Patient Preparation:
(1) Before testing the patient, a normal response to exogenous ACTH should be demonstrated, in order to reduce the risk of adrenal crisis in patients with primary adrenal insufficiency.
(2) The testing is performed over several days. The first 2 days are used for specimen collection to determine baseline levels. On the third day a dose of metyrapone (15 mg/kg up to 750 mg) is given orally every 4 hours for 6 doses. Specimen collection is continued to determine the response to these doses.
(3) The multi-dose stimulation test should be done on inpatients. This reduces the risk from adverse effects and ensures proper specimen collection.
(4) Adverse effects can be minimized by keeping the patient supine during testing.
Specimen Collection:
(1) day 1: starting at 8 AM begin a 24 hour urine collection
(2) day 2: starting at 8 AM begin a 24 hour urine collection
(3) day 3: starting at 8 AM begin a 24 hour urine collection
(4) day 4: starting at 8 AM begin a 24 hour urine collection. Four hours following the final metyrapone dose, collect a serum sample.
(5) day 5: complete the previous day's 24-hour urine specimen collection.
Testing:
(1) day 2: test first day's 24 hour urine collection for creatinine, 17-hydroxycorticosteroids and 17-ketogenic steroids
(2) day 3: test second day's 24 hour urine collection for creatinine, 17-hydroxycorticosteroids and 17-ketogenic steroids
(3) day 4: test third day's 24 hour urine collection for creatinine, 17-hydroxycorticosteroids and 17-ketogenic steroids. Test serum for cortisol and 11-deoxycortisol
(4) day 5: test fourth day's 24 hour urine collection for creatinine, 17-hydroxycorticosteroids and 17-ketogenic steroids
Relative Contraindications: In patients with possible primary adrenal insufficiency, this test can precipitate adrenal crisis. The test should be performed with caution in such patients. All patients should be monitored during testing, with supportive measures and cortisone replacement therapy initiated if adrenal crisis should develop.
Interpretation:
• Normal persons show a 2-4 fold increase in 17-hydroxycorticosteroids and a 2 fold increase in 17-ketogenic steroids in the urine specimens started on day 3 or day 4.
• Normal persons show increased deoxycortisol levels (> 7 µg/dL) and decreased cortisol levels (< 3 µg/dL, or < 30% of (cortisol + deoxycortisol)).
• Patients with hypopituitarism, Cushing's disease due to adrenal tumors or nonendocrine tumors secreting ACTH will have no response or an impaired response to the metyrapone.
• Reduced response is seen in drug therapy with drugs that increase hepatic metyrapone metabolism (phenytoin, phenobarbital) or with steroid therapy (glucocorticoids, oral contraceptives, estrogens).
• An exaggerated response can be seen in pituitary ACTH secreting adenomas (pituitary Cushing's disease).
