Should I order Adrenocorticotropic Hormone (ACTH) and cortisol levels?

Should You Order ACTH and Cortisol?

Yes, you should order simultaneous morning (8 AM) ACTH and cortisol levels as the first-line diagnostic test when adrenal insufficiency is suspected, as this paired measurement is essential to distinguish primary from secondary adrenal insufficiency and guide appropriate management. 1

When to Order These Tests

Order morning ACTH and cortisol when patients present with:

• Unexplained hypotension or vasopressor-resistant shock – particularly if requiring multiple vasopressor agents 2
• Hyponatremia with hypo-osmolality – present in 90% of newly diagnosed adrenal insufficiency cases, though adrenal insufficiency can be indistinguishable from SIADH without specific testing 2, 3
• Unexplained fatigue, nausea, vomiting, or weight loss – especially with morning symptoms 2
• History of prolonged corticosteroid use (≥20 mg/day prednisone equivalent for ≥3 weeks) with unexplained symptoms 2
• Patients on immune checkpoint inhibitors with new constitutional symptoms 1
• Pancytopenia with disproportionate constitutional symptoms 3

Critical Timing and Collection Requirements

• Collect both tests simultaneously in the early morning (8 AM) to capture peak physiologic cortisol levels 1
• Include a basic metabolic panel to assess for hyponatremia and hyperkalemia, though the absence of hyperkalemia cannot rule out adrenal insufficiency (present in only ~50% of cases) 2, 3

Interpreting Initial Results

Primary Adrenal Insufficiency Pattern:

• Morning cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH is diagnostic in the setting of acute illness 2, 4
• Morning cortisol <400 nmol/L (<14.5 μg/dL) with elevated ACTH raises strong suspicion 4
• Often accompanied by hyponatremia and hyperkalemia (though hyperkalemia absent in 50% of cases) 2

Secondary Adrenal Insufficiency Pattern:

• Low cortisol with low or inappropriately normal ACTH indicates central/secondary adrenal insufficiency 1
• Hyponatremia may be present, but hyperkalemia is typically absent 2

Indeterminate Results Requiring Further Testing:

• Morning cortisol between 110-300 nmol/L (4-11 μg/dL) requires ACTH stimulation testing for definitive diagnosis 2, 5
• Morning cortisol ≥300 nmol/L (≥11 μg/dL) effectively excludes adrenal insufficiency in non-acute cases 5

When to Proceed to ACTH Stimulation Testing

Order the cosyntropin (ACTH) stimulation test when:

• Morning cortisol is indeterminate (between 110-300 nmol/L) 2, 5
• Clinical suspicion remains high despite borderline normal morning cortisol 2
• Distinguishing adrenal insufficiency from SIADH in hyponatremic patients 2, 3

ACTH Stimulation Test Protocol:

• Administer 0.25 mg (250 μg) cosyntropin IV or IM 1, 6
• Measure cortisol at baseline and 30 minutes (60-minute measurement optional) 1, 6
• Peak cortisol <500 nmol/L (<14-15 μg/dL with newer specific assays) is diagnostic of adrenal insufficiency 2, 6
• Peak cortisol >550 nmol/L (>18-20 μg/dL) is normal 2, 6

Critical Pitfalls to Avoid

Never Delay Treatment for Testing:

If adrenal crisis is suspected (severe hypotension, collapse, severe symptoms), immediately administer IV hydrocortisone 100 mg and 0.9% saline infusion without waiting for test results – mortality is high if untreated 1, 2

Testing Limitations in Specific Scenarios:

• Patients currently on corticosteroids (including prednisone, inhaled fluticasone) will have suppressed cortisol and ACTH due to iatrogenic secondary adrenal insufficiency – testing cannot be accurately interpreted until steroids are discontinued 1, 2
• If you must treat but still want diagnostic confirmation, use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone doesn't interfere with cortisol assays 1, 2
• Wait at least 24 hours after last hydrocortisone dose before testing; other steroids require longer washout periods 2

Don't Rely on Electrolytes Alone:

• Hyperkalemia is absent in ~50% of adrenal insufficiency cases 2, 3
• Some patients have completely normal electrolytes at presentation 2
• Between 10-20% may have mild hypercalcemia 2

Additional Etiologic Testing After Diagnosis

Once adrenal insufficiency is confirmed:

For Primary Adrenal Insufficiency:

• Measure 21-hydroxylase autoantibodies (positive in ~85% of Western cases) 2, 4
• If autoantibodies negative, obtain adrenal CT imaging to evaluate for hemorrhage, tumor, tuberculosis, or other structural causes 2

For Secondary Adrenal Insufficiency:

• Consider MRI brain with pituitary cuts if multiple hormonal deficiencies, severe headaches, or vision changes present 1
• Evaluate other pituitary hormones (TSH, free T4, LH, FSH, testosterone/estrogen) 1

Management Implications

Once diagnosed, patients require:

• Lifelong glucocorticoid replacement (hydrocortisone 15-25 mg daily in divided doses) 2, 4
• Mineralocorticoid replacement with fludrocortisone 50-200 μg daily (primary adrenal insufficiency only) 2, 4
• Education on stress dosing (doubling/tripling dose during illness) 1, 2
• Emergency hydrocortisone 100 mg IM injection kit with self-injection training 2
• Medical alert bracelet indicating adrenal insufficiency 1, 2
• Mandatory endocrinology consultation 1