How do you interpret a cosyntropin (adrenocorticotropic hormone, ACTH) stimulation test?

How to Interpret the Cosyntropin Stimulation Test

Test Protocol and Timing

Administer 0.25 mg (250 mcg) cosyntropin intravenously or intramuscularly, then measure serum cortisol at baseline, 30 minutes, and 60 minutes post-injection. 1

• Obtain a baseline cortisol and ACTH level before administering cosyntropin 2, 1
• The high-dose (250 mcg) test is preferred over the low-dose (1 mcg) test due to easier administration, FDA approval, and comparable diagnostic accuracy 2, 3
• Blood samples must be drawn at exactly 30 and 60 minutes after cosyntropin administration 1

Interpretation Criteria

A peak cortisol level <18 mcg/dL (500 nmol/L) at either 30 or 60 minutes is diagnostic of adrenal insufficiency. 2, 3, 1

Normal Response

• Peak cortisol ≥18-20 mcg/dL (≥500-550 nmol/L) at 30 or 60 minutes indicates normal adrenal function 2, 3, 1
• This threshold applies to both primary and secondary adrenal insufficiency 3

Abnormal Response

• Peak cortisol <18 mcg/dL suggests adrenocortical insufficiency 1
• In critically ill patients, a delta cortisol (change from baseline) <9 mcg/dL may indicate critical illness-related corticosteroid insufficiency (CIRCI) 4, 3, 5

Distinguishing Primary from Secondary Adrenal Insufficiency

The baseline ACTH level, measured before cosyntropin administration, differentiates the etiology:

• Primary adrenal insufficiency: Low baseline cortisol (<9 mcg/dL or <250 nmol/L) with elevated ACTH, plus inadequate cortisol response to cosyntropin 2, 5
• Secondary adrenal insufficiency: Low baseline cortisol with low or inappropriately normal ACTH, plus inadequate cortisol response to cosyntropin 2, 5

The cosyntropin test itself only confirms whether adrenal insufficiency exists—the ACTH level determines whether it is primary (adrenal gland failure) or secondary (pituitary/hypothalamic failure) 2, 5

Critical Pre-Test Considerations

Medications That Invalidate Results

Stop these medications before testing to avoid false results:

• Glucocorticoids and spironolactone: Stop on the day of testing (long-acting glucocorticoids may require longer discontinuation) 1
• Estrogen-containing drugs: Stop 4-6 weeks before testing, as they elevate cortisol-binding globulin and falsely increase total cortisol levels 1
• Exogenous steroids including inhaled corticosteroids (e.g., fluticasone) can interfere with interpretation 2

Conditions Affecting Cortisol-Binding Globulin

Measure cortisol-binding globulin levels if the patient has conditions that alter its concentration:

• Low CBG (cirrhosis, nephrotic syndrome) falsely lowers total cortisol 1
• High CBG (pregnancy, estrogen use) falsely elevates total cortisol 1
• Consider free cortisol measurement if CBG abnormalities are suspected, though this is not routinely necessary 4

Common Pitfalls and How to Avoid Them

The Normal Response Paradox

A "normal" cosyntropin test (peak cortisol >18 mcg/dL) does NOT always exclude secondary adrenal insufficiency, particularly in early or partial ACTH deficiency. 6

• Patients with incomplete ACTH deficiency may have preserved adrenal reserve that responds to supraphysiologic cosyntropin doses but fails during physiologic stress 6
• If clinical suspicion remains high despite a normal test (e.g., unexplained hypotension, hypoglycemia, or symptoms during stress), consider glucocorticoid replacement regardless of test results 7, 6
• A low baseline cortisol (<5 mcg/dL) with clinical features of adrenal insufficiency warrants treatment even if the peak response is "normal" 7

Low-Dose Test Misinterpretation

If a low-dose (1 mcg) test was performed, do not use the standard 18 mcg/dL cutoff—it will produce false positives. 8, 9

• The appropriate cutoff for low-dose testing is approximately 14 mcg/dL, not 18 mcg/dL 8
• Discordant results (abnormal low-dose but normal high-dose test) usually indicate the low-dose test was falsely positive 9
• The high-dose test is more reliable and should be used preferentially 2, 3

Special Clinical Scenarios

Critically Ill Patients

In septic shock or critical illness, either a random cortisol <10 mcg/dL OR a delta cortisol <9 mcg/dL after cosyntropin may indicate CIRCI. 4, 3, 5

• The task force makes no definitive recommendation between these two criteria, as both have limitations 4
• Clinical context is paramount—if the patient has refractory hypotension despite vasopressors, empiric hydrocortisone may be warranted regardless of test results 2

Suspected Adrenal Crisis

Never delay treatment for diagnostic testing if adrenal crisis is suspected. 2, 3, 5

• Administer 100 mg IV hydrocortisone immediately if the patient has unexplained hypotension, hypoglycemia, or shock 2
• Draw baseline cortisol and ACTH before treatment if possible, but do not wait for results 2, 5
• Mortality is high if adrenal crisis goes untreated 2

Distinguishing from SIADH

Adrenal insufficiency must be excluded before diagnosing SIADH, as both present with euvolemic hyponatremia. 2

• Hyponatremia is present in 90% of newly diagnosed adrenal insufficiency cases 2
• The absence of hyperkalemia does not rule out adrenal insufficiency (present in only ~50% of cases) 2
• The cosyntropin test is medically necessary to differentiate these conditions 2

Cushing's Disease Workup

The cosyntropin test is NOT used to diagnose Cushing's disease—it is used to distinguish pituitary from ectopic ACTH sources in ACTH-dependent Cushing's syndrome. 4

• Increased ACTH and cortisol following CRH or desmopressin (not cosyntropin) suggests Cushing's disease rather than ectopic ACTH 4
• Inferior petrosal sinus sampling (IPSS) with CRH or desmopressin stimulation is the gold standard for this distinction 4

Assay-Specific Considerations

Cutoff values may vary depending on the cortisol assay used by your laboratory. 1

• Verify your laboratory's reference range and assay method 1
• Some assays may have different cutoffs for normal adrenal function 1
• Ensure the assay measures cortisol specifically and does not cross-react with synthetic glucocorticoids 2