What is the role of the Cosyntropin (Adrenocorticotropic hormone, ACTH) Stimulation Test in diagnosing and managing a patient with suspected adrenal insufficiency characterized by symptoms such as fatigue, weight loss, and hypotension?

Cosyntropin Stimulation Test in Suspected Adrenal Insufficiency

The cosyntropin stimulation test is the gold standard confirmatory test when initial cortisol and ACTH measurements are equivocal, using 0.25 mg (250 mcg) cosyntropin IV or IM with cortisol measured at 30 and/or 60 minutes—a peak cortisol <500 nmol/L (<18 mcg/dL) confirms adrenal insufficiency. 1, 2

When to Perform the Test

The cosyntropin stimulation test is indicated in the following scenarios:

• Equivocal morning cortisol values: When morning (8 AM) serum cortisol is neither clearly normal (>500 nmol/L) nor clearly diagnostic (<250 nmol/L), the test definitively rules in or rules out adrenal insufficiency 1, 3
• Suspected secondary adrenal insufficiency: When morning cortisol is 140-275 nmol/L (5-10 μg/dL) with low or inappropriately normal ACTH, the test is necessary to confirm the diagnosis 3
• Hyponatremia workup: The test is medically necessary to distinguish adrenal insufficiency from SIADH, as both present with identical euvolemic hypo-osmolar hyponatremia and the absence of hyperkalemia cannot exclude adrenal insufficiency 3

Critical Caveat: Never Delay Treatment for Testing

If the patient is clinically unstable with suspected acute adrenal crisis (hypotension, collapse, vomiting), give 100 mg IV hydrocortisone immediately plus 0.9% saline at 1 L/hour—do NOT wait for diagnostic testing. 1, 3 Blood samples for cortisol and ACTH can be drawn before treatment if possible, but treatment must never be delayed 1

Standard Test Protocol

The recommended protocol follows these steps:

• Dose: Administer 0.25 mg (250 mcg) cosyntropin intramuscularly or intravenously 1, 3
• Timing: Obtain baseline serum cortisol and ACTH before administration, then measure serum cortisol at 30 and/or 60 minutes post-injection 1, 3
• Time of day: Preferably perform in the morning, though not strictly necessary 3

Interpretation of Results

Diagnostic Thresholds

• Normal response: Peak cortisol >500-550 nmol/L (>18-20 μg/dL) at either 30 or 60 minutes excludes adrenal insufficiency 1, 3
• Diagnostic of adrenal insufficiency: Peak cortisol <500 nmol/L (<18 μg/dL) confirms the diagnosis 1, 3
• Acute illness context: Basal cortisol <250 nmol/L with elevated ACTH is diagnostic of primary adrenal insufficiency; basal cortisol <400 nmol/L with elevated ACTH raises strong suspicion 1, 3

Assay-Specific Considerations

Be aware that cortisol cutoffs vary by immunoassay method—monoclonal antibody-based assays (Abbott Architect, Roche Elecsys II) require lower thresholds (14.6 μg/dL for Abbott at 60 minutes) compared to the historical 18 μg/dL cutoff for polyclonal assays. 4 Using outdated cutoffs with newer assays leads to false-positive results and overtreatment 4

Test Performance Characteristics

• Primary adrenal insufficiency: The 250 mcg test has 97% sensitivity at 95% specificity, making it highly reliable 5
• Secondary adrenal insufficiency: The test has only 57% sensitivity at 95% specificity, with a positive likelihood ratio of 11.5 and negative likelihood ratio of 0.45 5
• Low-dose (1 mcg) vs high-dose (250 mcg): Both tests have similar diagnostic accuracy for secondary adrenal insufficiency (likelihood ratios 5.9 vs 9.1), but the high-dose test is recommended due to easier practical administration and FDA approval 3, 5, 6

Common Pitfalls to Avoid

Exogenous Steroid Interference

Do not perform the test in patients currently taking corticosteroids—exogenous steroids suppress the HPA axis and cause false-positive results showing "adrenal insufficiency" that simply reflects expected iatrogenic suppression. 3 Specific considerations:

• Hydrocortisone: Must be held for 24 hours before testing 3
• Prednisone and other steroids: Require longer washout periods; wait until the patient has been weaned off corticosteroids before performing definitive testing 3
• Dexamethasone exception: If you must treat suspected adrenal crisis but still want diagnostic testing later, use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone does not interfere with cortisol assays 3

Drug Interactions

• Inhaled steroids (fluticasone) can suppress the HPA axis and confound results 1, 3
• Medications increasing hydrocortisone requirements: Anti-epileptics, antituberculosis drugs, antifungals, etomidate, topiramate 3
• Grapefruit juice and liquorice: Decrease hydrocortisone requirements and should be avoided before testing 3

Clinical Context Matters

The test performs poorly in patients on chronic prednisone—approximately one-third to one-half of patients taking 5-20 mg prednisolone daily fail the test despite having adequate adrenal reserve. 3 In cases of ongoing steroid use with clinical uncertainty, opt for empiric glucocorticoid replacement and retest for ongoing need at 3 months rather than attempting diagnostic testing while on steroids 3

Management After Diagnosis

If Test Confirms Adrenal Insufficiency

• Glucocorticoid replacement: Hydrocortisone 15-25 mg daily in divided doses (typically 10 mg at 7 AM, 5 mg at noon, 2.5-5 mg at 4 PM) or prednisone 4-5 mg daily 1, 3
• Mineralocorticoid replacement (primary adrenal insufficiency only): Fludrocortisone 50-200 µg daily, adjusted based on blood pressure, salt cravings, and plasma renin activity 1, 3
• Patient education: All patients require instruction on stress dosing (doubling or tripling dose during illness), medical alert bracelet, and emergency injectable hydrocortisone 100 mg IM kit with self-injection training 1, 3
• Mandatory endocrine consultation: For newly diagnosed patients, pre-operative planning, and any patient with recurrent adrenal crises 3

Establishing Etiology After Diagnosis

Once adrenal insufficiency is confirmed, determine the cause:

• First step: Measure 21-hydroxylase (anti-adrenal) autoantibodies, as autoimmunity accounts for ~85% of primary adrenal insufficiency cases 1, 3
• If antibodies negative: Obtain adrenal CT imaging to evaluate for hemorrhage, metastatic disease, tuberculosis, or other structural abnormalities 1, 3
• In male patients: Assay very long-chain fatty acids to check for adrenoleukodystrophy 1, 3

Annual Screening for Associated Conditions

Patients with confirmed adrenal insufficiency require ongoing surveillance:

• Thyroid function: TSH, FT4, and TPO antibodies every 12 months, as hypothyroidism and thyrotoxicosis frequently develop 1
• Diabetes screening: Plasma glucose and HbA1c annually 1
• Vitamin B12: Annual monitoring for pernicious anemia due to autoimmune gastritis 1
• Celiac disease: Tissue transglutaminase 2 autoantibodies and total IgA in patients with frequent or episodic diarrhea 1