What is the role of the dexamethasone suppression test in diagnosing and managing a patient suspected of having Cushing's syndrome?

Dexamethasone Suppression Test in Cushing's Syndrome

Primary Role and Test Selection

The overnight 1-mg dexamethasone suppression test (DST) serves as a first-line screening test for Cushing's syndrome, with the Endocrine Society recommending it due to its high sensitivity (>90%) and excellent ability to rule out the condition when negative. 1

The test protocol is straightforward:

• Administer 1 mg dexamethasone orally between 11:00 PM and midnight 2
• Measure serum cortisol at 8:00 AM the following morning 2
• Normal response: cortisol <1.8 μg/dL (50 nmol/L) 1, 2

Diagnostic Interpretation Framework

Clear-Cut Results

Cortisol <1.8 μg/dL effectively rules out Cushing's syndrome with high confidence, requiring no further biochemical testing for hypercortisolism. 1, 2

Cortisol >5.0 μg/dL (138 nmol/L) indicates overt autonomous cortisol secretion and warrants proceeding to ACTH measurement to determine if the syndrome is ACTH-dependent or ACTH-independent. 1, 3

The Diagnostic Gray Zone (1.8-5.0 μg/dL)

When cortisol falls in this borderline range, do not escalate to high-dose testing—instead, pursue additional evaluation: 2

• Measure dexamethasone levels concomitantly with cortisol to identify false-positive results from inadequate drug exposure (dexamethasone <1.8 ng/mL or 4.6 nmol/L invalidates the test). 1, 2, 4, 5
• Obtain 2-3 additional screening tests: 24-hour urinary free cortisol (UFC), late-night salivary cortisol (LNSC), and repeat overnight 1-mg DST to account for intra-patient variability and cyclic Cushing's syndrome. 2

Comprehensive Screening Strategy

For intermediate to high clinical suspicion, perform 2-3 screening tests simultaneously (LNSC, 24-hour UFC, overnight DST) rather than relying on a single test. 1, 3

• Late-night salivary cortisol: Abnormal threshold >3.6 nmol/L, sensitivity 92-100%, specificity 93-100%. 3
• 24-hour urinary free cortisol: Obtain at least 2-3 collections due to 50% random variability between samples; values >100 μg/24 hours are typically diagnostic in symptomatic patients. 1, 3
• Overnight 1-mg DST: Sensitivity >90%, with the interpretation thresholds described above. 1, 3

Critical Pitfalls and How to Avoid Them

False-Positive Results (Inadequate Suppression Despite Normal HPA Axis)

CYP3A4 inducers accelerate dexamethasone metabolism, causing falsely elevated cortisol. Common culprits include phenobarbital, carbamazepine, rifampin, and St. John's wort. 1, 3, 2

Oral estrogen-containing medications (oral contraceptives, hormone replacement therapy) increase cortisol-binding globulin (CBG), falsely elevating total cortisol while free cortisol remains normal—always inquire about these medications before pursuing extensive workup. 1, 3

Fluticasone inhalers and other exogenous steroids can interfere with test interpretation; consider using additional screening tests (LNSC, 24-hour UFC) that may be less affected. 3

Pseudo-Cushing's states (depression, alcoholism, severe obesity, polycystic ovary syndrome) activate the HPA axis, causing mild hypercortisolism that mimics true Cushing's syndrome. 1, 3, 2

False-Negative Results (Suppression Despite True Cushing's)

CYP3A4 inhibitors (fluoxetine, cimetidine, diltiazem) increase dexamethasone levels, causing inappropriate suppression. 2

Cyclic Cushing's syndrome produces weeks to months of normal cortisol secretion interspersed with hypercortisolism episodes—if clinical suspicion remains high despite normal results, perform serial testing over 3-6 months during symptomatic periods. 1, 2

Mild or early Cushing's syndrome may show suppression on a single test; research demonstrates that in patients with mild/periodic disease, sensitivity can be as low as 41% even with the 1.8 μg/dL cutoff. 6

Optimizing Test Accuracy

Measuring dexamethasone levels concomitantly with cortisol reduces false-positive results by confirming adequate drug absorption and metabolism (lower limit of normal: 1.8 ng/mL or 4.6 nmol/L). 1, 4, 5 This approach increases clinical specificity from 67.5% to 92.4% while preserving 100% sensitivity. 4

Special Clinical Contexts

Adrenal Incidentalomas

All patients with adrenal incidentalomas require overnight 1-mg DST screening to detect subclinical Cushing's syndrome. 1, 2

• Cortisol >5 μg/dL identifies dysregulated cortisol secretion from the incidentaloma. 1
• Cortisol <1.8 μg/dL classifies the mass as non-functioning from a cortisol perspective. 3

Patients with Disrupted Circadian Rhythm

DST may be preferred over late-night salivary cortisol for shift workers and patients with uneven sleep schedules, as LNSC requires intact circadian rhythm for accurate interpretation. 1

Distinguishing Pseudo-Cushing's from True Disease

When screening tests remain equivocal and pseudo-Cushing's states are suspected, consider the combined low-dose dexamethasone-CRH test (Dex-CRH) or desmopressin test to distinguish true Cushing's syndrome from physiologic HPA axis activation. 1, 2

Diagnostic Algorithm After Abnormal Screening

When ≥2 screening tests are persistently abnormal: 1, 3

1. Measure 9 AM ACTH to determine if Cushing's is ACTH-dependent or ACTH-independent
2. If ACTH is normal or elevated (ACTH-dependent): Proceed to pituitary MRI
3. If pituitary adenoma ≥10 mm: Presume Cushing's disease
4. If adenoma <6 mm or no adenoma visible: Consider inferior petrosal sinus sampling (IPSS) to distinguish pituitary from ectopic ACTH sources

Alternative DST Protocols

The 2-day low-dose DST (0.5 mg every 6 hours for 48 hours) has sensitivity of 95% and specificity of 80%, with normal response defined as cortisol suppression <1.8 μg/dL. 1, 2 This test is more cumbersome but may be useful when the overnight test yields equivocal results.

High-dose DST (8 mg overnight or 32 mg over 24 hours) should never be used for diagnosis—these tests differentiate pituitary from ectopic ACTH sources only after Cushing's syndrome is already confirmed. 2, 7, 8