When should a morning serum cortisol be drawn?

When Should Morning Cortisol Be Measured

Morning serum cortisol should be drawn between 8:00 AM and 9:00 AM, ideally as close to 8:00 AM as possible, to capture the physiological peak of cortisol secretion and allow accurate interpretation using established diagnostic thresholds. 1

Optimal Timing and Rationale

• The test must be performed in the morning (preferably at 8:00 AM) because cortisol follows a strict circadian rhythm with peak levels occurring shortly after awakening. 1, 2
• Samples obtained later in the day will yield falsely low values that cannot be reliably interpreted using standard diagnostic cut-offs, potentially leading to false-positive diagnoses of adrenal insufficiency. 1
• The morning timing is critical because diagnostic thresholds (e.g., <250 nmol/L or <9 μg/dL for primary adrenal insufficiency) were established based on early morning samples. 1, 2

Paired ACTH Measurement

• Always obtain plasma ACTH simultaneously with the morning cortisol sample—this single paired measurement is the first-line diagnostic test for suspected adrenal insufficiency. 1, 2
• The ACTH-cortisol relationship distinguishes primary adrenal insufficiency (high ACTH with low cortisol) from secondary adrenal insufficiency (low or inappropriately normal ACTH with low cortisol). 1, 2

Diagnostic Interpretation Thresholds

• Morning cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH in acute illness is diagnostic of primary adrenal insufficiency. 1
• Morning cortisol <400 nmol/L (<14.5 μg/dL) with elevated ACTH raises strong suspicion and warrants further testing. 1
• Morning cortisol >375 nmol/L (>13.6 μg/dL) predicts adrenal sufficiency with 95% specificity, potentially obviating the need for ACTH stimulation testing in the appropriate clinical context. 3
• Morning cortisol ≤2.6 µg/dL is definitively abnormal and strongly suggests adrenal insufficiency requiring urgent evaluation. 2

Critical Pitfalls to Avoid

• Never attempt morning cortisol measurement in patients actively taking corticosteroids (hydrocortisone, prednisone, prednisolone, or inhaled fluticasone)—the assay measures both endogenous and exogenous steroids, rendering results uninterpretable. 1
• Inhaled corticosteroids such as fluticasone propionate can completely abolish the normal circadian rhythm of cortisol secretion, making morning cortisol measurements meaningless. 4
• Do not rely on morning cortisol alone if the value falls in the indeterminate range (approximately 5-18 μg/dL or 140-500 nmol/L)—proceed directly to ACTH stimulation testing for definitive diagnosis. 1, 2
• Treatment of suspected acute adrenal crisis must NEVER be delayed for diagnostic testing—give IV hydrocortisone 100 mg immediately and draw blood for cortisol and ACTH before treatment only if this does not cause delay. 1, 2

When Morning Cortisol Is NOT Useful

• In patients on established glucocorticoid replacement therapy for confirmed adrenal insufficiency, there is no reason to check cortisol levels—the diagnosis is already established. 1
• In critically ill patients or those with suspected adrenal crisis, clinical assessment and immediate treatment take precedence over diagnostic testing. 1
• For monitoring adequacy of glucocorticoid replacement therapy, clinical assessment (weight, energy, symptoms) is superior to serum cortisol measurements. 5

Special Situations Requiring Modified Approach

• In patients with suspected malabsorption or erratic symptoms despite treatment, a cortisol day curve (measuring cortisol before and 2,4, and 6 hours after the morning hydrocortisone dose) is more useful than a single morning cortisol. 5
• For patients being evaluated after discontinuing exogenous corticosteroids, wait at least 24 hours after the last hydrocortisone dose (longer for other steroids) before attempting morning cortisol measurement. 1
• In patients with hyponatremia and hypo-osmolality, morning cortisol with ACTH is essential to distinguish adrenal insufficiency from SIADH, as both conditions present identically and hyponatremia occurs in 90% of newly diagnosed adrenal insufficiency cases. 1