Overnight Dexamethasone Suppression Test in Cushing's Syndrome Diagnosis
The overnight 1-mg dexamethasone suppression test (DST) is a first-line screening test for Cushing's syndrome, with abnormal results defined as serum cortisol ≥1.8 μg/dL (≥50 nmol/L) at 0800h after 1 mg dexamethasone given at 2300-2400h, and cortisol >5 μg/dL (138 nmol/L) indicating overt Cushing's syndrome. 1, 2
Test Performance and Interpretation
The overnight 1-mg DST demonstrates sensitivity >90% for detecting Cushing's syndrome, making it highly effective at ruling out the condition when negative. 1, 2 The test is particularly valuable because:
- Normal response (cortisol <1.8 μg/dL) strongly predicts absence of Cushing's syndrome 2
- Values >5 μg/dL generally identify patients with dysregulated cortisol secretion 2
- The test is simpler for both patients and medical personnel compared to 24-hour urinary free cortisol or 48-hour dexamethasone testing 3
Diagnostic Algorithm Integration
The Endocrine Society recommends a stratified approach based on clinical suspicion: 4, 1
- Low clinical suspicion: Start with late-night salivary cortisol (≥2 tests) 4
- Intermediate or high suspicion: Perform 2-3 screening tests including overnight DST, late-night salivary cortisol, and 24-hour urinary free cortisol 4, 1
- Abnormal screening results: Repeat 1-2 screening tests to confirm before proceeding to ACTH measurement 4
Critical Pitfalls and How to Avoid Them
False-Positive Results
Measure dexamethasone levels concomitantly with cortisol to reduce false-positive results (lower limit of normal dexamethasone: 1.8 ng/mL or 4.6 nmol/L). 1, 2 False positives occur with:
- Oral estrogen-containing medications (including oral contraceptives) that increase cortisol-binding globulin, falsely elevating total cortisol while free cortisol remains normal 1, 5
- CYP3A4 inducers (phenytoin, phenobarbital, ephedrine, rifampin) that accelerate dexamethasone metabolism 1, 5
- Pseudo-Cushing's states including depression, alcoholism, severe obesity, and polycystic ovary syndrome 1, 6
- Indomethacin therapy, which can cause false-negative results 5
False-Negative Results
CYP3A4 inhibitors can increase dexamethasone levels, causing false-negative DST results. 1
Special Populations
- DST is preferred for shift workers with disrupted circadian rhythm, as late-night salivary cortisol testing is unreliable in these patients 1, 2
- DST may not be reliable in women on oral estrogen; consider alternative tests like Dex-CRH 2
- For adrenal incidentalomas, DST is particularly useful as first-line testing to identify dysregulated cortisol secretion 2
Limitations in Mild or Cyclic Cushing's Syndrome
The overnight 1-mg DST has significantly reduced sensitivity (18-41%) in patients with mild and/or periodic Cushing's syndrome. 7 In one study of 17 patients with proven mild/periodic Cushing's:
For suspected cyclic Cushing's syndrome, periodic repeated testing is necessary as cortisol levels fluctuate between normal and elevated. 6
High-Dose DST for Differential Diagnosis
Once Cushing's syndrome is confirmed and ACTH-dependent disease is established, the overnight 8-mg high-dose DST can differentiate Cushing's disease from ectopic ACTH syndrome, with suppression of plasma cortisol to <50% of baseline indicating Cushing's disease (sensitivity 92%, specificity 100%). 8 However, revised criteria measuring cortisol at 0900-1000h (rather than 0700-0800h) improve specificity to 100% with 71% sensitivity. 9
Confirmatory Testing Strategy
When initial overnight DST is abnormal, confirm with repeat screening tests (at least 2-3 collections for 24h UFC or ≥2 consecutive days for late-night salivary cortisol) before proceeding to ACTH measurement and localization studies. 4, 1 This approach minimizes false positives while maintaining high diagnostic accuracy.