In a 23-year-old woman with amenorrhea, fatigue, weight gain, central obesity and abdominal striae suggestive of Cushing syndrome, which tests confirm hypercortisolemia?

Confirming Hypercortisolemia in Suspected Cushing's Syndrome

The correct answers are both (a) 24-hour urinary free cortisol and (e) 1 mg dexamethasone suppression test, as these are the recommended first-line screening tests to confirm hypercortisolemia, with the overnight dexamethasone suppression test being preferred for its 95% sensitivity and 80% specificity. 1

Algorithmic Approach to Diagnosis

Step 1: Confirm Hypercortisolemia (Not Etiology)

The question specifically asks which tests confirm hypercortisolemia—this is the critical first step before determining the cause of Cushing's syndrome. 2

First-line screening tests include: 1, 3

• 24-hour urinary free cortisol (UFC) - Option (a) is correct
• Overnight 1 mg dexamethasone suppression test - Option (e) is correct
• Late-night salivary cortisol (not listed as an option)

The Endocrine Society and ACC/AHA guidelines recommend starting with 2-3 of these screening tests to confirm hypercortisolism. 3 Any of these three tests can confirm hypercortisolemia when abnormal. 3

Step 2: Understanding Why Other Options Are Incorrect

Option (b) - ACTH sampling from inferior petrosal sinuses: This is NOT used to confirm hypercortisolemia. 2 This invasive procedure is reserved for determining the source of ACTH in patients with already-confirmed ACTH-dependent Cushing's syndrome when imaging is equivocal. 2, 4 It requires a central-to-peripheral ACTH ratio ≥3:1 after stimulation to confirm pituitary origin. 2

Option (c) - ACTH concentration: This determines the etiology (ACTH-dependent vs. ACTH-independent), not whether hypercortisolemia exists. 2, 1 Morning plasma ACTH is measured after confirming hypercortisolism to guide further workup. 2, 1

Option (d) - Morning CRH levels: CRH levels are not measured diagnostically. 2 The CRH stimulation test (not basal levels) is used to differentiate Cushing's disease from ectopic ACTH syndrome in patients with already-confirmed ACTH-dependent disease. 2

Specific Test Characteristics for Confirmation

24-Hour Urinary Free Cortisol (UFC)

• Sensitivity: 89%, Specificity: 100% in pediatric/young adult populations 2
• Should be collected for 3 consecutive days for optimal accuracy 2
• Diagnostic cut-off: >193 nmol/24h (>70 μg/m²) 2
• UFC rises proportionally more than plasma cortisol because cortisol-binding globulin saturates around 500 nmol/L 5

1 mg Overnight Dexamethasone Suppression Test

• Sensitivity: 95%, Specificity: 80% 2, 1
• Dexamethasone 1 mg given at 23:00h, measure serum cortisol at 09:00h 2
• Abnormal result: cortisol ≥50 nmol/L (≥1.8 μg/dL) indicates lack of suppression 2, 3
• In normal individuals, morning cortisol suppresses to <80 nmol/L 5

Important Clinical Pitfalls

False positives with dexamethasone suppression: 6

• Women taking oral contraceptives have elevated cortisol-binding globulin, leading to false-positive results with the 1 mg test 6
• Consider 2-day low-dose dexamethasone test (2d-DST) in women on oral contraceptives, as it has better accuracy (27% unclear results vs. 63% with 1 mg test) 6

Mild or cyclical Cushing's syndrome: 7

• Neither a single normal UFC nor normal salivary cortisol excludes mild Cushing's syndrome 7
• Multiple samples (urine/saliva) and repeated testing are needed when clinical suspicion remains high 7
• Only 4 of 11 patients with confirmed mild Cushing's had elevated UFC, and none exceeded 2× upper limit of normal 7

Pseudo-Cushing's states: 4, 5

• Severe depression and stress can cause incomplete suppression on dexamethasone testing ("false-positives") 5
• However, UFC remains normal or only slightly elevated in pseudo-Cushing's, while it is markedly increased in true Cushing's syndrome 5