When should cortisol levels be checked?

When to Check Cortisol Levels

Cortisol levels should be checked in patients with clinical features suggestive of cortisol disorders, including those with adrenal incidentalomas, suspected Cushing's syndrome, or adrenal insufficiency, using appropriate screening tests based on the suspected condition. 1

Screening for Hypercortisolism (Cushing's Syndrome)

Clinical Indications for Testing

• Patients with unexplained:

  • Weight gain with central obesity
  • Facial plethora, moon faces
  • Purple striae (>1 cm wide)
  • Easy bruising
  • Proximal muscle weakness
  • Hypertension with hypokalemia
  • Diabetes mellitus
  • Menstrual irregularities
  • Osteoporosis or fragility fractures
  • Depression or sleep disturbances 1

• In children and adolescents:

  • Unexplained weight gain WITH growth rate deceleration or height centile decrement
  • This combination has high sensitivity and specificity for Cushing's syndrome 1

First-Line Screening Tests

1. Late-night salivary cortisol (LNSC)

   • Collect at bedtime or midnight
   • At least 2-3 samples recommended
   • Sensitivity: 95%, Specificity: 100% 1, 2, 3

2. 1 mg overnight dexamethasone suppression test (DST)

   • Dexamethasone 1 mg at 11 PM, measure serum cortisol at 8 AM
   • Normal response: cortisol <1.8 μg/dL (50 nmol/L)
   • Sensitivity: >95%, Specificity: 80% 1

3. 24-hour urinary free cortisol (UFC)

   • Collect at least 2-3 samples
   • Sensitivity: 89%, Specificity: 100% 1

Screening for Adrenal Incidentalomas

When to Screen

• All patients with adrenal incidentalomas should be screened for autonomous cortisol secretion 1

Recommended Tests

• 1 mg DST is the preferred screening test 1
• Interpretation:
  • <50 nmol/L: excludes cortisol hypersecretion
  • 51-138 nmol/L: possible autonomous cortisol secretion

  • 138 nmol/L: evidence of cortisol hypersecretion 1

Screening for Adrenal Insufficiency

Clinical Indications for Testing

• Fatigue, weakness, weight loss
• Nausea, vomiting, abdominal pain
• Hypotension, hyperpigmentation (primary AI)
• Recent discontinuation of glucocorticoid therapy
• Patients on immune checkpoint inhibitor therapy 1, 4, 5

Recommended Tests

• Early-morning (8 AM) serum cortisol and ACTH levels

  • Primary AI: Low cortisol (<5 μg/dL), high ACTH
  • Secondary AI: Low cortisol, low or normal ACTH 4, 5

• ACTH stimulation test for indeterminate results

  • Measure cortisol before and 60 minutes after cosyntropin (250 μg)
  • Normal response: cortisol >18-20 μg/dL 1, 4

Special Considerations

Ectopic ACTH Production

• Check cortisol levels in patients with small cell lung cancer or bronchial carcinoid with:
  • Hypertension with hypokalemia
  • Metabolic alkalosis
  • Peripheral edema
  • Skin hyperpigmentation 1

Potential False Results

• False positive DST results may occur with:

  • Medications affecting CYP3A4 (phenobarbital, carbamazepine)
  • Increased CBG levels (oral estrogens, pregnancy)
  • Rapid absorption/malabsorption of dexamethasone 1

• False negative DST results may occur with:

  • Medications inhibiting dexamethasone metabolism (fluoxetine, cimetidine)
  • Decreased CBG levels (nephrotic syndrome) 1

Avoid Testing In

• Night-shift workers (for LNSC)
• Patients with acute illness (unless adrenal crisis suspected)
• Patients currently taking exogenous glucocorticoids (unless testing for adrenal suppression) 1, 5

Important Pitfalls to Avoid

1. Never rely on a single test - use at least two different screening methods for Cushing's syndrome
2. Consider pseudo-Cushing's states - psychiatric disorders, alcohol use disorder, and obesity can activate the HPA axis
3. Rule out exogenous glucocorticoid use before biochemical testing for Cushing's syndrome
4. Measure dexamethasone levels with cortisol during DST to ensure proper absorption
5. Consider renal function when interpreting UFC (avoid in CrCl <60mL/min)

By following these guidelines, clinicians can appropriately screen for cortisol disorders, leading to earlier diagnosis and improved patient outcomes.