What is the role of Adrenocorticotropic hormone (ACTH) stimulation tests in primary adrenal insufficiency (AI)?

ACTH Stimulation Testing in Primary Adrenal Insufficiency

The ACTH stimulation test is the gold standard confirmatory test for primary adrenal insufficiency when basal cortisol levels are indeterminate (between 100-450 nmol/L or 3.6-16.3 μg/dL), but it is unnecessary when basal morning cortisol is <100 nmol/L with elevated ACTH (diagnostic) or >450 nmol/L (excludes AI). 1, 2

When ACTH Stimulation Testing is Required

Indeterminate basal cortisol levels mandate confirmatory testing:

• Basal cortisol 100-450 nmol/L (3.6-16.3 μg/dL) requires ACTH stimulation testing to definitively diagnose or exclude adrenal insufficiency 2, 3
• This "gray zone" represents approximately 60% of patients tested for suspected AI, where dynamic testing provides critical diagnostic clarity 2

When ACTH Stimulation Testing Can Be Avoided

High diagnostic accuracy of extreme basal values eliminates need for dynamic testing in nearly 40% of cases:

• Basal cortisol ≤100 nmol/L (≤3.6 μg/dL) with elevated ACTH has 93.2% positive predictive value for primary AI—diagnosis confirmed without stimulation testing 2
• Basal cortisol ≥450 nmol/L (≥16.3 μg/dL) has 98.7% negative predictive value—excludes AI without further testing 2
• Morning cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH in acute illness is diagnostic of primary AI 1

Test Protocol and Interpretation

Use the high-dose (250 μg) cosyntropin test with standardized timing:

• Administer 250 μg cosyntropin (tetracosactide) intramuscularly or intravenously 1
• Measure serum cortisol at baseline and 30 minutes (60-minute measurement adds minimal diagnostic value) 1, 2
• Peak cortisol <500-550 nmol/L (<18-20 μg/dL) is diagnostic of adrenal insufficiency 1
• Peak cortisol >550 nmol/L (>20 μg/dL) is normal and excludes AI 1

The high-dose test is preferred over low-dose (1 μg) testing:

• Both tests have similar diagnostic accuracy (likelihood ratio 9.1 vs 5.9 for high vs low dose in adults) 4
• High-dose testing is easier to perform, requires no bedside dilution, and is FDA-approved 4, 1
• Low-dose testing requires dilution of commercial preparations, making it impractical for routine use 4

Critical Timing Considerations

Basal cortisol measured between 0900-1300h has superior diagnostic performance compared to strict morning (0800h) testing:

• Basal cortisol at 0900-1300h has AUC of 0.82 versus 0.69 for morning cortisol 3
• This flexibility improves practicality without sacrificing diagnostic accuracy 3
• Using basal cortisol with proposed cut-offs can eliminate approximately 30% of ACTH stimulation tests 3

Distinguishing Primary from Secondary AI

ACTH levels differentiate primary from secondary adrenal insufficiency:

• Primary AI: Low cortisol with high ACTH (>2x upper limit of normal) 1
• Secondary AI: Low cortisol with low or inappropriately normal ACTH 1
• This distinction is critical as primary AI requires both glucocorticoid and mineralocorticoid replacement, while secondary AI requires only glucocorticoid replacement 1, 5

Common Pitfalls to Avoid

Never delay treatment for diagnostic testing in suspected adrenal crisis:

• If patient is hemodynamically unstable with suspected adrenal crisis, immediately administer IV hydrocortisone 100 mg plus 0.9% saline infusion 1
• Draw blood for cortisol and ACTH before treatment if possible, but do not delay therapy 1
• If diagnosis uncertain and you need to preserve ability to test later, use dexamethasone 4 mg IV instead of hydrocortisone (does not interfere with cortisol assays) 1

Exogenous steroids confound testing:

• Prednisolone, inhaled fluticasone, and other exogenous steroids suppress the HPA axis and invalidate test results 1
• Patients on chronic steroids (≥20 mg/day prednisone equivalent for ≥3 weeks) should be presumed to have secondary AI until proven otherwise 1

Electrolyte abnormalities are unreliable for diagnosis:

• Hyponatremia occurs in 90% of primary AI cases, but hyperkalemia is present in only ~50% 1
• Normal electrolytes do not exclude adrenal insufficiency—10-20% of patients have normal sodium and potassium at presentation 1

Technical Factors Affecting Accuracy

Assay methodology and sample handling impact results:

• Different cortisol assays have varying cut-off values—use site-specific reference ranges 6, 2
• Time of day affects basal cortisol but not stimulated values in the ACTH test 6
• Clinical context (likelihood of AI before testing) must inform interpretation of borderline results 6