Metyrapone Stimulation

Rationale: Metyrapone selectively inhibits the adrenal enzyme 11-β-hydroxylase which converts 11-deoxycortisol (compound S, 11-S) to cortisol.1-4 As cortisol levels fall, the pituitary secretes ACTH, which in turn stimulates the adrenal to increase 11-S production. Because 11-S does not have glucocorticoid activity, it does not inhibit pituitary secretion of ACTH. In individuals with a normal hypothalamic-pituitary-adrenal (HPA) axis, metyrapone stimulation results in 11-S levels >70 ng/mL. Adequate metyrapone activity is verified by measuring cortisol. Cortisol levels >5 μg/dL indicate that 11-β-hydroxylase has not been adequately inhibited for proper interpretation of the test.


Adrenal Insufficiency. This test has been used to assess the entire HPA axis but will not differentiate primary from secondary adrenal insufficiency. Adrenal insufficiency is diagnosed if the 11-S level does not exceed 70 ng/mL and the cortisol level is <5 μg/dL1

Cushing Syndrome. The metyrapone stimulation test has been used to localize the cause of secondary hypercortisolism. Metyrapone produces a supranormal increase in 11-S in patients with pituitary-based hypercortisolism (Cushing disease). Some patients with ectopic ACTH-secreting tumors often show little or no increase in 11-S because the tumors are not sensitive to low cortisol levels; however, since as many as 60% of patients with ectopic ACTH-producing tumors have been found to respond, many institutions no longer use the metyrapone test in the differential diagnosis of Cushing syndrome.3,5

Protocol: At 11 PM, the patient should take metyrapone (30 mg/kg, maximum 3 g) orally, with a snack to prevent gastric irritation. On the following morning, at 8 AM, blood should be drawn for cortisol and 11-deoxycortisol.1

Orderable Tests: See Comprehensive List of Procedures section for individual test information.

Note: Due to the risk of acute adrenal insufficiency precipitated by metyrapone ingestion, this test should be conducted on an inpatient basis. At the conclusion of the test, a prophylactic dose of glucocorticoid should be administered to individuals with suspected hypopituitarism.1

Approximately 4% of individuals will produce inadequate inhibition (postmetyrapone cortisol >5 μg/dL) due to enhanced clearance of metyrapone. A number of drugs that induce hepatic cytochrome P-450, including phenytoin, phenobarbital, rifampin, and glucocorticoids, accelerate the clearance of metyrapone.2


1. Grinspoon SK, Biller BM. Clinical Review 62: Laboratory assessment of adrenal insufficiency. J Clin Endocrinol Metab. 1994; 79(4):923-931. PubMed 7962298

2. Orth DN, Kovacs WJ, Debold CR. In Wilson JD, Foster DW, eds. The adrenal cortex: Evaluation of adrenocortical function. Textbook of Endocrinology. 8th ed. Philadelphia, Pa: WB Saunders; 1992:575-591.

3. Perry LA, Grossman AB. The role of the laboratory in the diagnosis of Cushing's syndrome. Ann Clin Biochem. 1997; 34(Pt 4):345-359. PubMed 9247665

4. Fiad TM, Kirby JM, Cunningham SK, et al. The overnight single-dose metyrapone test Is a simple and reliable index of the hypothalamic-pituitary-adrenal axis. Clin Endocrinol. 1994; 40(5):603-609. PubMed 8013141

5. Howlett TA, Drury PL, Perry L, et al. Diagnosis and management of ACTH-dependent Cushing's syndrome: Comparison of the features in ectopic and pituitary ACTH production. Clin Endocrinol.1986; 24(6):699-713. PubMed 3024870


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