Indications for Cortisol Testing
Cortisol testing should be ordered when clinical features suggest either cortisol excess (Cushing's syndrome) or deficiency (adrenal insufficiency), with specific high-risk scenarios requiring immediate evaluation.
Clinical Scenarios Requiring Cortisol Testing
Suspected Adrenal Insufficiency (Primary or Secondary)
Order cortisol testing in patients presenting with:
- Unexplained collapse, hypotension, vomiting, or diarrhea 1
- Hyperpigmentation (suggests primary adrenal insufficiency) 1
- Electrolyte abnormalities: hyponatremia, hyperkalaemia, or acidosis 1
- Hypoglycemia, particularly in children but also in adults 1
- Unexplained fatigue, weight loss, or weakness with supporting laboratory findings 1
Additional clinical features that increase suspicion include mild eosinophilia, lymphocytosis, increased liver transaminases, and mild-to-moderate hypercalcemia (10-20% of patients) 1.
Critical Illness-Related Corticosteroid Insufficiency (CIRCI)
In critically ill patients, consider cortisol testing when:
- Patients are in septic shock requiring vasopressor support 1
- There is refractory hypotension despite adequate fluid resuscitation 1
- Clinical suspicion exists for inadequate cortisol response to critical illness 1
Important caveat: The Surviving Sepsis Campaign guidelines suggest NOT using the ACTH stimulation test to select patients with septic shock for hydrocortisone treatment, as treatment decisions should be based on clinical criteria rather than test results 1.
Suspected Cushing's Syndrome
Test for cortisol excess in patients with:
- Multiple and progressive features compatible with Cushing's syndrome, particularly those with high discriminatory value 2
- Adrenal incidentaloma discovered on imaging 2, 3
- Features such as easy bruising, proximal muscle weakness, wide purple striae, or unexplained osteoporosis 2
Adrenal Incidentalomas
All patients with incidentally discovered adrenal masses require:
- 1 mg overnight dexamethasone suppression test to exclude autonomous cortisol secretion, using a cut-off of serum cortisol ≤50 nmol/L (1.8 μg/dL) 3
- This testing is mandatory even in asymptomatic patients to identify "autonomous cortisol secretion" (formerly called subclinical Cushing's syndrome) 3
Immune Checkpoint Inhibitor Therapy
Screen for adrenal insufficiency in cancer patients receiving ICIs when:
- Morning serum cortisol falls within the grey zone (83-414 nmol/L) 4
- Clinical symptoms suggest adrenal insufficiency during or after ICI treatment 4
- Early identification is crucial to prevent life-threatening consequences 4
Post-Adrenalectomy for Mild Autonomous Cortisol Secretion
Postoperative cortisol assessment is indicated:
- On postoperative day 1 with morning cortisol levels 5
- When preoperative plasma ACTH <7.0 pg/mL or cortisol >4.2 μg/dL on low-dose dexamethasone test (independent predictors of need for steroid replacement) 5
Common Pitfalls to Avoid
Do not delay treatment for diagnostic testing in suspected acute adrenal insufficiency—treatment should never be postponed while awaiting test results 1. In acute presentations with suspected adrenal crisis, draw blood for cortisol and ACTH, then immediately administer hydrocortisone.
Recognize that "normal" cortisol may be inadequate: In patients with sepsis or acute illness, serum cortisol within the normal range may be inappropriately low for the disease state 1. A cortisol <250 nmol/L with increased ACTH in acute illness is diagnostic of primary adrenal insufficiency, while cortisol <400 nmol/L raises strong suspicion 1.
Consider confounding medications: Exogenous steroids (oral prednisolone, dexamethasone) and inhaled steroids (fluticasone) may confound interpretation of low serum cortisol levels 1.
Timing matters for interpretation: Morning cortisol (8 AM-12 PM) has different thresholds than afternoon samples (12 PM-6 PM) for predicting adrenal insufficiency 6. A morning cortisol <275 nmol/L or afternoon cortisol <250 nmol/L identifies subnormal-stimulated cortisol with >96% sensitivity 6.