Can an evening cortisol level be checked to evaluate a patient suspected of having adrenal insufficiency or Cushing's syndrome?

Evening Cortisol for Diagnostic Evaluation

Yes, evening cortisol measurement is an excellent and highly accurate screening test for Cushing's syndrome, but it has no role in evaluating adrenal insufficiency. 1, 2

For Cushing's Syndrome Evaluation

Why Evening Cortisol Works

Loss of normal circadian rhythm is the hallmark of Cushing's syndrome—patients fail to achieve the normal cortisol nadir at night. 1, 2 Healthy individuals should have cortisol levels drop to <50 nmol/L (<1.8 μg/dL) by late evening, tightly entrained to sleep onset. 2, 3

Specific Testing Options

Late-night salivary cortisol (LNSC) is the preferred evening cortisol measurement with the following characteristics:

• Collect at 11 PM-midnight (2300-2400h) or at bedtime 1, 2
• Sensitivity: 92-100% and specificity: 93-100% for Cushing's syndrome 4, 5, 6
• Abnormal threshold: >3.6 nmol/L (>0.1 μg/dL) per Endocrine Society guidelines 2
• Always obtain at least 2-3 samples due to test-to-test variability and possibility of cyclic Cushing's 1, 2

Midnight serum cortisol is an alternative but less practical:

• Must be drawn while patient is sleeping 2, 7
• Abnormal threshold: ≥50 nmol/L (≥1.8 μg/dL) 2, 3, 7
• Achieves 100% sensitivity in multiple studies 7
• Major limitation: requires hospitalization or home nursing visit, making it stressful and less reproducible 8

Critical Pitfalls to Avoid

Night-shift workers should never undergo late-night cortisol testing due to disrupted circadian rhythm. 2, 3

Topical hydrocortisone preparations contaminate salivary samples—patients must avoid all topical steroids before collection. 2

Oral contraceptives and estrogen therapy increase cortisol-binding globulin (CBG), falsely elevating total serum cortisol while free cortisol remains normal—this affects serum measurements but not salivary cortisol. 2, 9

Avoid blood contamination from dental work or teeth brushing within 1-2 hours of salivary collection. 2, 9

Pseudo-Cushing's states (severe obesity, depression, alcoholism, PCOS) can cause mildly elevated evening cortisol—if results are equivocal, consider Dex-CRH or desmopressin testing to distinguish. 1, 2

For Adrenal Insufficiency Evaluation

Evening cortisol has absolutely no role in diagnosing adrenal insufficiency. 2, 3, 9

Why Morning Cortisol is Required

Cortisol peaks at 8-9 AM physiologically—this is when you can assess the adrenal gland's maximum capacity. 9

• Morning cortisol >14 μg/dL (>386 nmol/L) rules out adrenal insufficiency 2, 9
• Morning cortisol <10 μg/dL (<275 nmol/L) warrants ACTH stimulation testing 3, 9
• Peak cortisol <18 μg/dL (<500 nmol/L) after ACTH stimulation is diagnostic of adrenal insufficiency 2, 3

In acute illness with suspected adrenal crisis, immediately administer IV hydrocortisone 100 mg and saline without waiting for any cortisol results. 3, 9

Practical Algorithm

If Suspecting Cushing's Syndrome:

1. Order late-night salivary cortisol on 2-3 separate nights 1, 2
2. Simultaneously order 24-hour urinary free cortisol (2-3 collections) and/or overnight 1-mg dexamethasone suppression test 1, 2
3. If ≥2 screening tests are abnormal, measure 9 AM ACTH to determine ACTH-dependent vs. ACTH-independent disease 1, 2
4. Proceed to pituitary MRI if ACTH is normal/elevated 1

If Suspecting Adrenal Insufficiency:

1. Order 8-9 AM serum cortisol and ACTH simultaneously 9
2. If morning cortisol <10 μg/dL, perform ACTH stimulation test 3, 9
3. Never use evening cortisol for this indication 2, 3, 9