Clinical Information

11-Deoxycortisol (Compound S) is the immediate precursor of cortisol:

                           11 beta-hydroxylase

11-deoxycortisol--------------------------->cortisol

Compound S is typically increased when adrenocorticotropic hormone (ACTH) levels are increased (eg, Cushing disease, ACTH-producing tumors) or in 11 beta-hydroxylase deficiency, a rare subform of congenital adrenal hyperplasia (CAH). In CAH due to 11 beta-hydroxylase deficiency, cortisol levels are low, resulting in increased pituitary ACTH production and increased serum and urine 11-deoxycortisol levels.

Pharmacological blockade of 11 beta-hydroxylase with metyrapone can be used to assess the function of the hypothalamic-pituitary-adrenal axis (HPA). In this procedure metyrapone is administered to patients, and serum 11-deoxycortisol levels or urinary 17-hydroxy steroid levels are measured either at baseline (midnight) and 8 hours later (overnight test), or at baseline and once per day during a 2-day metyrapone test (4-times a day metyrapone administration over 2 days). Two-day metyrapone testing has been largely abandoned because of the logistical problems of multiple timed urine and blood collections and the fact that overnight testing provides very similar results. In either case, the normal response to metyrapone administration is a fall in serum cortisol levels, triggering a rise in pituitary ACTH secretion, which, in turn, leads to a rise in 11-deoxycortisol levels due to the ongoing 11-deoxycortisol-to-cortisol conversion block.

In the diagnostic workup of suspected adrenal insufficiency, the results of overnight metyrapone testing correlate closely with the gold standard of HPA-axis assessment, insulin hypoglycemia testing. Combining 11-deoxycortisol measurements with ACTH measurements during metyrapone testing further enhances the performance of the test. Impairment of any component of the HPA-axis results in a subnormal rise in 11-deoxycortisol levels. By contrast, standard-dose or low-dose ACTH(1-24) (cosyntropin)-stimulation testing, which forms the backbone for diagnosis of primary adrenal failure (Addison disease), only assess the ability of the adrenal cells to respond to ACTH stimulation. While this allows unequivocal diagnosis of primary adrenal failure, in the setting of secondary or tertiary adrenal insufficiency, metyrapone testing is more sensitive and specific than either standard-dose or low-dose ACTH(1-24)-stimulation testing.

Metyrapone testing is also sometimes employed in the differential diagnosis of Cushing syndrome. In Cushing disease (pituitary-dependent ACTH overproduction), the ACTH-hypersecreting pituitary tissue remains responsive to the usual feedback stimuli, just at a higher "set-point" than in the normal state, resulting in increased ACTH secretion and 11-deoxycortisol production after metyrapone administration. By contrast, in Cushing syndrome due to primary adrenal corticosteroid oversecretion or ectopic ACTH secretion, pituitary ACTH production is appropriately shut down and there is usually no further rise in ACTH and, hence 11-deoxycortisol, after metyrapone administration. The metyrapone test has similar sensitivity and specificity to the high-dose dexamethasone suppression test in the differential diagnosis of Cushing disease but is less widely used because of the lack of availability of an easy, automated 11-deoxycortisol assay. In recent years, both tests have been supplanted to some degree by corticotropin-releasing hormone (CRH)-stimulation testing with petrosal sinus serum ACTH sampling.

For more information see Steroid Pathways.