What is the dexamethasone suppression test?

The Dexamethasone Suppression Test: A Key Diagnostic Tool for Cushing's Syndrome

The dexamethasone suppression test (DST) is a first-line screening test for Cushing's syndrome that evaluates the feedback inhibition of the hypothalamic-pituitary-adrenal axis by measuring cortisol suppression after dexamethasone administration. 1

Types of Dexamethasone Suppression Tests

• Overnight 1-mg DST: The most commonly used screening test where 1 mg of dexamethasone is administered at 11 PM, followed by measurement of serum cortisol at 8 AM the next morning 1, 2
• Low-dose 2-day DST (LDDST): Involves administration of 0.5 mg dexamethasone every 6 hours for 2 days with subsequent cortisol measurement 3
• High-dose DST: Uses 8 mg dexamethasone (either as a single overnight dose or divided over 2 days) to differentiate between pituitary and ectopic sources of ACTH-dependent Cushing's syndrome 4
• Very high-dose DST: Uses 32 mg dexamethasone over 24 hours in cases where standard high-dose testing is inconclusive 5

Physiological Basis

• In healthy individuals, dexamethasone suppresses corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) secretion, thereby reducing cortisol production 3
• Patients with Cushing's syndrome demonstrate resistance to this negative feedback mechanism, resulting in inadequate cortisol suppression 3
• Different etiologies of Cushing's syndrome show varying degrees of resistance to dexamethasone suppression 1, 6

Interpretation of Results

• Normal response: Cortisol suppression to <1.8 μg/dL (50 nmol/L) strongly excludes Cushing's syndrome 3, 1
• Abnormal response: Cortisol levels >1.8 μg/dL suggest possible Cushing's syndrome 3, 2
• Differential diagnosis:
  • In pituitary Cushing's disease, high-dose dexamethasone typically suppresses cortisol by >50% from baseline 4
  • In ectopic ACTH syndrome or adrenal tumors, cortisol typically shows minimal or no suppression with high-dose dexamethasone 4, 5

Clinical Applications

• Screening for Cushing's syndrome: The overnight 1-mg DST has high sensitivity (>95%) for excluding Cushing's syndrome when negative 1, 2
• Differential diagnosis: High-dose DST helps distinguish between pituitary and non-pituitary sources of ACTH-dependent Cushing's syndrome 4
• Adrenal incidentalomas: DST is particularly useful for identifying autonomous cortisol secretion from adrenal incidentalomas 1

Improving Test Accuracy

• Measuring dexamethasone levels: Concomitant measurement of dexamethasone (lower limit of normal: 1.8 ng/mL or 4.6 nmol/L) can identify false positives due to inadequate dexamethasone exposure 7
• Method-specific cortisol cutoffs: Using assay-specific cortisol thresholds improves test specificity while maintaining sensitivity 7
• Multiple testing: Repeating tests or using complementary tests (LNSC, UFC) can increase diagnostic accuracy 3

Factors Affecting Test Results

False Positives (inadequate suppression despite absence of Cushing's syndrome)

• Medications affecting dexamethasone metabolism (CYP3A4 inducers like phenytoin, phenobarbital, rifampin) 8
• Increased corticosteroid binding globulin levels (oral estrogens, pregnancy) 2
• Rapid dexamethasone metabolism or malabsorption 1
• Severe obesity, uncontrolled diabetes, alcoholism, depression (pseudo-Cushing's states) 6

False Negatives (adequate suppression despite presence of Cushing's syndrome)

• Up to 18% of patients with Cushing's disease may suppress cortisol to <5 μg/dL with the overnight 1-mg test 9
• Some patients may even suppress to <2 μg/dL despite having confirmed Cushing's disease 9
• Cyclical Cushing's syndrome may show normal suppression if tested during a quiescent phase 3

Special Considerations

• Shift workers: DST is preferred over late-night salivary cortisol for those with disrupted circadian rhythms 3, 2
• Women on oral estrogens: Test results may be less reliable; consider measuring dexamethasone levels or using alternative tests 3
• Renal impairment: May lead to higher dexamethasone concentrations and potentially false negative results 7
• Cyclic Cushing's syndrome: May require periodic re-evaluation and multiple testing 3

Pitfalls and Caveats

• Reliance on a single test: No single test is 100% accurate; consider using multiple tests when clinical suspicion is high 3, 9
• Mild Cushing's syndrome: May show borderline results requiring repeated testing 3
• Pseudo-Cushing's states: Conditions like depression, alcoholism, and severe obesity can cause false positive results 6
• Drug interactions: Medications affecting dexamethasone metabolism can significantly impact test results 8

The dexamethasone suppression test remains a cornerstone in the diagnosis of Cushing's syndrome when properly performed and interpreted in the appropriate clinical context 1, 2.