How does the dexamethasone (corticosteroid) suppression test work?

How the Dexamethasone Suppression Test Works

The dexamethasone suppression test (DST) works by evaluating the negative feedback mechanism of the hypothalamic-pituitary-adrenal (HPA) axis by administering exogenous dexamethasone, which should suppress cortisol production in normal individuals but fails to do so in patients with Cushing's syndrome. 1

Basic Mechanism

• The DST exploits the normal negative feedback mechanism where exogenous glucocorticoids (dexamethasone) should suppress ACTH production by the pituitary gland, leading to decreased cortisol secretion 2
• In normal individuals, dexamethasone administration results in cortisol suppression below 1.8 μg/dL (50 nmol/L), indicating proper functioning of the HPA axis 1
• In patients with Cushing's syndrome, this negative feedback mechanism is disrupted, resulting in failure to suppress cortisol production despite dexamethasone administration 2, 1

Types of Dexamethasone Suppression Tests

Overnight 1-mg DST

• Patient takes 1 mg of dexamethasone orally at 11:00 PM, and serum cortisol is measured at 8:00 AM the following morning 1
• Normal response: cortisol suppression to <1.8 μg/dL (50 nmol/L) 1, 3
• Sensitivity of approximately 95% for detecting Cushing's syndrome 2
• Particularly useful for ruling out dysregulated cortisol production from adrenal incidentalomas 1

2-Day Low-Dose DST (LDDST)

• Dexamethasone is administered at 0.5 mg every 6 hours (09:00,15:00,21:00,03:00) for 48 hours 4
• Cortisol measurements are taken at 0,24, and 48 hours 4
• Normal response: cortisol suppression to <1.8 μg/dL (50 nmol/L) 1, 4
• Sensitivity of 95% and specificity of 80% for diagnosing Cushing's syndrome 4

Factors Affecting Test Accuracy

• False positive results (failure to suppress despite no Cushing's) can occur with:

  • Medications affecting dexamethasone metabolism (CYP3A4 inducers like phenobarbital, carbamazepine) 4, 5
  • Estrogen therapy (oral contraceptives) 2, 1
  • Rapid dexamethasone metabolism 1
  • Stress, depression, alcoholism, and severe obesity 2

• False negative results (suppression despite Cushing's) can occur with:

  • Medications inhibiting dexamethasone metabolism (fluoxetine, cimetidine) 4
  • Decreased corticosteroid binding globulin (CBG) levels 1
  • Mild or cyclic Cushing's syndrome 6

Improving Test Accuracy

• Measuring dexamethasone levels concomitantly with cortisol can reduce false-positive results 1, 7
• The lower limit of normal dexamethasone concentration should be 1.8 ng/mL (4.6 nmol/L) 1
• About 6% of non-Cushing's patients do not achieve adequate dexamethasone levels, which can lead to false-positive results 7

Clinical Pitfalls and Considerations

• The DST should not be used as the sole criterion to exclude Cushing's syndrome, as some patients with confirmed disease may show suppression 6
• The FDA warns that phenytoin, phenobarbital, ephedrine, and rifampin may enhance dexamethasone metabolism, potentially causing false-positive results 5
• Indomethacin can cause false-negative results in the DST 5
• For optimal diagnostic accuracy, the DST should be combined with other tests such as late-night salivary cortisol or 24-hour urinary free cortisol 2, 1

Diagnostic Algorithm

• For patients with suspected Cushing's syndrome, start with either the overnight 1-mg DST, 24-hour urinary free cortisol, or late-night salivary cortisol 2, 1
• If the initial test is abnormal, perform additional confirmatory tests 2
• After confirming Cushing's syndrome, measure ACTH levels to determine if it is ACTH-dependent or ACTH-independent 2
• For ACTH-dependent Cushing's, additional tests like pituitary MRI or inferior petrosal sinus sampling may be needed 2