What is the indication for a morning cortisol test?

Indications for Morning Cortisol Testing

Morning cortisol (drawn at 8:00-9:00 AM) is indicated as the initial screening test when evaluating for suspected adrenal insufficiency or autonomous cortisol hypersecretion, including patients with adrenal incidentalomas, those on immune checkpoint inhibitors, and individuals with clinical features of Cushing's syndrome. 1, 2

Primary Clinical Scenarios Requiring Morning Cortisol

Suspected Adrenal Insufficiency

• Order morning cortisol when patients present with nonspecific symptoms including fatigue (50-95% of cases), nausea/vomiting (20-62%), anorexia, weight loss (43-73%), orthostatic hypotension, or unexplained hyponatremia with hyperkalemia 3, 2
• Patients recently tapering or discontinuing supraphysiological glucocorticoid doses require screening for glucocorticoid-induced adrenal insufficiency 2
• Those on immune checkpoint inhibitor therapy with new symptoms of fatigue, weakness, or electrolyte abnormalities need evaluation for immune-related adrenal insufficiency 3

Screening for Autonomous Cortisol Secretion

• All patients with adrenal incidentalomas must be screened for autonomous cortisol secretion, with the 1 mg dexamethasone suppression test (measuring 8:00 AM cortisol) as the preferred initial test 3, 4
• Patients with clinical features suggesting Cushing's syndrome (weight gain, proximal muscle weakness, wide purple striae, easy bruising, facial plethora) require screening 3

Hypophysitis and Pituitary Disorders

• Patients with suspected hypophysitis (particularly those on immune checkpoint inhibitors) need simultaneous morning ACTH and cortisol measurement to distinguish primary from secondary adrenal insufficiency 3
• Those with known pituitary tumors, pituitary surgery, or radiation therapy require assessment for secondary adrenal insufficiency 2

Critical Timing Requirements

The 8:00-9:00 AM window is mandatory for accurate interpretation because this captures the physiologic peak of cortisol secretion, providing optimal sensitivity (68%) and specificity (100%) for detecting ACTH-dependent hypercortisolism 1

Exceptions to Morning Timing

• Shift workers and patients with disrupted circadian rhythms should NOT have morning cortisol testing, as their cortisol peaks occur at different times and yield unreliable results 1, 4
• For these patients, the 1 mg dexamethasone suppression test is the preferred alternative 4

Diagnostic Interpretation Framework

For Suspected Adrenal Insufficiency

• Morning cortisol <5 µg/dL (<138 nmol/L or <110 nmol/L depending on assay) suggests adrenal insufficiency and warrants further testing 2, 5
• Morning cortisol ≥300 nmol/L (≥10.9 µg/dL) excludes adrenal insufficiency in most cases 5, 6
• Intermediate values (5-10 µg/dL or 138-300 nmol/L) require dynamic testing with ACTH stimulation test 2, 6

Distinguishing Primary vs. Secondary Adrenal Insufficiency

• Simultaneous morning ACTH and cortisol measurement is essential: high ACTH (>1.1 pmol/L) with low cortisol indicates primary adrenal insufficiency, while low ACTH with low cortisol indicates secondary or glucocorticoid-induced adrenal insufficiency 3, 1, 2
• ACTH is extremely labile and requires immediate processing on ice, so coordinate with the laboratory before drawing 1

Common Pitfalls to Avoid

Medications and Physiologic States Affecting Results

• Document all medications affecting corticosteroid binding globulin (CBG): oral estrogens, pregnancy, and chronic active hepatitis increase total cortisol levels and can lead to false interpretation 1
• CYP3A4 inducers or inhibitors affect dexamethasone metabolism and can cause false results in suppression testing 4
• Patients on corticosteroids for other conditions will have low morning cortisol due to iatrogenic secondary adrenal insufficiency, making diagnosis challenging 3

Stress and Activity Considerations

• Recent physical or mental stress significantly elevates cortisol; patients should avoid strenuous exercise for 24-48 hours before testing and should not undergo cognitive assessments immediately before blood draw 1
• Never interpret a single cortisol value without knowing the exact time of collection, as the same value may be normal at 9:00 AM but pathologically elevated at midnight 1

When Morning Cortisol Alone Is Insufficient

Morning cortisol serves as a screening test but often requires confirmatory dynamic testing 2, 6:

• Values in the intermediate range (approximately 5-10 µg/dL) necessitate ACTH stimulation testing 2, 6
• For suspected Cushing's syndrome, additional tests including late-night salivary cortisol, 24-hour urinary free cortisol, or dexamethasone suppression testing are needed 3, 4
• When clinical suspicion remains high despite normal morning cortisol, proceed with dynamic testing 5, 6