During a cosyntropin (synthetic ACTH) stimulation test, should a plasma ACTH sample also be collected?

Should ACTH Be Collected During a Cosyntropin Stimulation Test?

Yes, plasma ACTH should be collected at baseline during a cosyntropin stimulation test when evaluating for adrenal insufficiency, as it is essential for distinguishing primary from secondary adrenal insufficiency and is specifically recommended by clinical practice guidelines. 1

Rationale and Clinical Algorithm

When to Collect ACTH

The Endocrine Society Clinical Practice Guideline explicitly recommends measuring plasma ACTH to establish primary adrenal insufficiency (PAI), stating that the sample can be obtained at the same time as the baseline sample in the corticotropin test 1. This is a strong recommendation (Grade 1QQQE).

Diagnostic Value of ACTH Measurement

ACTH measurement serves critical diagnostic purposes:

• Distinguishes primary from secondary adrenal insufficiency: In confirmed cortisol deficiency, a plasma ACTH ≥2-fold the upper limit of normal is consistent with primary adrenal insufficiency 1
• Highly predictive when paired with low cortisol: A low cortisol (<140 nmol/L or 5 μg/dL) combined with elevated ACTH indicates the adrenal cortex cannot respond to ACTH stimulation and is highly predictive for PAI 1
• Detects early-stage disease: An elevated ACTH with normal-range cortisol can be the first sign of early-stage primary adrenal insufficiency 1

Specific ACTH Thresholds

• Maximum adrenal stimulation occurs at ACTH >300 ng/L (66 pmol/L) 1
• PAI diagnosis: ACTH ≥2× upper limit of reference range in the setting of confirmed cortisol deficiency 1
• Caveat: ACTH assays have significant analytical variability, so interpretation must use laboratory-specific reference ranges 1

Practical Implementation

Timing of Collection

• Obtain the ACTH sample at baseline (time 0) before administering cosyntropin 1, 2
• Can alternatively be paired with a morning cortisol sample if not doing stimulation testing 1
• The FDA label for cosyntropin does not mandate ACTH collection but focuses on cortisol measurement at 0,30, and 60 minutes 2

Sample Handling

• Use plasma (not serum) for ACTH measurement 1
• ACTH is labile and requires proper collection technique with immediate processing

Clinical Decision-Making

If you confirm cortisol deficiency on the cosyntropin test:

• Elevated ACTH (≥2× upper limit) → Primary adrenal insufficiency
• Low or inappropriately normal ACTH → Secondary adrenal insufficiency (pituitary/hypothalamic cause)

Without ACTH measurement, you cannot distinguish between these two fundamentally different etiologies, which have different:

• Treatment implications (mineralocorticoid replacement needed only in primary AI)
• Underlying causes requiring investigation
• Associated autoimmune conditions (in primary AI)

Important Caveats

• Assay variability: ACTH assays demonstrate significant analytical bias, so always interpret results using your laboratory's specific reference ranges 1
• Not needed for diagnosis confirmation alone: The cosyntropin test itself confirms adrenal insufficiency; ACTH determines the etiology 1
• Additional testing: In primary AI, also measure plasma renin and aldosterone simultaneously to assess mineralocorticoid deficiency 1

Bottom line: Collect baseline plasma ACTH during every cosyntropin stimulation test. It adds minimal cost and effort but provides essential diagnostic information that cannot be reliably obtained later and directly impacts patient management.