What is the role of the dexamethasone suppression test in diagnosing Cushing's syndrome?

Dexamethasone Suppression Test in Diagnosing Cushing's Syndrome

Primary Diagnostic Role

The overnight 1-mg dexamethasone suppression test (DST) serves as a first-line screening test for Cushing's syndrome, with high sensitivity (>90%) and excellent ability to rule out the condition when cortisol suppresses to <1.8 μg/dL (50 nmol/L). 1

The Endocrine Society recommends the overnight 1-mg DST as one of three equally valid first-line screening tests, alongside late-night salivary cortisol and 24-hour urinary free cortisol. 1

Test Protocol and Interpretation

Standard Administration

• Administer 1 mg dexamethasone orally between 11:00 PM and midnight 2
• Measure serum cortisol at 8:00 AM the following morning 2

Diagnostic Thresholds

• Cortisol <1.8 μg/dL (50 nmol/L): Normal response—effectively rules out Cushing's syndrome 1, 2
• Cortisol 1.8-5.0 μg/dL: Borderline/gray zone—requires additional evaluation 1, 2
• Cortisol >5.0 μg/dL (138 nmol/L): Strongly suggests autonomous cortisol secretion or overt Cushing's syndrome 3, 2

Optimizing Test Accuracy

Measuring Dexamethasone Levels

Concomitant measurement of dexamethasone levels with cortisol dramatically improves specificity by identifying false-positive results from inadequate drug exposure. 1, 4, 5

• Dexamethasone level <1.8 ng/mL (4.6 nmol/L) indicates inadequate drug exposure and invalidates the test 1, 2
• Adding dexamethasone measurement increases clinical specificity from 67.5% to 92.4% while maintaining 100% sensitivity 5
• Approximately 6% of patients fail to achieve adequate dexamethasone levels, accounting for 40% of false-positive results 4

Test Performance Characteristics

The 2-day low-dose DST (0.5 mg every 6 hours for 48 hours) has 95% sensitivity and 80% specificity, with the same cortisol suppression threshold of <1.8 μg/dL. 1

Critical Pitfalls and False Results

False-Positive Results (Cortisol Fails to Suppress Appropriately)

• CYP3A4 inducers accelerate dexamethasone metabolism: phenobarbital, carbamazepine, phenytoin, rifampin, St. John's wort 3, 2
• Oral estrogen/contraceptives increase cortisol-binding globulin: elevates total cortisol without true hypercortisolism 3
• Pseudo-Cushing's states: depression, alcoholism, severe obesity, polycystic ovary syndrome 1, 3
• Rapid dexamethasone absorption or malabsorption 2

False-Negative Results (Cortisol Suppresses Despite True Cushing's)

• CYP3A4 inhibitors slow dexamethasone metabolism: fluoxetine, cimetidine, diltiazem 2
• Decreased cortisol-binding globulin levels 1

Special Populations Requiring Alternative Testing

• Shift workers and patients with disrupted circadian rhythm: DST may be preferred over late-night salivary cortisol 1
• Women on oral estrogen: DST results may be unreliable; consider Dex-CRH test 1
• Patients using fluticasone inhalers: may interfere with interpretation; use multiple screening modalities 3

Diagnostic Algorithm for Screening

Initial Approach Based on Clinical Suspicion

Low clinical suspicion: Start with late-night salivary cortisol 1

Intermediate to high clinical suspicion: Perform 2-3 screening tests simultaneously (late-night salivary cortisol, 24-hour urinary free cortisol, overnight 1-mg DST) 1, 3

Interpreting Screening Results

• All tests normal: Cushing's syndrome unlikely—no further workup needed 1
• One test abnormal: Repeat screening tests to account for intra-patient variability 3
• ≥2 tests persistently abnormal: Proceed to ACTH measurement to determine ACTH-dependent vs. ACTH-independent disease 1, 3

Managing Borderline Results (Cortisol 1.8-5.0 μg/dL)

When post-dexamethasone cortisol falls in the gray zone, do NOT proceed directly to high-dose testing or imaging—additional confirmatory testing is required. 2

Recommended Steps for Borderline Results

1. Measure dexamethasone level from the same sample: If <1.8 ng/mL, the test is invalid and should be repeated 2
2. Obtain 2-3 additional screening tests: 24-hour urinary free cortisol, late-night salivary cortisol, repeat overnight DST 2
3. Review medication list: Identify and discontinue CYP3A4 inducers/inhibitors if possible 3, 2
4. Exclude pseudo-Cushing's states: Evaluate for depression, alcoholism, severe obesity, PCOS 3, 2
5. Consider Dex-CRH test: Helps distinguish true Cushing's from pseudo-Cushing's states 1, 2
6. Monitor for cyclic disease: If suspicion remains low, observe for 3-6 months with serial testing during symptomatic periods 3, 2

Role in Specific Clinical Contexts

Adrenal Incidentalomas

All patients with adrenal incidentalomas require overnight 1-mg DST to screen for subclinical Cushing's syndrome. 2

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

Differential Diagnosis (High-Dose DST)

The high-dose DST (8 mg overnight) is NOT used for diagnosis—it only differentiates pituitary from ectopic ACTH sources AFTER Cushing's syndrome is confirmed. 2, 6

• Administered after diagnosis is established and ACTH is elevated 6, 7
• Cortisol suppression >50% suggests pituitary Cushing's disease (sensitivity 78-92%, specificity 67-100%) 6, 8
• However, clinical variables (age, sex, duration, hypokalemia, baseline ACTH) often provide equal or better diagnostic accuracy than high-dose DST 7
• Inferior petrosal sinus sampling remains the gold standard for localizing ACTH source 1

Key Clinical Pearls

• Never use DST alone for diagnosis: Always obtain 2-3 screening tests to account for cyclic disease and test variability 1, 3
• Verify adequate dexamethasone levels when available: This single intervention eliminates most false-positive results 4, 5
• Do not skip confirmatory testing: Even with abnormal screening, confirm active hypercortisolism before proceeding to localization studies 1
• Treatment should never be delayed for testing in suspected acute adrenal crisis 3