What is the process for testing for hypercortisolism?

Testing Process for Hypercortisolism

All patients with suspected hypercortisolism should undergo initial screening with at least one (preferably two or three) of the following first-line tests: 24-hour urinary free cortisol (UFC), late-night salivary cortisol (LNSC), or 1 mg overnight dexamethasone suppression test (DST), followed by plasma ACTH measurement to determine the source of excess cortisol. 1, 2

Step 1: Exclude Exogenous Glucocorticoid Use

• Before any testing, confirm the patient is not taking exogenous glucocorticoids (oral, inhaled, topical, or injected), as this is the most common cause of hypercortisolism and will cause false results 2, 3

Step 2: Initial Screening Tests (Choose 2-3 Tests)

24-Hour Urinary Free Cortisol (UFC)

• Collect 2-3 samples on separate days to account for day-to-day variability 1
• Values >193 nmol/24h (>70 μg/m²) have 89% sensitivity and 100% specificity for Cushing syndrome 1
• Avoid in patients with renal impairment (CrCl <60 mL/min) or significant polyuria, as results become unreliable 1

Late-Night Salivary Cortisol (LNSC)

• Obtain at least 2-3 samples on separate days between 11 PM and midnight 1, 4
• Offers 95% sensitivity and 100% specificity when multiple samples are obtained 1
• Preferred test for patients with renal impairment, shift workers, or those with disrupted circadian rhythm 1, 2
• Routine immunoassay performs better than liquid chromatography/mass spectrometry for diagnostic purposes 4

1 mg Overnight Dexamethasone Suppression Test (DST)

• Patient takes 1 mg dexamethasone at 11 PM, measure serum cortisol at 8 AM 5, 1
• Failure to suppress cortisol to <50 nmol/L (<1.8 μg/dL) suggests hypercortisolism 1, 2
• Cortisol 51-138 nmol/L indicates possible autonomous cortisol secretion; >138 nmol/L indicates overt hypercortisolism 5
• Avoid in patients on oral estrogen therapy (causes false positives); measuring dexamethasone levels can help identify false positives 1, 2
• Preferred for suspected adrenal tumors (LNSC has lower specificity in this setting) 2

Step 3: Confirm Hypercortisolism and Exclude Pseudo-Cushing States

• A single normal test does not exclude Cushing syndrome, especially in mild or cyclic cases; multiple abnormal tests are needed for confirmation 1, 3
• Consider pseudo-Cushing states that can cause mildly elevated cortisol: psychiatric disorders (especially depression), alcoholism, obesity, polycystic ovary syndrome, uncontrolled diabetes, and pregnancy 1, 2, 3
• In patients with suspected pseudo-Cushing states, monitor for 3-6 months to see if symptoms resolve; treatment of underlying conditions (such as depression) can restore normal cortisol levels 5
• Desmopressin test can differentiate Cushing disease from pseudo-Cushing states with high specificity 1

Step 4: Determine the Source of Hypercortisolism

Measure Morning Plasma ACTH

• Normal or elevated ACTH (>1.1 pmol/L or >5 ng/L) indicates ACTH-dependent Cushing syndrome (pituitary or ectopic source) 1, 2
• Low or undetectable ACTH indicates ACTH-independent Cushing syndrome (adrenal source) 1, 2

For ACTH-Independent (Adrenal Source)

• Perform adrenal CT or MRI to identify adrenal adenoma, carcinoma, or bilateral disease 2

For ACTH-Dependent (Pituitary vs Ectopic)

• Obtain pituitary MRI with contrast (3T preferred over 1.5T where available) to look for pituitary adenoma 5, 2
• Perform CRH stimulation test: administer CRH 1.0 μg/kg IV, measure ACTH and cortisol at baseline and post-stimulation; ≥20% increase in cortisol from baseline suggests pituitary origin (Cushing disease) 1, 2
• Desmopressin stimulation test can also be used; increased plasma ACTH and cortisol following desmopressin usually indicates Cushing disease 5, 1
• If suspicion is high for ectopic ACTH syndrome (male patient, very high UFC, profound hypokalemia), perform neck-to-pelvis thin-slice CT scan 5

Step 5: Bilateral Inferior Petrosal Sinus Sampling (BIPSS) for Equivocal Cases

• BIPSS is indicated when non-invasive tests do not allow diagnostic definition or when pituitary MRI is negative despite ACTH-dependent hypercortisolism 5, 1, 3
• Must be performed at a specialized center due to patient risk 5
• Central-to-peripheral ACTH ratio ≥2:1 before CRH/desmopressin and ≥3:1 after stimulation confirms pituitary source 5, 1
• Essential that patient is hypercortisolemic at the time of IPSS; prolactin measurement may improve diagnostic accuracy 5

Step 6: Advanced Imaging for Ectopic Sources (When Indicated)

• 68Ga-DOTATATE PET/CT localizes approximately 65% of ectopic ACTH-secreting neuroendocrine tumors, including those not seen on conventional imaging 5
• Particularly useful when BIPSS suggests ectopic source but CT/MRI is negative 5

Critical Pitfalls to Avoid

• Never proceed to differential diagnosis without first confirming hypercortisolism biochemically; this leads to misdiagnosis and inappropriate treatment 3
• Do not rely on a single test; use at least two screening tests, especially when clinical suspicion is intermediate or high 2, 3
• Remember cyclic Cushing syndrome: patients may have normal results during quiescent periods; repeat testing over time if clinical suspicion remains high 5, 1
• No single laboratory test or combination can absolutely differentiate between pituitary and ectopic ACTH-secreting tumors; use both clinical context and test results together 5
• Tumor size does not correlate with degree of hypercortisolism in Cushing disease; larger adenomas frequently present with milder hypercortisolism 5