What is a dexamethasone suppression test?

What is a Dexamethasone Suppression Test?

The dexamethasone suppression test (DST) is a diagnostic procedure that evaluates the body's cortisol regulation by administering synthetic glucocorticoid (dexamethasone) and measuring whether cortisol production is appropriately suppressed—failure to suppress indicates autonomous cortisol secretion, as seen in Cushing's syndrome. 1

Test Principle and Mechanism

The DST exploits the normal negative feedback mechanism of the hypothalamic-pituitary-adrenal (HPA) axis. 1 In healthy individuals, exogenous dexamethasone suppresses ACTH release from the pituitary gland, which in turn reduces cortisol production by the adrenal glands. 1 Patients with autonomous cortisol secretion (Cushing's syndrome) fail to suppress cortisol appropriately because their cortisol production is independent of normal regulatory mechanisms. 2

Types of Dexamethasone Suppression Tests

Overnight 1-mg DST (Low-Dose)

• Protocol: Administer 1 mg dexamethasone orally between 11:00 PM and midnight, then measure serum cortisol at 8:00 AM the following morning. 1
• Normal response: Serum cortisol < 1.8 μg/dL (50 nmol/L) strongly predicts absence of Cushing's syndrome with sensitivity >90%. 1, 2
• Abnormal response: Cortisol ≥1.8 μg/dL suggests possible Cushing's syndrome; cortisol >5.0 μg/dL (138 nmol/L) indicates overt autonomous cortisol secretion. 1, 3

2-Day Low-Dose DST (LDDST)

• Protocol: Administer 0.5 mg dexamethasone orally every 6 hours for 48 hours (total 4 mg), with cortisol measurements at 0,24, and 48 hours. 1, 2
• Normal response: Cortisol suppression to < 1.8 μg/dL (50 nmol/L). 1
• Diagnostic performance: Sensitivity 95%, specificity 80% for Cushing's syndrome. 2

High-Dose DST (8 mg)

• This test is not used for initial diagnosis of Cushing's syndrome but rather to differentiate pituitary Cushing's disease from ectopic ACTH syndrome after hypercortisolism is confirmed. 2, 4
• The overnight 8-mg test has limited clinical utility, with sensitivity 81% and specificity only 67% in differentiating these conditions. 5, 6

Clinical Applications

Primary Screening for Cushing's Syndrome

• The overnight 1-mg DST is recommended as one of three first-line screening tests (alongside late-night salivary cortisol and 24-hour urinary free cortisol) when Cushing's syndrome is suspected. 7, 2
• For intermediate or high clinical suspicion: Perform 2-3 different screening tests simultaneously to account for variability and cyclic disease. 7
• For low clinical suspicion: Start with late-night salivary cortisol; DST can be added if initial results are abnormal. 7

Evaluation of Adrenal Incidentalomas

• All patients with adrenal incidentalomas require hormone screening with overnight 1-mg DST to detect subclinical Cushing's syndrome. 1
• DST is particularly useful as the first-line test in this population, with cortisol >5 μg/dL identifying dysregulated cortisol secretion from the incidentaloma. 2

Special Populations

• Shift workers and disrupted circadian rhythm: DST may be preferred over late-night salivary cortisol due to unreliable circadian patterns. 7, 2
• Women on oral estrogen/contraceptives: DST may be unreliable because estrogen increases cortisol-binding globulin, falsely elevating total cortisol; alternative tests should be considered. 7, 2

Interpretation Algorithm

Normal Result (Cortisol < 1.8 μg/dL)

• Cushing's syndrome is effectively ruled out with high confidence. 1, 2
• No further biochemical testing for hypercortisolism is indicated based on this result alone. 1
• The result demonstrates intact negative feedback of the HPA axis. 1

Borderline Result (Cortisol 1.8-5.0 μg/dL)

• This represents a diagnostic gray zone requiring additional evaluation rather than immediate escalation. 1
• Recommended approach: 1
  • Measure dexamethasone level concomitantly with cortisol to identify false-positives from rapid metabolism or malabsorption (dexamethasone <1.8 ng/mL invalidates the test)
  • Obtain 2-3 additional screening tests (24-hour UFC, late-night salivary cortisol, repeat DST)
  • Consider monitoring for 3-6 months if clinical suspicion is low and mild hypercortisolism is present

Abnormal Result (Cortisol ≥5.0 μg/dL)

• Indicates overt autonomous cortisol secretion. 1, 3
• Proceed to ACTH measurement to determine if Cushing's syndrome is ACTH-dependent (pituitary or ectopic) or ACTH-independent (adrenal). 7

Critical Pitfalls and How to Avoid Them

False-Positive Results (Failure to Suppress Despite Normal HPA Axis)

• CYP3A4 inducers (phenobarbital, carbamazepine, phenytoin, rifampin, St. John's wort) accelerate dexamethasone metabolism, causing inadequate drug levels. 1, 2
• Rapid gut transit or malabsorption reduces dexamethasone absorption. 1
• Pseudo-Cushing's states (depression, alcoholism, severe obesity, PCOS) can activate the HPA axis, mimicking true hypercortisolism. 7, 2
• Oral estrogen/contraceptives increase cortisol-binding globulin, elevating total cortisol without true hypercortisolism. 2, 3

Prevention strategy: Measure dexamethasone levels concomitantly with cortisol to confirm adequate drug exposure (dexamethasone should be ≥1.8 ng/mL). 1, 2

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

• CYP3A4 inhibitors (fluoxetine, cimetidine, diltiazem) increase dexamethasone levels, causing excessive suppression. 1, 2
• Mild Cushing's syndrome: Up to 18% of patients with confirmed Cushing's disease suppress to <5 μg/dL, and 8% suppress to <2 μg/dL on the 1-mg test. 8
• Cyclic Cushing's syndrome: Patients may have normal cortisol during quiescent periods. 7, 2

Prevention strategy: Perform multiple screening tests (2-3 collections of each modality) and consider serial testing over 3-6 months if cyclic disease is suspected. 7, 2

Medication and Physiologic Interferences

• Exogenous glucocorticoids (oral, inhaled fluticasone, topical, intra-articular injections) must be excluded before testing, as they suppress endogenous cortisol and invalidate results. 7, 3
• Pregnancy and chronic active hepatitis increase cortisol-binding globulin, falsely elevating total cortisol. 3
• Acute stress, illness, or recent exercise can transiently elevate cortisol. 3

Test Validation and Quality Control

• Measuring dexamethasone levels concomitantly with cortisol reduces false-positive DST results and confirms test validity. 1, 2
• Verify local laboratory reference ranges, as different assays may have slightly different cutoffs. 2
• Ensure proper timing: dexamethasone at 11 PM-midnight, cortisol measurement at 8 AM. 1

When DST Should NOT Be Used

• Never use DST alone to exclude Cushing's syndrome in patients with mild hypercortisolism; combine with other screening tests. 7, 8
• Do not use high-dose DST (8 mg) for initial diagnosis of hypercortisolism—it is only for differentiating pituitary from ectopic ACTH sources after Cushing's is confirmed. 2
• Inferior petrosal sinus sampling should never be used to diagnose hypercortisolism; it is only for localization after biochemical confirmation. 7