What are normal cortisol levels in patients with Cushing's syndrome and how are elevated levels managed?

Cortisol Levels in Cushing's Syndrome

In Cushing's syndrome, cortisol levels are pathologically elevated with loss of normal circadian rhythm, characterized by late-night salivary cortisol >3.6 nmol/L, 24-hour urinary free cortisol >193 nmol/24h, and failure to suppress serum cortisol to <1.8 μg/dL (50 nmol/L) after overnight 1-mg dexamethasone administration. 1, 2

Diagnostic Cortisol Thresholds

Screening Tests (Perform 2-3 Tests for Confirmation)

Late-Night Salivary Cortisol (LNSC):

• Abnormal: >3.6 nmol/L (upper limit of normal) 1
• Sensitivity >90%, highest specificity among screening tests 1
• Patients with mild Cushing's may have values just above the upper limit 1
• At least 2-3 tests recommended due to variability 1
• Research shows mean values of 24.0 ± 4.5 nmol/L in proven Cushing's vs 1.2 ± 0.1 nmol/L in normal subjects, with 92% sensitivity 3

24-Hour Urinary Free Cortisol (UFC):

• Abnormal: >193 nmol/24h (>70 μg/m²/24h) 2
• Sensitivity >90%, but lowest among the three screening tests 1
• At least 2-3 collections needed due to 50% random variability 1
• Research demonstrates mean values of 540 ± 50 nmol/d in mild Cushing's vs 160 ± 28 nmol/d in normals 4

Overnight 1-mg Dexamethasone Suppression Test (DST):

• Abnormal: Serum cortisol ≥1.8 μg/dL (≥50 nmol/L) at 0800h after 1 mg dexamethasone given at 2300-2400h 1, 2
• Sensitivity >90%, highest among screening tests but lowest specificity 1
• Cortisol >5 μg/dL (138 nmol/L) indicates overt Cushing's syndrome 1
• Cortisol <1.8 μg/dL effectively excludes Cushing's syndrome 1

Confirmatory Findings

Midnight Serum Cortisol:

• Abnormal: ≥50 nmol/L (≥1.8 μg/dL) in sleeping individuals 2
• Research shows mean midnight cortisol of 510 ± 232 nmol/L in Cushing's patients vs 99 ± 76 nmol/L in excluded patients 5
• No Cushing's patient had midnight cortisol below 140 nmol/L in large series 5

Morning Cortisol:

• Normal reference range: 5-23 μg/dL (138-635 nmol/L), typically 10-20 μg/dL (276-552 nmol/L) 2
• Morning cortisol alone cannot distinguish mild Cushing's from pseudo-Cushing's states due to significant overlap 4
• Research demonstrates mean morning cortisol of 574 ± 242 nmol/L in Cushing's vs 393 ± 136 nmol/L in excluded patients 5

Critical Pitfalls to Avoid

False Positives:

• Exclude exogenous steroid use (oral prednisolone, dexamethasone, fluticasone inhaler) before testing 2, 6
• Oral contraceptives and topical hydrocortisone elevate cortisol-binding globulin, falsely increasing total cortisol 1, 6
• CYP3A4 inducers (phenobarbital, carbamazepine, St. John's wort) accelerate dexamethasone metabolism, causing false-positive DST 1
• Pseudo-Cushing's states (depression, alcoholism, severe obesity) can cause mild hypercortisolism 1, 6
• Night-shift workers should not undergo LNSC testing due to disrupted circadian rhythm 1

False Negatives:

• Cyclic Cushing's syndrome requires sequential LNSC measurements over weeks to months to capture hypercortisolemic episodes 1, 6
• CYP3A4 inhibitors (fluoxetine, cimetidine, diltiazem) increase dexamethasone levels, causing false-negative DST 1
• Renal impairment (CrCl <60 mL/min) or polyuria (>5 L/24h) invalidates UFC; use LNSC instead 1

Measuring dexamethasone levels concomitantly with cortisol reduces false-positive DST results 1

Management Target for Medical Therapy

For patients on medical therapy, target mean daily serum cortisol between 150-300 nmol/L to normalize cortisol production rate 7

• This range correlates with normal isotopic cortisol production rates (22-83 μmol/24h) 7
• Serial measurements at 0900,1200,1500,1800,2100, and 2400h provide accurate mean daily cortisol 7

Algorithmic Approach to Diagnosis

1. Exclude exogenous glucocorticoid exposure (topical, inhaled, oral preparations) 2, 6
2. Perform 2-3 screening tests (LNSC, UFC, overnight 1-mg DST) to confirm pathologic hypercortisolism 1, 6
3. If screening tests positive, measure morning plasma ACTH to differentiate ACTH-dependent (ACTH >5 ng/L) from ACTH-independent causes 6
4. For cyclic Cushing's, perform sequential LNSC measurements over weeks to months 1, 6
5. Obtain pituitary MRI if ACTH >29 ng/L (70% sensitivity, 100% specificity for Cushing's disease) 6