What is Cosyntropin and How Does It Work in a Stim Test?
Cosyntropin is a synthetic peptide consisting of the first 24 amino acids of natural ACTH (adrenocorticotropic hormone) that directly stimulates the adrenal cortex to produce cortisol, and in a stimulation test, it assesses whether the adrenal glands can respond appropriately to maximal stimulation. 1, 2
What Cosyntropin Is
Cosyntropin (also known as tetracosactide or Synacthen) is a synthetic analog of ACTH that contains only the biologically active N-terminal portion of the full 39-amino acid ACTH molecule 1. The key advantage is that the first 24 amino acids retain full corticosteroidogenic activity while having minimal immunologic activity, unlike natural ACTH which contains the highly antigenic C-terminal portion (amino acids 22-39) 2. This makes cosyntropin safer with less risk of allergic reactions compared to natural ACTH preparations.
The molecular weight is 2933 g/mol, and it's supplied as a sterile lyophilized powder containing 0.25 mg per vial 2.
How the Stimulation Test Works
The Mechanism
When administered, cosyntropin binds to melanocortin-2 receptors on the adrenal cortex and provides maximal stimulation equivalent to 25 units of natural ACTH 1. A dose of 0.25 mg (250 μg) produces maximum secretion of cortisol from healthy adrenal glands 2. The test essentially bypasses the hypothalamic-pituitary axis and directly challenges the adrenal glands' capacity to produce cortisol.
Standard Test Protocol
The corticotropin stimulation test is the diagnostic gold standard for primary adrenal insufficiency 1. The standard protocol involves:
- Baseline cortisol measurement before cosyntropin administration
- Administration of 250 μg cosyntropin via IV or IM bolus injection 1
- Cortisol measurement at 30 and/or 60 minutes post-injection 1
- Peak cortisol >500 nmol/L (18 μg/dL) traditionally indicates adequate adrenal function 1
The test can be performed at any time of day since results are not significantly affected by diurnal variations 1, which is a practical advantage over morning cortisol measurements alone.
Interpretation Framework
For primary adrenal insufficiency (PAI), the test has 92% sensitivity 1. A normal response (peak cortisol >500 nmol/L or 18 μg/dL) essentially excludes PAI. However, assay-specific cutoffs are critical—newer immunoassays may require different thresholds, with some evidence suggesting 15.6 μg/dL may be more appropriate to reduce false positives 3.
Important caveats:
- The test is most validated for primary adrenal insufficiency, not secondary 1
- Results must be interpreted alongside plasma ACTH levels (>2-fold upper limit suggests primary AI) 1
- Conditions affecting cortisol-binding globulin (CBG)—such as oral contraceptives, nephrotic syndrome, or liver disease—can significantly alter results 1
Low-Dose Alternative
A 1 μg low-dose test exists but provides no better diagnostic accuracy than the standard 250 μg dose for primary AI 1. The low-dose test should only be used when cosyntropin is in short supply 1. Notably, the low-dose test may have higher sensitivity for secondary adrenal insufficiency 1, though this remains controversial.
Critical Clinical Considerations
Drug Interactions
Stop these medications before testing 2:
- Glucocorticoids and spironolactone on the day of testing (may falsely elevate cortisol)
- Estrogen-containing drugs 4-6 weeks before testing (elevate CBG and total cortisol)
When to Skip the Test
In acutely ill patients with suspected adrenal crisis, immediately administer IV hydrocortisone at stress doses without waiting for test results 1. Draw baseline ACTH and cortisol before giving steroids if possible, but never delay treatment. Confirmatory testing can be performed later after temporary cessation of hydrocortisone.
Limitations in Critical Illness
The cosyntropin test's utility in critically ill patients is highly controversial 4, 5. Sepsis, malnutrition, altered protein binding, and ICU medications can all affect baseline cortisol levels and blunt the response to stimulation 4. Current evidence does not support using the cosyntropin test to guide steroid therapy in critical illness 5.
Glucocorticoid-Induced AI
For patients tapering off chronic glucocorticoids, morning cortisol alone may be sufficient in many cases 6:
- Morning cortisol >310-350 nmol/L (>11.2-12.6 μg/dL) excludes AI with 98-100% sensitivity 6
- Morning cortisol <124-152 nmol/L (<4.5-5.5 μg/dL) confirms AI with 97-100% specificity 6
The cosyntropin test adds confirmatory value when morning cortisol falls in the intermediate range.