Overnight Metyrapone Test Procedure
The overnight metyrapone test is performed by administering 30 mg/kg of metyrapone (maximum 3 grams) orally at midnight with milk, yogurt, or a snack, followed by blood sampling at 7:30-8:00 AM the next morning for measurement of 11-deoxycortisol and ACTH. 1
Pre-Test Requirements
Before conducting the test, you must:
- Stop all drugs affecting pituitary or adrenocortical function for at least 5 half-lives to avoid interference with testing 1
- Verify adrenal responsiveness to exogenous ACTH before employing metyrapone as a test 1
- Consider hospitalization overnight for patients with suspected adrenocortical insufficiency as a precautionary measure 1
Test Protocol
Dosing
- Timing: Administer at midnight (2400 hours)
- Dose: 30 mg/kg orally (maximum 3 grams total) 1
- Administration: Give with milk, yogurt, or a snack to minimize gastrointestinal side effects 1
Blood Sampling
- Timing: Collect blood between 7:30-8:00 AM (approximately 8 hours post-dose) 1
- Tests: Measure both 11-deoxycortisol and ACTH 1
- After blood collection, consider administering a prophylactic glucocorticoid dose in high-risk patients 1
Interpretation
11-Deoxycortisol Levels
An intact HPA axis is generally indicated by:
- 11-deoxycortisol >200 nmol/L (7 mcg/dL) suggests normal HPA function 1, 2
- Some sources use a higher cutoff of >260 nmol/L (10 mcg/dL) for increased sensitivity 2
The most recent research from 2024 demonstrates that using the 10 mcg/dL cutoff identifies more patients with secondary adrenal insufficiency that would be missed by cosyntropin testing alone 2.
ACTH Levels
- ACTH >150-175 ng/L generally indicates adequate pituitary response 3
- However, ACTH response alone cannot reliably distinguish between normal and abnormal function due to overlap 1
- Combined assessment of both 11-deoxycortisol and ACTH provides optimal diagnostic accuracy 3
Critical Considerations
Assay Interference
Metyrapone causes marked elevation of 11-deoxycortisol, which cross-reacts in many cortisol immunoassays, artificially elevating apparent cortisol values and potentially masking hypoadrenalism 4. Liquid chromatography-tandem mass spectrometry assays for cortisol circumvent this issue 4.
Safety Profile
The overnight test is remarkably safe when properly conducted:
- In a series of 576 tests, no serious adverse events occurred 5
- Mild adverse events occur in approximately 6% of patients 2
- Most common side effects: gastrointestinal disturbances, nausea, dizziness, headache 1
- One hospitalization reported in 114 tests in recent data 2
Diagnostic Superiority
The overnight metyrapone test is more sensitive than the cosyntropin stimulation test for detecting secondary adrenal insufficiency. In the 2024 study, cosyntropin testing had 100% specificity but only 52% sensitivity compared to metyrapone 2. The 2000 study similarly showed that 50% of patients with proven ACTH deficiency on metyrapone testing had falsely normal responses to low-dose ACTH stimulation 6.
This is why guidelines recommend metyrapone testing when cosyntropin testing is normal but clinical suspicion remains high 7.
When to Use This Test
The overnight metyrapone test is indicated when 8, 7:
- Cosyntropin testing is normal but clinical signs suggest ACTH insufficiency
- Diagnostic certainty is required regarding the ACTH axis
- Other anterior pituitary deficiencies are identified
- Insulin tolerance testing is contraindicated (seizures, coronary disease, stroke history, advanced age)
The test can be performed as an outpatient procedure in most cases, making it practical and cost-effective 2, 3.