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The Metyrapone and Dexamethasone Suppression Tests for the Differential Diagnosis of the Adrenocorticotropin-Dependent Cushing Syndrome: A Comparison

Peter C. Avgerinos; Jack A. Yanovski; Edward H. Oldfield; Lynnette K. Nieman; and Gordon B. Cutler
[+] Article, Author, and Disclosure Information

From the National Institute of Child Health and Human Development and the National Institute of Neurological Disease and Stroke, National Institutes of Health, Bethesda, Maryland. Requests for Reprints: Peter C. Avgerinos, MD, National Institutes of Health, Building 10, Room 10N262, Bethesda, MD 20892. Acknowledgments: The authors thank the nursing staff of the 10-West and 9-West wards for their invaluable assistance in carrying out the studies, Dr. James D. Malley for statistical consultation, and the Burroughs Wellcome Company for providing metyrapone. Investigators desiring metyrapone for their patients may obtain metyrapone capsules directly from the manufacturer under an investigational new drug exemption.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1994;121(5):318-327. doi:10.7326/0003-4819-121-5-199409010-00002
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Objective: To develop criteria for interpreting results of the metyrapone test for the differential diagnosis of the adrenocorticotropin (ACTH)-dependent Cushing syndrome and to compare its diagnostic accuracy with that of the high-dose dexamethasone suppression test.

Design: Retrospective cohort study.

Setting: Inpatient research ward.

Patients: 186 patients believed to have the ACTH-Dependent Cushing syndrome who had the metyrapone test, the dexamethasone test, and a surgical procedure to remove the source of excessive ACTH.

Measurements: The sensitivity, specificity, and diagnostic accuracy were determined for the metyrapone test using urine excretion of hydroxysteroid and plasma levels of 11-deoxycortisol. For the dexamethasone suppression test, urine excretions of 17-hydroxysteroid (17-OHS) and free cortisol were used.

Main Results: 156 patients had pituitary disease, 15 had ectopic ACTH secretion, and 15 had no diagnosis after pituitary surgery. Of those 15 patients, 14 were ultimately classified as having pituitary disease on the basis of follow-up, and 1 was found to have ACTH-independent Cushing syndrome. After administration of metyrapone, stimulation of 17-OHS excretion greater than 70% or of a plasma 11-deoxycortisol level greater than 400-fold did not result in the misclassification of any of the patients with surgically confirmed cases of ectopic ACTH secretion. When these criteria were combined, the percentage of correct predictions (122 of 186 [71%; 95% CI, 62% to 79%]) was higher than that for either steroid alone (116 of 186 [62%; CI, 52% to 71%]) for excretion of 17-OHS and that for plasma 11-deoxycortisol (82 of 186 [44%; CI, 34% to 54%]). When the criteria for both the metyrapone test and the dexamethasone test were combined, the percentage of correct predictions (153 of 186 [82%; CI, 75% to 87%]) was higher than that obtained when the criteria for either test alone were used (P = 0.001). Similar results were found when the 15 patients with indeterminate surgery were assigned to the appropriate group on the basis of follow-up. When the criteria for both the metyrapone and dexamethasone tests were combined to identify patients with the pituitary Cushing syndrome, the sensitivity and diagnostic accuracy improved to 88% and 89%, respectively.

Conclusions: The metyrapone test, which can be done in 48 hours, has a sensitivity and specificity for the diagnosis of the Cushing syndrome identical to that of the standard 6-day high-dose dexamethasone suppression test. Combining both tests results in greater accuracy than that obtained with either test alone.


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Figure 1.
A diagnostic approach to confirm the existence of the Cushing syndrome and to determine its cause.

*See reference 32.

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Figure 2.
Stimulation of urine 17-hydroxysteroid (left) and plasma 11-deoxycortisol (right) during the metyrapone test in 186 patients with the Cushing syndrome.[14][1]

Stimulation of urine 17-hydroxysteroid excretion is expressed as the percentage increase on the day of metyrapone administration compared with the baseline value on the previous day (day 3 compared with day 2). Stimulation of 11-deoxycortisol is expressed as the ratio of stimulated value (day 4 value) divided by the baseline value (the mean of the two preceding days). For determining sensitivity and specificity of the metyrapone test, patients were classified as positive or negative for the pituitary Cushing syndrome according to the results of surgical exploration: patients with surgically confirmed pituitary syndrome, those with surgically confirmed ectopic adrenocorticotropic hormone (ACTH) syndrome, and those in whom trans-sphenoidal surgery (TSS) failed to confirm a pituitary adenoma (failed TSS) but who were diagnosed after follow-up as having the pituitary forms of Cushing syndrome and the ACTH-independent Cushing syndrome . The 10 data points at the top of the panels represent values above the scale of the vertical axis.

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Figure 3.
Suppression of urine 17-hydroxysteroid (left) and urine free cortisol (right) during a standard 6-day dexamethasone suppression test in 186 patients with the Cushing syndrome.

Suppression of urine 17-hydroxysteroid and free cortisol excretion is expressed as the percentage decrease on day 6 (last day of high-dose dexamethasone) compared with the mean baseline values from days 1 and 2. The patient groups are the same as in Figure 2. ACTH =adrenocorticotropic hormone; TSS = trans-sphenoidal surgery.

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Figure 4.
Receiver operating characteristic curves for the diagnosis of the Cushing syndrome in patients with the ACTH-dependent Cushing syndrome.Parts A and Dgray linestriped lineblack lineB and Egray linestriped lineblack lineC and Fgray linestriped lineblack line

Parts A, B, and C compare the tests against the strict gold standard of response to pituitary surgery or positive surgical pathologic specimens. Parts D, E, and F compare the tests against the diagnoses made either at surgery or at follow-up. . Receiver operating characteristic curves of the metyrapone test for plasma 11-deoxycortisol ( ) and urine 17-hydroxysteroid ( ) levels, and a composite rule that combined both endpoints of the metyrapone test ( ). Parts . Receiver operating characteristic curves for the high-dose dexamethasone test for urine free cortisol ( ), and urine 17-hydroxysteroid ( ), and a composite rule that combined both end points of the dexamethasone test ( ). Parts . Receiver operating characteristic curves for the composite rules for the high-dose dexamethasone test using end points from both urine free cortisol and 17-hydroxysteroid ( ), the metyrapone test using end points from both plasma 11-deoxycortisol and 17 hydroxysteroid ( ), and the combined composite rule using all four end points ( ).

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