What to do if post-dexamethasone (cortisol suppression test) cortisol level is borderline, should I proceed with an 8 mg dexamethasone (cortisol suppression test)?

Borderline Post-Dexamethasone Cortisol: Next Steps

When post-dexamethasone cortisol is borderline (1.8-5.0 μg/dL), do not proceed directly to an 8 mg dexamethasone suppression test; instead, repeat initial screening tests, measure dexamethasone levels to exclude false-positives, and consider the Dex-CRH test or desmopressin test to distinguish true Cushing's syndrome from pseudo-Cushing's states. 1, 2

Understanding Borderline Results

Borderline cortisol values (1.8-5.0 μg/dL) after 1 mg dexamethasone represent a diagnostic gray zone where the test is neither clearly normal (<1.8 μg/dL) nor definitively diagnostic of overt Cushing's syndrome (>5.0 μg/dL). 2, 3 This range requires additional evaluation rather than escalation to high-dose testing.

Why the 8 mg Test is Not the Next Step

The 8 mg (high-dose) dexamethasone suppression test is not used for diagnosing hypercortisolism—it is used only after Cushing's syndrome is confirmed to differentiate between pituitary Cushing's disease and ectopic ACTH secretion. 1 Proceeding to this test prematurely bypasses critical diagnostic steps.

Recommended Diagnostic Algorithm for Borderline Results

Step 1: Measure Dexamethasone Levels

Measure the post-test dexamethasone level concomitantly with cortisol to identify false-positive results due to rapid dexamethasone metabolism or malabsorption. 1, 2, 3 A dexamethasone level <1.8 ng/mL (4.6 nmol/L) suggests inadequate drug exposure, invalidating the test result. 2

• CYP3A4 inducers (phenobarbital, carbamazepine, St. John's wort) accelerate dexamethasone clearance, causing falsely elevated cortisol. 3
• If dexamethasone levels are adequate (>5.0 nmol/L), cortisol suppression should be independent of dexamethasone concentration in this range. 4

Step 2: Repeat Initial Screening Tests

Obtain 2-3 additional screening tests to account for intra-patient variability and cyclic Cushing's syndrome. 1, 5

• 24-hour urinary free cortisol (UFC): Collect 2-3 samples, as UFC can vary by up to 50% between collections. 1, 5 Values >100 μg/24h (1.6 μmol/24h) are diagnostic in symptomatic patients. 5
• Late-night salivary cortisol (LNSC): Perform 2-3 tests; values >3.6 nmol/L are abnormal with >90% sensitivity. 5
• Repeat overnight 1 mg DST: Ensure proper timing (dexamethasone at 11 PM-midnight, cortisol at 8 AM). 3

Step 3: Exclude Pseudo-Cushing's States and Interfering Factors

Identify conditions that mimic Cushing's syndrome or interfere with test interpretation:

• Oral estrogen/contraceptives: Increase cortisol-binding globulin (CBG), falsely elevating total cortisol while free cortisol remains normal. 5, 6 In women on oral contraceptives, only 25.5% had abnormal post-DST total cortisol, and measuring free cortisol improved diagnostic accuracy to 87.3%. 6
• Pseudo-Cushing's states: Depression, alcoholism, severe obesity, and polycystic ovary syndrome activate the HPA axis, causing mild hypercortisolism. 1, 5
• Cyclic Cushing's syndrome: Produces weeks-to-months of normal cortisol interspersed with excess, requiring extended monitoring. 1, 5

Step 4: Consider Advanced Testing if Discordance Persists

If repeated screening tests remain equivocal or discordant, proceed to second-line tests:

• Dex-CRH test: Distinguishes ACTH-dependent Cushing's syndrome from pseudo-Cushing's states, though diagnostic accuracy varies. Use at an expert center with dexamethasone level measurement. 1, 3
• Desmopressin test: High specificity for Cushing's disease, less complex and expensive than Dex-CRH, with excellent agreement when both tests are performed. 1

Critical Pitfalls to Avoid

• Do not use the 8 mg DST for diagnosis: This test differentiates pituitary from ectopic ACTH sources only after Cushing's syndrome is confirmed. 1
• Do not ignore medication interactions: CYP3A4 inducers cause false-positives; CYP3A4 inhibitors (fluoxetine, cimetidine, diltiazem) cause false-negatives. 3
• Do not rely on a single test: Intra-patient variability and cyclic disease require multiple measurements. 1, 5
• Do not overlook oral contraceptives: Measure free cortisol in women on estrogen therapy to avoid false-positive results. 6

When to Monitor Rather Than Pursue Further Testing

In patients with mild hypercortisolism and low clinical suspicion, monitor for 3-6 months to see if symptoms resolve. 1 Treatment of underlying conditions (e.g., depression) can restore normal HPA axis function and cortisol levels. 1 Serial LNSCs or repeat DSTs over time correlate with the clinical picture in this population. 1