Urinary free cortisol is cortisol in urine that is not conjugated to amino acids or glucuronic acid and, hence, is “free.” Urinary free cortisol retains its preferential solubility in organic solvents and can be extracted from urine with diethyl ether or dichloromethane. After extraction, the organic solvent is evaporated and the residual cortisol is measured by one of several techniques. The most popular is radioimmunoassay (RIA).1

The advantage of the measurement of urinary free cortisol over other techniques used to document hypercortisolism is sensitivity. Patients with hypercortisolism rarely fall into the normal range.2,3 and 4 The ranges of urinary free cortisol excretion for normal persons and persons subsequently proved to have hypercortisolism overlap by only 1% to 2%. This overlap is considerably greater with other methods. The physiologic mechanism underlying this high degree of specificity is probably the relationship between corticosteroid-binding globulin (CBG) binding capacity and the normal cortisol production rate. The binding capacity of CBG is nearly saturated at normal rates of cortisol production. At greater than normal rates of cortisol secretion, the unbound fraction of plasma cortisol increases disproportionately. Because urinary free cortisol is derived from the unbound or bioactive cortisol by glomerular filtration, the free cortisol concentration in the urine rises rapidly as the binding capacity of CBG is exceeded. Thus, the urinary free cortisol level directly reflects the bioactive plasma cortisol concentration. The most important variable affecting the excretion of urinary free cortisol is its reabsorption by the nephron. Because >95% of filtered cortisol is reabsorbed, small changes in the reabsorbed fraction can make large differences in the quantitative urinary excretion of the hormone. Fortunately, this is not a complicating variable in most cases of hypercortisolism. The normal values for urinary free cortisol, as with all tests, vary with the individual laboratory, but the normal basal excretion of urinary free cortisol typically is <100 μg/d.