Interpretation
Standard 3-Day Metyrapone Test
The increase in serum 11-deoxycortisol is used as a criterion of response as in the single-dose overnight test. Measuring serum cortisol and plasma ACTH is important, as a fall in serum cortisol confirms the metyrapone-induced biosynthetic blockade and an increase in plasma ACTH confirms that the changes in steroid levels are ACTH dependent.
A normal response is a two- to threefold increase above the baseline 24-hour urinary 17-OHCS excretion on either the day of or, more often, the day after metyrapone administration. The serum cortisol concentration should decrease to <5 μg/dL. The plasma ACTH concentration should exceed 75 pg/mL, with a mean of about 200 pg/mL 4 hours after the last metyrapone dose. An increase in serum 11-deoxycortisol to 7–22 μg/dL or more at 8
AM
, 4 hours after the last dose of metyrapone.
Two-Day Metyrapone Test
A normal response to the 2-day test has not been defined. In the differential diagnosis of ACTH-dependent Cushing syndrome, however, a clear rise in plasma ACTH concentration indicates that the ACTH-secreting tumor responds to falling serum cortisol concentrations. In one large study, as an example, a positive response was defined as a >70% increase in urinary 17-OHCS excretion and/or more than a fourfold increase in serum 11-deoxycortisol concentrations.
Overnight Single-Dose Metyrapone Test
A normal response is 8
AM
serum 11-deoxycortisol concentration of 7–22 μg/dL. A serum cortisol concentration at 8
AM
of <5 μg/dL confirms adequate metyrapone blockade and thereby documents compliance and normal metabolism of metyrapone. Serum 11-deoxycortisol concentrations <7 μg/dL with concomitantly suppressed cortisol values indicate adrenal insufficiency.
The ACTH response to metyrapone can distinguish between primary and secondary insufficiency. In general, patients with secondary adrenal insufficiency have ACTH responses from 10 to 200 pg/mL, whereas patients with primary adrenal insufficiency have higher responses. However, healthy individuals have an ACTH response of 42–690 pg/mL. Because of this overlap, the ACTH response alone cannot be used to distinguish between healthy individuals and those with adrenal insufficiency.
Limitations
Adrenal tumor with excess cortisol production: no increase or fall in urinary 17-KS. The test is positive in 100% of patients with adrenal hyperplasias without tumor, 50% of those with adrenal adenomas, and 25% of those with adrenal carcinomas.
Ectopic ACTH syndrome: It may not be accurate in this condition.
Metyrapone administration may result in hypotension, nausea, and vomiting in patients with adrenal insufficiency; as a result, the 2- and 3-day tests should not be performed outside of the hospital in patients suspected of having this disorder.
Acute or chronic ingestion of synthetic glucocorticoids can result in a subnormal response as a result of suppression of the corticotropes.
