From the Guidelines
To test for high cortisol, the most effective initial approach is to conduct a 24-hour urine collection test, measuring urinary free cortisol (UFC) excretion, with a diagnostic cut-off of >193 nmol/24 h (>70 μg/m2), which has a sensitivity of 89% and specificity of 100% 1.
Testing Options
When testing for high cortisol, several options are available, each with its own sensitivity and specificity:
- 24-hour urine collection test for UFC excretion, which is highly sensitive and specific 1
- Serum cortisol circadian rhythm study, which can be less specific but still useful for diagnosis 1
- Late-night salivary cortisol test, with a sensitivity of 95% and specificity of 100% when using local assay cut-offs 1
- Low-dose dexamethasone suppression test (LDDST), which can help confirm the diagnosis of Cushing's syndrome 1
Diagnostic Approach
The diagnostic approach for high cortisol involves:
- Confirming hypercortisolism through one of the above tests
- Determining the cause of hypercortisolism, which may involve further testing such as plasma ACTH levels, CRH testing, or pituitary MRI scans 1
- Considering bilateral inferior petrosal sinus sampling (BSIPSS) for ACTH in cases where the source of ACTH excess is unclear, with a central-to-peripheral ACTH ratio of ≥3:1 after CRH or desmopressin stimulation confirming a pituitary source 1
Important Considerations
When interpreting test results, it is essential to consider the patient's symptoms, medical history, and any medications that may affect cortisol levels 1.
Key Recommendations
The most recent and highest quality study recommends using a 24-hour urine collection test as the initial diagnostic test for high cortisol, due to its high sensitivity and specificity 1. In cases where Cushing's disease is suspected, a CRH test with a ≥20% increase in cortisol from baseline can support the diagnosis 1. BSIPSS should only be offered in specialist centers with expertise in the procedure and by experienced interventional radiologists 1.
From the FDA Drug Label
Because of these actions, Metopirone is used as a diagnostic test, with urinary 17‑hydroxycorticosteroids (17-OHCS) measured as an index of pituitary ACTH responsiveness. To test for high cortisol, Metyrapone can be used as a diagnostic test. The test involves measuring urinary 17-hydroxycorticosteroids (17-OHCS), which serves as an index of pituitary ACTH responsiveness 2.
- The test is based on the ability of Metyrapone to reduce cortisol and corticosterone production by inhibiting the 11-beta-hydroxylation reaction in the adrenal cortex.
- This leads to an increase in adrenocorticotropic hormone (ACTH) production by the pituitary, which in turn causes an increase in the secretion of cortisol precursors, such as 11-desoxycortisol and desoxycorticosterone.
- The metabolites of these precursors can be measured in the urine as 17-OHCS or 17-ketogenic steroids (17-KGS) 2.
From the Research
Testing for High Cortisol
To test for high cortisol, several methods can be employed, including:
- 24-hour urine free cortisol (UFC) test: This test measures the amount of cortisol in the urine over a 24-hour period 3, 4, 5, 6.
- Overnight 1 mg dexamethasone suppression test (DST): This test involves taking a dose of dexamethasone at night and measuring cortisol levels in the blood the next morning 7, 4, 5.
- Low-dose dexamethasone suppression test (LDDST): This test is similar to the overnight DST but involves taking a lower dose of dexamethasone 5.
- High-dose dexamethasone suppression test (HDDST): This test involves taking a higher dose of dexamethasone to differentiate between pituitary and non-pituitary causes of Cushing's syndrome 5, 6.
Interpretation of Test Results
The interpretation of test results varies depending on the test used:
- 24-hour UFC test: A very high level of UFC can confirm the diagnosis of Cushing's syndrome, but a normal or slightly elevated level may require further testing 3, 4.
- Overnight DST: A cortisol level above 50 nmol/L after taking dexamethasone indicates a lack of suppression and may suggest Cushing's syndrome 4.
- LDDST and HDDST: The sensitivity and specificity of these tests vary depending on the cutoff points used, but a suppression rate of ≥50% can help differentiate between pituitary and non-pituitary causes of Cushing's syndrome 5, 6.
Pitfalls and Limitations
Each test has its own pitfalls and limitations:
- 24-hour UFC test: Sample collection and laboratory methods can affect results, and cortisol is not uniformly secreted throughout the day 3.
- DST: False positives can occur in patients with severe mental depression or stress, and false negatives can occur in patients with cyclic Cushing's syndrome 4.
- LDDST and HDDST: The choice of cutoff points and suppression rates can affect the sensitivity and specificity of the tests 5, 6.