are resistant to metabolism.
