At what time should serum cortisol levels be measured to diagnose adrenal insufficiency?

From the Guidelines

Serum cortisol should be drawn in the early morning, ideally between 7-9 AM, to diagnose adrenal insufficiency. This timing is crucial because cortisol levels follow a diurnal pattern, with peak levels occurring in the early morning and lowest levels at night, as noted in the context of diagnosing adrenal insufficiency 1. A morning cortisol level below 5 μg/dL (138 nmol/L) strongly suggests adrenal insufficiency, while levels above 15 μg/dL (414 nmol/L) generally rule it out. For values between 5-15 μg/dL, further testing with an ACTH stimulation test is recommended, considering the guidelines for the diagnosis and treatment of primary adrenal insufficiency 1.

The patient should avoid taking exogenous glucocorticoids before testing as they can suppress cortisol production and interfere with results, a consideration also relevant when managing patients on immune checkpoint inhibitor therapy 1. If the patient is critically ill or if testing must be done at other times of day, interpretation should be adjusted accordingly. Blood should be collected before administering any stress doses of steroids in emergency situations, though treatment should not be delayed if adrenal crisis is suspected, emphasizing the importance of prompt action in potential adrenal crisis situations 1.

Key considerations include:

• The timing of the test is important because misinterpreting a normal afternoon cortisol as low could lead to misdiagnosis, while missing a truly low morning cortisol could leave adrenal insufficiency undetected.
• Patients on corticosteroids for other conditions may require special consideration, including potentially holding hydrocortisone for 24 hours before assessing endogenous function, as discussed in the management of immune-related adverse events 1.
• Education on stress dosing, use of emergency steroid injectables, and recognition of impending adrenal crisis is crucial for patients with adrenal insufficiency, highlighting the need for comprehensive patient education and management plans 1.

From the FDA Drug Label

Obtain blood sample for baseline serum cortisol. Obtain blood samples again for assessment of cortisol levels exactly 30 minutes and 60 minutes after administration of cosyntropin for injection.

Serum cortisol should be drawn at the following times to diagnose adrenal insufficiency:

• Baseline: before administration of cosyntropin for injection
• 30 minutes: after administration of cosyntropin for injection
• 60 minutes: after administration of cosyntropin for injection 2

From the Research

Diagnosing Adrenal Insufficiency

To diagnose adrenal insufficiency, serum cortisol levels can be drawn at various times. The optimal timing for drawing serum cortisol is as follows:

• Morning serum cortisol is a useful first-step diagnostic test in patients with clinically suspected adrenal insufficiency 3
• Basal cortisol levels can be used to predict adrenal insufficiency, with a level of ≥450 nmol/L having a negative predictive value of 98.7% to rule out adrenal insufficiency, and a level of ≤100 nmol/L having a positive predictive value of 93.2% to rule in adrenal insufficiency 4
• A basal morning serum cortisol level of >285 nmol/L can be used to diagnose adrenal insufficiency with 100% sensitivity and 61% specificity, while a level of >98 nmol/L can exclude adrenal insufficiency with 100% specificity 5

Key Findings

Some key findings related to diagnosing adrenal insufficiency include:

• The area under the curve values of morning serum cortisol to predict adrenal insufficiency at +30 minutes, +60 minutes, or at maximal cortisol response were 0.874,0.897, and 0.925, respectively 3
• The use of assay-specific cutoffs is essential for reducing misclassification and overtreatment in patients with suspected adrenal insufficiency 6
• The low-dose adrenocorticotropic hormone (ACTH) stimulation test has been shown to be more sensitive and specific than the high-dose test, but the high-dose test is preferred since the low-dose test has not been validated 7

Diagnostic Thresholds

Diagnostic thresholds for adrenal insufficiency using different assays include:

• An optimized threshold for cortisol using the Abbott Architect immunoassay of 14.6 μg/dL at 60 minutes after stimulation (sensitivity, 92%; specificity, 96%) 6
• A threshold of 18 μg/dL for the level of cortisol at 60 minutes after ACTH stimulation for polyclonal antibody-based immunoassays 6