How does the dexamethasone (dex) suppression test indicate Cushing's syndrome?

How the Dexamethasone Suppression Test Indicates Cushing's Syndrome

The dexamethasone suppression test indicates Cushing's syndrome by demonstrating failure of the normal negative feedback mechanism, where exogenous dexamethasone fails to suppress cortisol production in patients with pathological hypercortisolism. 1

Physiological Basis

The dexamethasone suppression test works based on the following mechanism:

• In normal individuals, administration of dexamethasone (a potent synthetic glucocorticoid) suppresses ACTH secretion from the pituitary through negative feedback
• This leads to decreased stimulation of the adrenal glands and reduced cortisol production
• In Cushing's syndrome, this normal feedback mechanism is disrupted:
  • In Cushing's disease (pituitary adenoma): the tumor partially or completely ignores the negative feedback signal
  • In ectopic ACTH syndrome: tumors produce ACTH autonomously without responding to feedback
  • In adrenal Cushing's: adrenal tumors produce cortisol independently of ACTH regulation

Types of Dexamethasone Suppression Tests

1. Overnight 1-mg Dexamethasone Suppression Test (DST):

   • Excellent for initial screening with very low false-negative rate (1.9%) 2
   • Procedure: 1 mg dexamethasone administered at 11 PM, cortisol measured at 8 AM the next day
   • Interpretation: Failure to suppress morning cortisol suggests Cushing's syndrome

2. Low-dose DST (2-mg over 2 days):

   • Used for definitive diagnosis of Cushing's syndrome
   • Combined with basal measurements of urinary free cortisol and late evening plasma cortisol 2

3. High-dose DST (8-mg):

   • Used for differential diagnosis of ACTH-dependent Cushing's syndrome
   • Helps distinguish between pituitary and ectopic sources of ACTH 3

Interpretation Challenges

• False positives can occur due to:

  • Estrogen-containing oral contraceptives (affects dexamethasone metabolism) 1
  • Insufficient dexamethasone serum exposure or missed intake 4
  • Medications that enhance dexamethasone clearance

• False negatives can occur in:

  • Up to 18% of patients with Cushing's disease may suppress cortisol to <5 μg/dL on the 1-mg test 5
  • 8% of Cushing's disease patients may show suppression to <2 μg/dL 5

Improving Test Accuracy

Recent research has shown that measuring serum dexamethasone levels simultaneously with cortisol can improve test specificity:

• The lower limit of normal for dexamethasone is 1.8 ng/mL
• Using method-specific cortisol cutoffs (2.4 μg/dL) and excluding samples with low dexamethasone levels increased specificity from 67.5% to 92.4% while maintaining 100% sensitivity 4

Clinical Applications

• Screening: The overnight 1-mg DST is recommended for initial screening in suspected cases 1
• Adrenal Incidentalomas: DST is valuable in evaluating adrenal incidentalomas, as subclinical Cushing's syndrome is the most common hormonal dysfunction in these cases 6, 1
• Differential Diagnosis: Higher doses of dexamethasone (8-mg overnight or 32-mg) can help differentiate between pituitary and non-pituitary causes 3, 7

Important Considerations

• The Endocrine Society recommends a three-step approach to diagnose Cushing's syndrome:

  1. Confirm hypercortisolism (using DST, 24-hour urinary free cortisol, or late-night salivary cortisol)
  2. Determine if ACTH-dependent or independent
  3. Identify the source through imaging and dynamic testing 1

• For adrenal incidentalomas with abnormal dexamethasone suppression but without overt Cushing's symptoms (mild autonomous cortisol secretion), management should consider patient preference and severity of comorbidities 6

• Progression from subclinical to frank Cushing's syndrome is rare, but monitoring is essential as the condition is associated with diabetes, obesity, dyslipidemia, and hypertension 6, 1