What cortisol level would be concerning?

What Cortisol Level Would Be Concerning?

A morning serum cortisol <275 nmol/L (<10 μg/dL) is concerning and warrants further investigation with ACTH stimulation testing, while a post-dexamethasone suppression test cortisol >50 nmol/L (>1.8 μg/dL) is concerning for Cushing's syndrome. 1

Context-Dependent Thresholds for Concerning Cortisol Levels

For Suspected Adrenal Insufficiency (Low Cortisol)

Morning (8 AM - 12 PM) samples:

• Cortisol <275 nmol/L (<10 μg/dL) requires ACTH stimulation testing to rule out adrenal insufficiency, as this threshold identifies subnormal adrenal function with 96.2% sensitivity 2
• Cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH in acute illness is diagnostic of primary adrenal insufficiency 3
• Cortisol <400 nmol/L (<14.5 μg/dL) with elevated ACTH in acute illness raises strong suspicion of adrenal insufficiency 3

Afternoon (12 PM - 6 PM) samples in outpatients:

• Cortisol <250 nmol/L (<9 μg/dL) warrants ACTH stimulation testing with 96.1% sensitivity 2

Post-ACTH stimulation (30-60 minutes after 0.25 mg cosyntropin):

• Peak cortisol <500 nmol/L (<18 μg/dL) is diagnostic of adrenal insufficiency 1, 3
• Peak cortisol >550 nmol/L (>20 μg/dL) is considered normal 3

For Suspected Cushing's Syndrome (High Cortisol)

Post-dexamethasone suppression test (1 mg at bedtime, cortisol measured at 8 AM):

• Cortisol >50 nmol/L (>1.8 μg/dL) is concerning and suggests failure to suppress, indicating possible Cushing's syndrome 1
• Cortisol >138 nmol/L (>5 μg/dL) is highly suggestive of autonomous cortisol production from an adrenal incidentaloma with overt Cushing's syndrome 1

Late-night salivary cortisol:

• Values above the upper limit of normal (ULN) indicate loss of normal circadian rhythm and are concerning for Cushing's syndrome; at least 2-3 tests are recommended 1

24-hour urinary free cortisol:

• Values above the upper limit of normal on 2-3 collections suggest Cushing's syndrome, though this test has the lowest sensitivity among screening tests 1

Midnight serum cortisol:

• Cortisol ≥50 nmol/L (≥1.8 μg/dL) at midnight (while sleeping) has 100% sensitivity for Cushing's syndrome in children and young people 1

Critical Clinical Pitfalls

Never delay treatment for testing in suspected adrenal crisis:

• If a patient presents with unexplained hypotension, collapse, or gastrointestinal symptoms (vomiting/diarrhea), immediately administer IV hydrocortisone 100 mg and 0.9% saline infusion without waiting for cortisol results 3
• Hyponatremia is present in 90% of newly diagnosed adrenal insufficiency cases, but absence of hyperkalemia (present in only ~50% of cases) cannot rule out the diagnosis 3

Factors that confound cortisol interpretation:

• Increased cortisol-binding globulin (CBG) from oral estrogens, pregnancy, or chronic hepatitis falsely elevates total serum cortisol 1
• Decreased CBG from nephrotic syndrome or malnutrition falsely lowers total serum cortisol 1
• CYP3A4 inducers (phenobarbital, carbamazepine, St. John's wort) accelerate dexamethasone metabolism, causing false-positive suppression tests 1
• Exogenous steroids including inhaled fluticasone can suppress the HPA axis and confound results 3

Time of day matters:

• Morning cortisol measurements (8 AM - 12 PM) are most reliable for initial screening 3, 2
• The 30-minute post-ACTH cortisol response is constant regardless of time of day or basal cortisol level, making it the optimal measurement point 4
• Afternoon ACTH stimulation tests show higher early responses (5 and 15 minutes) but equivalent 30-minute values compared to morning tests 4

Assay-specific considerations:

• The thresholds provided are based on immunoassay methods; LC-MS/MS assays may require different cut-offs that are not yet fully validated 5
• Always interpret results using your laboratory's specific reference ranges and assay method 1