Is a random cortisol level sufficient to assess adrenal function?

Random Cortisol Testing for Adrenal Function Assessment

Random cortisol testing alone is not sufficient to assess adrenal function and should be replaced by early morning serum cortisol measurement followed by confirmatory testing with a cosyntropin stimulation test when results are inconclusive. 1

Diagnostic Approach for Adrenal Insufficiency

Initial Testing

• Early morning serum cortisol (8am-12pm) is the recommended first-line screening test 1
• Morning cortisol thresholds have established clinical utility:

  • 300 nmol/L (>10.8 μg/dL): Generally excludes adrenal insufficiency 2, 3

  • <110 nmol/L (<4 μg/dL): Highly suggestive of adrenal insufficiency 2
  • Values between 110-300 nmol/L: Require confirmatory testing 2, 3

Confirmatory Testing

• The cosyntropin (synthetic ACTH) stimulation test is the standard confirmatory test 1
• A peak cortisol level >18-20 μg/dL (>500-550 nmol/L) after cosyntropin administration is considered a normal response 1
• The Endocrine Society recommends the high-dose (250-μg) ACTH stimulation test as superior to other tests for diagnosing primary adrenal insufficiency 4

Limitations of Random Cortisol Testing

• Random cortisol levels fail to account for the diurnal variation of cortisol secretion 1
• Cortisol levels are naturally highest in the early morning and lowest in the evening
• Random sampling may lead to false positives (when sampled in the evening) or false negatives (when sampled during stress)
• The 2017 Society of Critical Care Medicine and European Society of Intensive Care Medicine guidelines specifically make no recommendation regarding using random plasma cortisol of <10 μg/dl for diagnosing Critical Illness-Related Corticosteroid Insufficiency (CIRCI) 4

Evidence Quality and Considerations

• The most recent and comprehensive guidelines from the Endocrine Society (reflected in the Praxis Medical Insights) strongly recommend morning cortisol testing followed by confirmatory testing 1
• Multiple validation studies support using morning cortisol as a screening tool with specific cutoff values:
  • Woods et al. (2019) validated a morning cortisol threshold of <275 nmol/L to identify subnormal stimulated cortisol with 96.2% sensitivity 3
  • Yo et al. (2020) found a morning cortisol cutoff of 234.2 nmol/L with 83.3% sensitivity and 89.1% specificity 5

Clinical Algorithm for Adrenal Function Assessment

1. Measure early morning (8am-12pm) serum cortisol
2. Interpret results:
   • If >300 nmol/L (>10.8 μg/dL): Adrenal insufficiency unlikely
   • If <110 nmol/L (<4 μg/dL): Adrenal insufficiency likely
   • If 110-300 nmol/L: Proceed to confirmatory testing
3. Perform cosyntropin stimulation test (250 μg)
4. Interpret stimulation test:
   • Peak cortisol >18-20 μg/dL (>500-550 nmol/L): Normal adrenal function
   • Peak cortisol <18 μg/dL (<500 nmol/L): Adrenal insufficiency confirmed

Common Pitfalls to Avoid

• Relying solely on random cortisol measurements can lead to misdiagnosis
• Failing to consider the timing of cortisol measurement relative to its diurnal variation
• Not measuring ACTH levels simultaneously with cortisol to differentiate between primary and secondary adrenal insufficiency 1
• Delaying treatment in suspected adrenal crisis while waiting for test results (hydrocortisone 100 mg IV should be administered immediately) 1
• Missing secondary adrenal insufficiency when the standard cosyntropin test is falsely normal 1

In conclusion, while random cortisol testing is convenient, it lacks the diagnostic accuracy needed for proper assessment of adrenal function. Early morning cortisol testing followed by appropriate confirmatory testing remains the standard approach for evaluating suspected adrenal insufficiency.