What are the diagnostic tests and treatment options for Cushing's syndrome?

Investigation for Cushing Syndrome

Initial Screening Strategy

Start with late-night salivary cortisol (LNSC) as your first-line screening test, collecting at least 2-3 samples on consecutive days, as it offers the highest combined sensitivity (95%) and specificity (91-100%) while being easiest for patient compliance. 1, 2

First-Line Screening Tests

Choose from three validated options based on clinical context:

• Late-Night Salivary Cortisol (LNSC): Collect ≥2-3 samples on consecutive days 1, 2

  • Sensitivity: 95%, Specificity: 91-100% 2, 3
  • Most convenient for patients—can be collected at home and mailed to laboratory 4
  • Cortisol remains stable at room temperature 4
  • Pitfall: Ensure adequate soaking of collection device; false results occur with inadequate sampling 4

• 24-Hour Urinary Free Cortisol (UFC): Collect 2-3 samples to account for day-to-day variability 1, 2

  • Sensitivity: 89-97%, Specificity: 91-100% 2, 5
  • Reflects integrated 24-hour cortisol exposure 4
  • Pitfall: Less useful in renal impairment (CrCl <60 mL/min) or significant polyuria (>5 L/24h) 1
  • Critical: Verify complete collection with appropriate total volume 4

• Overnight 1-mg Dexamethasone Suppression Test (DST): Give 1 mg dexamethasone at midnight, measure serum cortisol at 8 AM 1, 2

  • Normal response: cortisol <1.8 μg/dL (50 nmol/L) 2
  • Sensitivity: 95-100%, Specificity: 80-97% 6, 5
  • Preferred for shift workers with disrupted circadian rhythm 1
  • Contraindication: Unreliable in women taking estrogen-containing oral contraceptives 1
  • Enhancement: Measure dexamethasone level alongside cortisol to improve interpretability and identify false-positives from inadequate absorption 1

Interpretation Algorithm

If high clinical suspicion: Perform multiple tests (LNSC + UFC + DST) simultaneously 2, 7

If any test is abnormal: Repeat 1-2 screening tests to confirm before proceeding 2, 7

If all tests are normal: Cushing syndrome is unlikely 2

Ruling Out Pseudo-Cushing States

Common pitfalls: Severe obesity, uncontrolled diabetes, depression, alcoholism, polycystic ovary syndrome, and pregnancy can cause false-positive results with mildly elevated values (UFC typically <3-fold normal) 1, 2, 7

Management approach:

• Monitor for 3-6 months to see if symptoms resolve 1
• Treat underlying condition (e.g., depression) as this can restore normal HPA axis function 1
• Consider Dex-CRH test or desmopressin test at expert centers to distinguish true Cushing syndrome from pseudo-Cushing states 1

Determining Etiology After Confirmed Hypercortisolism

Step 1: Measure Morning Plasma ACTH

ACTH-dependent (normal/elevated ACTH >5 ng/L or >1.1 pmol/L): Suggests pituitary or ectopic ACTH source 2, 7, 6

ACTH-independent (low/undetectable ACTH): Indicates adrenal source 2, 7, 6

Step 2: Localization Based on ACTH Results

For ACTH-dependent Cushing syndrome:

• Perform pituitary MRI with gadolinium enhancement 7, 6

  • Sensitivity: 63%, Specificity: 92% 7, 6
  • Lesions ≥10 mm: Cushing disease presumed 7
  • Limitation: Approximately one-third of scans remain negative despite true disease 1

• If MRI negative or equivocal: Proceed to bilateral inferior petrosal sinus sampling (BIPSS) 1, 2, 7

  • Diagnostic criteria: Central-to-peripheral ACTH ratio ≥2:1 baseline, ≥3:1 after CRH/desmopressin stimulation 7
  • Sensitivity: 100% for distinguishing pituitary from ectopic sources 7, 6
  • Critical: Only perform BIPSS after confirming active hypercortisolism with LNSC, DST, or UFC in cyclic cases 1
  • Never use IPSS to diagnose hypercortisolism itself—gradients overlap with normal controls and pseudo-Cushing states 1

For ACTH-independent Cushing syndrome:

• Proceed directly to adrenal imaging (CT or MRI) 7
• Preferred screening test: DST rather than LNSC, as LNSC has lower specificity in adrenal tumor cases 1

Special Considerations

Cyclic Cushing syndrome: If results are inconsistent, document active phase with confirmatory LNSC, DST, or UFC before proceeding with dynamic or localization testing 1, 2

Assay considerations: No current preference for mass spectrometry over immunoassay, though mass spectrometry avoids cross-reactivity with cortisone and other metabolites that can cause false-positives 1, 4

Children and adolescents: Screen only if weight gain is inexplicable AND combined with decreased height velocity or standard deviation score 2, 6