When is ordering an Adrenocorticotropic Hormone (ACTH) stimulation test or an AM (Ante Meridiem) cortisol level recommended?

When to Order AM Cortisol Level and ACTH Stimulation Test

AM cortisol level should be ordered as the initial screening test for suspected adrenal insufficiency, while the ACTH stimulation test should be performed for indeterminate AM cortisol results or when clinical suspicion remains high despite normal AM cortisol. 1

Initial Screening with AM Cortisol

When to Order AM Cortisol:

• In patients with symptoms suggestive of adrenal insufficiency:
  • Unexplained fatigue, weight loss, hypotension
  • Nausea, vomiting, abdominal pain
  • Hyperpigmentation (primary adrenal insufficiency)
  • Hyponatremia, hyperkalemia, hypoglycemia
• In patients on immune checkpoint inhibitor therapy who develop symptoms of adrenal insufficiency
• In patients with adrenal incidentalomas to screen for autonomous cortisol secretion
• As part of the evaluation of suspected hypophysitis

Interpretation of AM Cortisol Results:

• AM cortisol <110 nmol/L (<4 μg/dL): Highly suggestive of adrenal insufficiency 2
• AM cortisol >300 nmol/L (>10.8 μg/dL): Generally excludes adrenal insufficiency in unstressed patients 2
• AM cortisol between 110-300 nmol/L (4-10.8 μg/dL): Indeterminate; requires ACTH stimulation test 1

ACTH Stimulation Test

When to Order ACTH Stimulation Test:

• When AM cortisol results are indeterminate (between 110-300 nmol/L)
• When clinical suspicion for adrenal insufficiency remains high despite normal AM cortisol
• To distinguish between primary and secondary adrenal insufficiency
• To confirm the diagnosis of adrenal insufficiency before initiating long-term treatment
• In patients with suspected adrenal insufficiency due to immune checkpoint inhibitors 1

Test Protocol:

1. Measure baseline cortisol and ACTH levels
2. Administer 250 μg synthetic ACTH intravenously
3. Measure cortisol levels at 30 and 60 minutes post-administration
4. Peak cortisol <500 nmol/L (<18 μg/dL) confirms adrenal insufficiency 1

Important Considerations

Primary vs. Secondary Adrenal Insufficiency:

• Primary adrenal insufficiency: High ACTH, low cortisol
• Secondary adrenal insufficiency: Low/normal ACTH, low cortisol 1

Pitfalls to Avoid:

• Never delay treatment of suspected acute adrenal insufficiency for diagnostic testing 1
• Morning cortisol should be drawn between 7:30-8:00 AM to capture the peak of the diurnal rhythm 3
• Patients on exogenous corticosteroids will have suppressed morning cortisol levels, making interpretation difficult 1
• Drugs affecting the HPA axis should be stopped before testing (if possible) 3
• In patients with suspected hypophysitis, ACTH stimulation may give false-negative results early in the disease process 1

Special Situations:

• For patients on corticosteroids for other conditions, AM cortisol testing is not reliable until the medication has been discontinued for an appropriate washout period 1
• In critically ill patients, a random cortisol <250 nmol/L with elevated ACTH is diagnostic of primary adrenal insufficiency 1
• In patients with suspected intermittent hypercortisolism, late-night salivary cortisol may be more informative than AM cortisol 4

By following this algorithmic approach to testing, clinicians can efficiently diagnose adrenal insufficiency while minimizing unnecessary testing and avoiding delays in treatment for patients with acute adrenal crisis.