What is the role of the dexamethasone (corticosteroid) suppression test in diagnosing Cushing's syndrome?

Dexamethasone Suppression Test in Cushing's Syndrome Diagnosis

The overnight 1-mg dexamethasone suppression test (DST) is a first-line screening test for Cushing's syndrome, where 1 mg dexamethasone is given between 11 PM and midnight, followed by measurement of serum cortisol at 8 AM the next morning, with a normal response being cortisol <1.8 μg/dL (50 nmol/L). 1, 2

Primary Screening Approach

The Endocrine Society positions the overnight 1-mg DST as one of three first-line screening options, alongside late-night salivary cortisol (LNSC) and 24-hour urinary free cortisol (UFC) 2. The test's strength lies in its high sensitivity and ability to effectively rule out Cushing's syndrome when negative 1.

Test Administration Protocol

• Administer 1 mg dexamethasone orally between 11 PM and midnight 2
• Measure only serum cortisol at 8 AM the following morning 2
• Do not measure ACTH during the initial overnight DST, as this is not part of standard protocol and may lead to misinterpretation 2

Interpretation of Results

Normal Response

• Cortisol <1.8 μg/dL (50 nmol/L) strongly predicts absence of Cushing's syndrome 1, 2
• This threshold provides optimal sensitivity for ruling out the condition 1

Abnormal Response

• Cortisol ≥1.8 μg/dL requires repeat screening tests 1
• Persistently abnormal results should proceed to ACTH measurement to differentiate ACTH-dependent from ACTH-independent causes 2
• For adrenal incidentalomas specifically, cortisol values >5 μg/dL generally identify dysregulated cortisol secretion 1

Enhancing Test Accuracy

Measuring dexamethasone levels concomitantly with cortisol can significantly reduce false-positive results, with a lower limit of normal dexamethasone concentration of 1.8 ng/mL (4.6 nmol/L) 1. This approach is particularly valuable since approximately 6% of non-Cushing's patients fail to achieve adequate dexamethasone levels, accounting for 40% of false-positive results 3.

Alternative DST Protocols

Two-Day Low-Dose DST (LDDST)

• Sensitivity of 95% and specificity of 80% 1
• Normal response: cortisol suppression below 50 nmol/L (1.8 μg/dL) 1
• More cumbersome but may be useful when overnight test results are equivocal 1

Lower Dose Variations

Research suggests that a 0.5 mg DST with a cortisol cut-off of 3.05 μg/dL achieves 99.1% sensitivity and 98.4% specificity for ACTH-dependent Cushing's syndrome 4, though this is not currently recommended in major guidelines.

Critical Pitfalls and False Results

False Positives (Test Suggests Cushing's When Absent)

• Rapid dexamethasone absorption or malabsorption 1, 2
• CYP3A4 inducers (anticonvulsants, rifampin) that accelerate dexamethasone metabolism 1, 2
• Increased corticosteroid binding globulin (CBG) levels, particularly in women on oral estrogen 1, 2
• Pseudo-Cushing's states (depression, alcoholism, obesity) may require additional testing with Dex-CRH test 1

False Negatives (Test Misses Cushing's)

• Inhibition of dexamethasone metabolism by medications 1, 2
• Decreased CBG levels 1, 2
• Important caveat: Up to 18% of patients with proven Cushing's disease may suppress cortisol to <5 μg/dL, and 8% may suppress to <2 μg/dL after the 1-mg test 5, emphasizing that DST should not be used as the sole criterion to exclude Cushing's syndrome

Special Clinical Scenarios

Preferred Populations for DST

• Shift workers and patients with disrupted circadian rhythm due to uneven sleep schedules, where late-night salivary cortisol may be unreliable 1
• Adrenal incidentaloma evaluation as a first-line test 1

When DST May Not Be Reliable

• Women on oral estrogen therapy should use alternative tests 1
• Suspected pseudo-Cushing's states may require Dex-CRH testing for differentiation 1

Diagnostic Algorithm Strategy

For low clinical suspicion: Start with late-night salivary cortisol 1

For intermediate to high clinical suspicion: Perform 2-3 screening tests including overnight DST, LNSC, and 24-hour UFC 1

If screening abnormal: Repeat screening tests; if persistently abnormal, measure ACTH to determine if Cushing's is ACTH-dependent (normal/high ACTH) or ACTH-independent (low ACTH) 2

Interpret multiple test results together rather than relying on a single test for increased diagnostic accuracy 2