What does a cortisol level indicate?

Understanding Cortisol Level Measurements

A cortisol level test measures the amount of cortisol hormone in your blood, urine, or saliva to evaluate adrenal gland function and screen for conditions like Cushing's syndrome or adrenal insufficiency, with interpretation depending on the time of collection, sample type, and assay method used. 1

Types of Cortisol Measurements

Serum (Blood) Cortisol

• Morning serum cortisol: Primary screening tool for adrenal function
  • Normal range: ≥300 nmol/L (≥10.8 μg/dL) typically excludes adrenal insufficiency
  • <110 nmol/L (<4 μg/dL) suggests adrenal insufficiency
  • Values between 110-300 nmol/L require further testing 2
• Measures total cortisol (bound + free)
• Affected by changes in cortisol-binding globulin (CBG) levels
• May be misleading in patients with altered serum protein concentrations 3

Late Night Salivary Cortisol (LNSC)

• Measures free (unbound) cortisol
• Used to assess loss of normal circadian rhythm in Cushing's syndrome
• Most specific test for Cushing's syndrome (>90% sensitivity) 1
• Sampling at bedtime rather than midnight may decrease false positives
• Not recommended for night-shift workers or those with disrupted sleep cycles 1

24-Hour Urinary Free Cortisol (UFC)

• Measures free cortisol excreted in urine over 24 hours
• Reflects overall cortisol production independent of CBG changes
• At least 2-3 collections recommended due to high variability (up to 50%)
• Less reliable in patients with renal impairment or significant polyuria 1

Dynamic Testing

Overnight Dexamethasone Suppression Test (DST)

• Evaluates feedback inhibition of the hypothalamic-pituitary-adrenal axis
• Normal response: serum cortisol <1.8 μg/dL (50 nmol/L) at 8 AM after 1 mg dexamethasone at bedtime
• Negative result strongly predicts absence of Cushing's syndrome
• Values >5 μg/dL (138 nmol/L) may indicate Cushing's syndrome 1

ACTH Stimulation Test

• Used to diagnose adrenal insufficiency
• High-dose (250-μg) ACTH test preferred over low-dose (1-μg) test 1
• Traditional cutoff of 500 nmol/L may need adjustment with newer, more specific assays
• With newer assays (e.g., Roche Cortisol II), a cutoff of 350 nmol/L is more appropriate 4

Clinical Interpretation Considerations

Factors Affecting Cortisol Levels

• Time of day: Cortisol follows a circadian rhythm (highest in morning, lowest at midnight)
• Stress: Acute illness, trauma, surgery can increase cortisol levels
• Medications: Oral estrogens, certain anticonvulsants, and many other drugs can affect results
• Protein levels: Changes in CBG or albumin affect total but not free cortisol 1

Diagnostic Patterns

• Primary adrenal insufficiency: Low cortisol, high ACTH, electrolyte abnormalities (↓Na, ↑K)
• Secondary adrenal insufficiency: Low cortisol, low ACTH, usually normal electrolytes
• Cushing's syndrome: Elevated cortisol, loss of circadian rhythm, failed suppression with dexamethasone 2, 5

Common Pitfalls in Cortisol Testing

1. Ignoring collection timing: Cortisol levels vary throughout the day; morning samples are highest
2. Single measurements: Due to variability, multiple samples are often needed
3. Assay differences: Immunoassays may lack specificity compared to LC-MS/MS methods 3
4. Not accounting for medication effects: Many drugs can interfere with cortisol levels or testing
5. Misinterpreting total cortisol: In conditions with altered binding proteins, free cortisol measurements may be more accurate 1

Best Practices for Cortisol Testing

• Choose the appropriate test based on the suspected diagnosis
• Consider time of day when interpreting results
• Use multiple measurements when possible
• Be aware of assay-specific reference ranges
• Consider factors that might affect binding proteins when interpreting total cortisol
• For Cushing's syndrome screening, late-night salivary cortisol and overnight DST have highest sensitivity 1
• For adrenal insufficiency, morning serum cortisol and ACTH stimulation test are most informative 2

By understanding the various cortisol measurement methods and their clinical implications, clinicians can more accurately diagnose and monitor conditions affecting the hypothalamic-pituitary-adrenal axis.