What does an 8 am serum cortisol of 556 nmol/L indicate and what are the appropriate next diagnostic steps to evaluate for Cushing’s syndrome?

Interpretation of Morning Cortisol 556 nmol/L

A morning cortisol of 556 nmol/L (approximately 20 μg/dL) falls within the normal reference range and does not indicate Cushing's syndrome on its own. 1

Understanding the Result

• The optimal morning serum cortisol in healthy individuals ranges from 138–635 nmol/L (5–23 μg/dL), with most values concentrated between 276–552 nmol/L (10–20 μg/dL). 1
• Your value of 556 nmol/L sits at the upper end of normal but remains within the established reference range. 1
• A single elevated-normal morning cortisol is not diagnostic of hypercortisolism because morning cortisol naturally peaks at this time due to circadian rhythm, and values can reach the upper limit in healthy individuals. 1, 2

Critical Distinction: Screening vs. Diagnosis

Morning cortisol alone is not a screening test for Cushing's syndrome because:

• Normal morning cortisol levels show significant overlap between healthy individuals and those with mild Cushing's syndrome. 3, 4
• The hallmark of Cushing's syndrome is loss of normal circadian rhythm—specifically, failure to suppress cortisol at midnight—not an elevated morning value. 5, 3
• Patients with proven Cushing's syndrome may have morning cortisol values within or only slightly above the normal range. 4

Appropriate Next Steps if Cushing's Syndrome is Suspected

If clinical features suggest hypercortisolism (central obesity, proximal muscle weakness, wide purple striae, easy bruising, facial plethora), proceed with proper screening tests:

First-Line Screening (obtain 2–3 measurements of each test)

1. Late-night salivary cortisol (LNSC) collected at 11 PM–midnight

   • Abnormal threshold: >3.6 nmol/L (>0.1 μg/dL) 6, 1
   • Sensitivity 92–100%, specificity 93–100% 1, 3
   • This test captures the loss of circadian rhythm, which is the physiologic hallmark of Cushing's syndrome 3

2. 24-hour urinary free cortisol (UFC) on 2–3 separate collections

   • Abnormal threshold: >100 μg/24 hours (>1.6 μmol/24 hours) 1
   • Must verify complete collection by measuring total volume and creatinine excretion 1
   • Accounts for 50% random variability between collections 1

3. Overnight 1-mg dexamethasone suppression test (DST)

   • Give 1 mg dexamethasone at 11 PM–midnight, measure cortisol at 8 AM 1
   • Abnormal threshold: cortisol ≥1.8 μg/dL (≥50 nmol/L); values >5 μg/dL (138 nmol/L) indicate overt Cushing's syndrome 1
   • Consider measuring dexamethasone levels concomitantly to exclude false-positive results from abnormal drug metabolism 1

Diagnostic Algorithm After Screening

If ≥2 screening tests are abnormal:

• Measure 9 AM plasma ACTH to determine ACTH-dependent vs. ACTH-independent disease 6, 7
  • ACTH >5 pg/mL indicates ACTH-dependent (pituitary or ectopic source) 6, 7
  • ACTH <5 pg/mL or undetectable indicates ACTH-independent (adrenal source) 6, 7
  • ACTH >29 pg/mL has 70% sensitivity and 100% specificity for Cushing's disease (pituitary adenoma) 6, 7

For ACTH-dependent disease:

• Obtain pituitary MRI with thin slices (3T preferred) 6
• If adenoma ≥10 mm: presume Cushing's disease and proceed to surgery 6
• If no adenoma or lesion <6 mm: perform bilateral inferior petrosal sinus sampling (BIPSS) at a specialized center 6
  • BIPSS diagnostic criteria: central-to-peripheral ACTH ratio ≥2:1 baseline or ≥3:1 after CRH/desmopressin stimulation 6

For ACTH-independent disease:

• Obtain adrenal CT or MRI to identify adrenal lesion(s) 6

Common Pitfalls to Avoid

• Do not pursue Cushing's workup based solely on a single morning cortisol value, even if at the upper limit of normal. 1, 2
• Exclude all exogenous glucocorticoid sources before testing: oral steroids, inhaled fluticasone, topical hydrocortisone, intra-articular/epidural injections, and over-the-counter supplements. 1
• Recognize pseudo-Cushing's states that can cause mildly elevated cortisol: severe obesity, depression, alcoholism, polycystic ovary syndrome, and uncontrolled diabetes. 1
• Account for medications affecting test interpretation: oral contraceptives/estrogens increase cortisol-binding globulin and falsely elevate total cortisol; CYP3A4 inducers accelerate dexamethasone metabolism causing false-positive DST. 1
• Obtain multiple measurements (2–3 of each screening test) to account for intra-patient variability and detect cyclic Cushing's syndrome, which can produce weeks of normal cortisol interspersed with hypercortisolism. 1, 4

When No Further Testing is Needed

If clinical suspicion for Cushing's syndrome is low and the morning cortisol of 556 nmol/L was obtained for another reason (e.g., evaluating adrenal insufficiency), no further hypercortisolism workup is indicated. 1 Morning cortisol >386 nmol/L (>14 μg/dL) effectively rules out adrenal insufficiency. 1