Clinical Use of ACTH Stimulation Testing
The ACTH stimulation test (also called cosyntropin or Synacthen test) is the diagnostic gold standard for confirming primary adrenal insufficiency by measuring the adrenal glands' ability to produce cortisol in response to synthetic ACTH administration. 1
Primary Diagnostic Application
The test serves as confirmatory testing for primary adrenal insufficiency (PAI) when clinical suspicion exists based on symptoms or initial laboratory findings. The Endocrine Society strongly recommends this test when patients present with:
- Volume depletion or hypotension
- Hyponatremia or hyperkalemia
- Unexplained fever or abdominal pain
- Hyperpigmentation
- Hypoglycemia (especially in children)
- Fatigue, anorexia, or weight loss 1
Test Protocol and Interpretation
The standard protocol uses 250 μg of synthetic ACTH (cosyntropin) administered intravenously or intramuscularly, with cortisol measurements at baseline and 30 or 60 minutes post-injection. 1
Key Technical Points:
- The 250 μg standard dose has superior validation compared to the 1 μg low-dose test, which does not provide better diagnostic accuracy despite being more physiologic 1
- The test can be performed at any time of day without concern for diurnal variation 1
- Peak stimulated cortisol concentration is the critical interpretive value
- Sensitivity for primary adrenal insufficiency is 92% (95% CI: 81-97%) 1, 2
Critical Limitation: Not for Secondary Adrenal Insufficiency
The ACTH stimulation test is NOT the gold standard for diagnosing secondary (central) adrenal insufficiency. 1 In secondary AI, the adrenal glands may still respond to exogenous ACTH despite pituitary dysfunction, leading to false-negative results. Both high-dose and low-dose tests show low sensitivity and high specificity for secondary AI, making them adequate to rule in but not rule out this condition 2.
Glucocorticoid-Induced Adrenal Insufficiency
For patients tapering off chronic glucocorticoid therapy, morning cortisol levels can effectively stratify risk:
- Morning cortisol >310-350 nmol/L (>11.2-12.6 μg/dL) excludes glucocorticoid-induced AI with 98% sensitivity 3
- Morning cortisol <124-152 nmol/L (<4.5-5.5 μg/dL) confirms AI with 97-98% specificity 3
- Intermediate values require ACTH stimulation testing for definitive diagnosis
When to Test Immediately vs. Treat First
In patients with suspected adrenal crisis or severe symptoms, immediately administer IV hydrocortisone at stress doses WITHOUT waiting for test results. 1 Draw baseline ACTH and cortisol before giving steroids, but never delay life-saving treatment. Confirmatory testing can be performed later after temporary cessation of glucocorticoids.
The diagnostic sequence should be:
- Draw baseline ACTH and cortisol if time permits
- Administer hydrocortisone immediately if critically ill
- Perform confirmatory ACTH stimulation test when stable
Important Caveats
Rare conditions can severely distort test results:
- Cortisol-binding globulin (CBG) deficiency
- Glucocorticoid resistance
- Glucocorticoid hypersensitivity 1
Timing considerations: Some patients, particularly those who are overweight or obese, may peak at 30 minutes, while normal or underweight individuals tend to peak at 60 minutes. Measuring cortisol at both 30 and 60 minutes prevents overdiagnosis of AI 4.
Baseline Laboratory Clues
Before performing the stimulation test, baseline findings highly suggestive of PAI include:
- Morning cortisol <140 nmol/L (5 μg/dL) PLUS
- Plasma ACTH elevated >2-fold above upper limit of normal
- ACTH >66 pmol/L represents maximal stimulus for cortisol secretion 1
When these baseline values are absolutely unequivocal, the stimulation test may not be necessary for diagnosis 1.
Not Routinely Used For
The ACTH stimulation test is not standard practice for: