What is the role of the cortisol with dexamethasone (DEX) suppression test in diagnosing and managing Cushing's syndrome in an adult patient?

Dexamethasone Suppression Test for Cushing's Syndrome

The dexamethasone suppression test is a first-line screening tool for Cushing's syndrome that measures the ability of exogenous glucocorticoid to suppress cortisol production, with the overnight 1-mg test being the most practical screening method and the 8-mg high-dose test reserved for differential diagnosis after Cushing's syndrome is confirmed. 1

Screening for Cushing's Syndrome: The Overnight 1-mg DST

Test Protocol and Interpretation

• 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), which effectively rules out Cushing's syndrome with >90% sensitivity 1, 2
• Cortisol >5.0 μg/dL (138 nmol/L) indicates autonomous cortisol secretion and overt Cushing's syndrome 1, 3

The Diagnostic Gray Zone (1.8-5.0 μg/dL)

When post-dexamethasone cortisol falls in this borderline range, do not escalate to high-dose testing—instead, perform additional evaluation 1:

• Measure concomitant dexamethasone levels with cortisol to identify false-positives from rapid drug metabolism or malabsorption (dexamethasone <1.8 ng/mL invalidates the test) 1
• Obtain 2-3 additional screening tests: 24-hour urinary free cortisol, late-night salivary cortisol, and repeat overnight DST to account for cyclic Cushing's syndrome and intra-patient variability 1, 2
• Consider monitoring for 3-6 months in patients with mild hypercortisolism and low clinical suspicion, as underlying conditions may resolve 1

Critical Pitfalls That Cause False Results

False-Positive Results (Cortisol Fails to Suppress)

• CYP3A4 inducers accelerate dexamethasone metabolism: phenobarbital, carbamazepine, rifampin, St. John's wort 1, 3
• Rapid gut transit or malabsorption reduces dexamethasone absorption 1
• Oral estrogen-containing contraceptives increase cortisol-binding globulin, falsely elevating total cortisol 3
• Pseudo-Cushing's states: depression, alcoholism, severe obesity, polycystic ovary syndrome activate the HPA axis without true Cushing's syndrome 1, 2, 3

False-Negative Results (Cortisol Suppresses Inappropriately)

• CYP3A4 inhibitors slow dexamethasone clearance: fluoxetine, cimetidine, diltiazem 1, 3
• Topical hydrocortisone contamination in salivary samples 3

How to Avoid These Pitfalls

• Always obtain medication history before testing, specifically asking about oral contraceptives, antiepileptics, antibiotics, and psychiatric medications 1, 3
• Measure dexamethasone levels concomitantly with cortisol to confirm adequate drug exposure and reduce false-positive rates 1, 3
• Discontinue oral estrogens 6 weeks before testing or use free cortisol measurements instead of total cortisol 3

Differential Diagnosis: The High-Dose 8-mg DST

The 8-mg dexamethasone suppression test should NEVER be used for initial screening—it is only performed after Cushing's syndrome is confirmed biochemically to differentiate pituitary from ectopic ACTH sources 1:

• Administer 8 mg dexamethasone at 11:00 PM, measure cortisol at 8:00 AM 4
• Cortisol suppression >50% from baseline suggests Cushing's disease (pituitary source) with 92% sensitivity and 100% specificity 4
• Lack of suppression suggests ectopic ACTH syndrome or adrenal tumor 4, 5

However, the high-dose DST has limitations: 26-42% of patients with proven Cushing's disease fail to suppress with 8 mg dexamethasone, particularly those with macroadenomas 6, 5. When the 8-mg test is non-diagnostic, proceed directly to inferior petrosal sinus sampling rather than escalating to higher dexamethasone doses 2.

Algorithmic Approach to Using the DST

Step 1: Initial Screening (Moderate-to-High Clinical Suspicion)

• Perform 2-3 first-line screening tests simultaneously: overnight 1-mg DST, late-night salivary cortisol (2-3 samples), and 24-hour urinary free cortisol (2-3 collections) 1, 2
• If clinical suspicion is low, start with late-night salivary cortisol alone 2

Step 2: Interpret Screening Results

• All tests normal: Cushing's syndrome unlikely, no further testing needed 2
• Any test abnormal: Repeat 1-2 screening tests to confirm 2
• Persistently abnormal results: Proceed to measure 9 AM plasma ACTH 2

Step 3: Determine Etiology Based on ACTH

• ACTH low/undetectable (<5 ng/L): ACTH-independent Cushing's syndrome → obtain adrenal CT imaging 2
• ACTH normal/elevated (>5 ng/L): ACTH-dependent Cushing's syndrome → obtain pituitary MRI 2

Step 4: Differential Diagnosis of ACTH-Dependent Disease

• Pituitary adenoma ≥10 mm on MRI: Presume Cushing's disease, proceed to surgery 1
• Pituitary adenoma <6 mm or no adenoma visible: Perform inferior petrosal sinus sampling (IPSS) to distinguish pituitary from ectopic ACTH 1, 2
• The 8-mg high-dose DST may be performed but has lower diagnostic accuracy than IPSS 4, 5

Special Clinical Contexts

Adrenal Incidentalomas

• All patients with adrenal incidentalomas require hormone screening, including overnight 1-mg DST 7
• Subclinical Cushing's syndrome (abnormal DST without overt symptoms) is the most common hormonal dysfunction in adrenal incidentalomas 7
• Management of subclinical Cushing's syndrome requires shared decision-making weighing patient preference, comorbidity severity (diabetes, hypertension, obesity), and surgical risk, as progression to overt Cushing's is rare 7

Preoperative Considerations

• In patients with confirmed Cushing's syndrome scheduled for adenoma resection, optimize comorbid conditions preoperatively: control diabetes and hypertension, provide prophylactic antibiotics 7

Cyclic Cushing's Syndrome

• Cyclic disease produces weeks-to-months of normal cortisol interspersed with hypercortisolism episodes, causing inconsistent test results 1, 2, 3
• Extended monitoring with multiple sequential late-night salivary cortisol measurements is particularly useful for detecting cyclic patterns 2
• Perform dynamic testing and localization studies only during documented active phases 3