Dexamethasone Suppression Test Protocol
Low-Dose Dexamethasone Suppression Test (LDDST)
For screening Cushing syndrome, perform the overnight 1-mg dexamethasone suppression test (DST) with a cortisol cutoff of <1.8 μg/dL (50 nmol/L) for normal suppression 1.
Overnight 1-mg DST Protocol
- Administration: Give 1 mg dexamethasone orally between 2300-2400 h (11 PM-midnight)
- Sampling: Measure serum cortisol at 0800-0900 h the following morning
- Interpretation:
The 2021 Lancet Diabetes & Endocrinology guideline emphasizes this cutoff provides optimal sensitivity (>90%) for detecting Cushing syndrome, though specificity is somewhat lower than other screening tests 1. The 2008 Endocrine Society guideline notes that higher cutoffs (e.g., 5 μg/dL) reduce sensitivity 2.
48-Hour Low-Dose DST (2 mg/day) Protocol
For improved specificity over the overnight test, particularly in patients with conditions that activate the HPA axis (psychiatric disorders, obesity, alcoholism), use the 48-hour LDDST 2.
- Administration: Give 0.5 mg dexamethasone every 6 hours for 48 hours (at 0900,1500,2100,0300 h), starting at 0900 h on day 1
- Sampling: Measure serum cortisol at 0900 h on day 3 (6 hours after the last dose)
- Interpretation: Normal suppression is cortisol <1.8 μg/dL (50 nmol/L) 2
- Pediatric dosing:
40 kg: Use adult protocol
- <40 kg: Adjust to 30 μg/kg/day in divided doses 2
Alternative Protocol (Yanovski)
- Administer dexamethasone starting at 1200 h
- Measure cortisol at 0800 h (2 hours after last dose instead of 6 hours) 2
High-Dose Dexamethasone Suppression Test (HDDST)
The high-dose DST is used to differentiate Cushing's disease (pituitary) from ectopic ACTH syndrome, though recent evidence suggests LDDST may provide similar diagnostic accuracy 3.
Overnight 8-mg DST Protocol
- Administration: Give 8 mg dexamethasone orally at 2300 h
- Sampling: Measure serum cortisol at multiple time points (0700,0800,0900,1000 h) the following morning for optimal accuracy 4
- Interpretation:
50% suppression of baseline cortisol suggests Cushing's disease (pituitary source)
- <50% suppression suggests ectopic ACTH syndrome or adrenal source
- Important caveat: The original criterion (>50% suppression at 0700-0800 h) has high sensitivity (88%) but low specificity (57%) 4
- Revised criterion: Using later sampling times (0900-1000 h) achieves 100% specificity with 71% sensitivity 4
48-Hour High-Dose DST (8 mg/day) Protocol
- Administration: Give 2 mg dexamethasone every 6 hours for 48 hours
- Sampling: Measure urinary free cortisol (UFC) and/or serum cortisol
- Interpretation: >50% suppression suggests Cushing's disease
Very High-Dose DST (32 mg)
For patients who fail to suppress with 8 mg dexamethasone (occurs in ~42% of Cushing's disease patients, especially those with macroadenomas), a 32-mg test may be considered 5:
- Administration: Give 8 mg dexamethasone four times over 24 hours (total 32 mg)
- Interpretation: Measure UFC; >50% suppression suggests Cushing's disease
- This protocol reduces non-suppressors from 42% to 26% for serum cortisol and to 16% for UFC 5
Critical Pitfalls and Considerations
False Positives (Inadequate Suppression in Normal Individuals)
- Drug interactions increasing dexamethasone clearance: Phenobarbital, carbamazepine, phenytoin, rifampin, St. John's wort 1, 2
- Malabsorption: Celiac disease, chronic diarrhea, rapid gut transit 1
- Increased CBG: Oral estrogens, pregnancy, chronic active hepatitis (increases total cortisol) 1
- Pseudo-Cushing states: Depression, anxiety, OCD, morbid obesity, alcoholism, poorly controlled diabetes 2
Solution: Measure dexamethasone levels concurrently with cortisol using laboratory-specific ranges to identify inadequate dexamethasone absorption/metabolism 1. Recent evidence supports reflex dexamethasone measurement only when cortisol is >2.1 μg/dL 6.
False Negatives (Inappropriate Suppression in Cushing Syndrome)
- Drug interactions decreasing dexamethasone clearance: Fluoxetine, cimetidine, diltiazem 1
- Decreased CBG/albumin: Nephrotic syndrome 1
Test Selection by Clinical Scenario
Avoid dexamethasone testing in:
- Pregnancy: Use UFC instead 2
- Epilepsy patients on enzyme-inducing antiepileptics: Use UFC, salivary cortisol, or serum cortisol instead 2
- Severe renal failure (CrCl <60 mL/min): Prefer 1-mg overnight DST over UFC 2
- Night-shift workers or variable sleep schedules: DST assumes normal circadian rhythm 1, 2
Cyclic Cushing syndrome: Use UFC or late-night salivary cortisol with multiple collections rather than DST 2
Adrenal incidentaloma with suspected mild autonomous cortisol secretion: Use 1-mg DST or late-night cortisol; cortisol <1.8 μg/dL excludes autonomous secretion, >5 μg/dL identifies overt hypercortisolism 1, 2
Diagnostic Algorithm
Initial screening: Perform overnight 1-mg DST
- If cortisol <1.8 μg/dL: Cushing syndrome excluded
- If cortisol >5 μg/dL: Highly suggestive of Cushing syndrome
- If cortisol 1.8-5 μg/dL or concern for false positive: Proceed to second test
Confirmatory testing: Perform 48-hour LDDST or alternative screening test (late-night salivary cortisol, 24-hour UFC)
Differential diagnosis (after confirming ACTH-dependent Cushing syndrome):
- Recent evidence suggests LDDST with UFC may differentiate Cushing's disease from ectopic ACTH syndrome as effectively as HDDST (AUC 0.883 vs 0.834) 3
- If LDDST shows <26% suppression of UFC: 100% specific for ectopic ACTH syndrome 3
- If LDDST shows ≥26% suppression: Likely Cushing's disease, but consider BIPSS if pituitary adenoma <6 mm 3
- Traditional approach: Perform overnight 8-mg DST with sampling at 0900-1000 h for optimal specificity 4