What's the next step in evaluating a patient with low cortisol and low Adrenocorticotropic hormone (ACTH) levels, but normal levels of all other pituitary hormones?

Next Diagnostic Step: ACTH Stimulation Test

In a patient with low cortisol and low ACTH but normal other pituitary hormones, the next essential test is the ACTH stimulation test (cosyntropin/Synacthen test) to confirm secondary (central) adrenal insufficiency and assess the adrenal glands' capacity to respond to stimulation. 1

Why ACTH Stimulation Testing is Necessary

• Low ACTH with low cortisol defines secondary adrenal insufficiency, distinguishing it from primary adrenal insufficiency where ACTH would be elevated 2, 1
• Morning cortisol that is neither clearly normal (>450 nmol/L or >16 μg/dL) nor clearly diagnostic (<250 nmol/L or <9 μg/dL) requires dynamic testing to definitively rule in or rule out adrenal insufficiency 1
• A morning cortisol of 140-275 nmol/L (5-10 μg/dL) with low or inappropriately normal ACTH is the classic pattern for secondary adrenal insufficiency, but confirmation is needed before committing to lifelong replacement therapy 3

ACTH Stimulation Test Protocol

Standard High-Dose Test (Recommended)

• Administer 0.25 mg (250 mcg) cosyntropin intramuscularly or intravenously 1
• Obtain baseline serum cortisol and ACTH before administration 1
• Measure serum cortisol at 30 and/or 60 minutes post-injection 1
• Peak cortisol <500-550 nmol/L (<18-20 μg/dL) is diagnostic of adrenal insufficiency 1, 3
• Peak cortisol >550 nmol/L (>18-20 μg/dL) is considered normal 1

Why High-Dose Over Low-Dose

• The high-dose test is preferred due to easier practical administration, comparable diagnostic accuracy, and FDA approval 1
• The low-dose (1 mcg) test requires bedside dilution of commercial preparation, making it less practical for routine use 1

Critical Pre-Test Considerations

Medication Review

• Stop all exogenous corticosteroids before testing, as they suppress the HPA axis and cause false results 1, 3
• Hydrocortisone must be held for 24 hours; prednisone and other steroids require longer washout periods 1
• Inhaled corticosteroids (particularly fluticasone) and topical steroids can also suppress the HPA axis and confound testing 3
• If the patient is on dexamethasone, it does not cross-react with cortisol assays but still suppresses ACTH 3

When Testing Cannot Be Done Safely

• If the patient is clinically unstable or has suspected adrenal crisis, never delay treatment for diagnostic testing 1, 3
• In such cases, give IV hydrocortisone 100 mg immediately plus 0.9% saline infusion 1
• If you need to treat but still want diagnostic capability later, use dexamethasone 4 mg IV instead, as it doesn't interfere with cortisol assays 1

Additional Workup to Perform Concurrently

Imaging Studies

• Obtain MRI brain with pituitary/sellar cuts in patients with multiple endocrine abnormalities, new severe headaches, or vision changes to identify structural causes of hypopituitarism 2, 3
• This is particularly important given isolated ACTH deficiency with normal other pituitary hormones, as it may indicate a focal pituitary lesion, hypophysitis, or infiltrative process 2, 4

Laboratory Assessment

• Basic metabolic panel to check for hyponatremia (present in 90% of adrenal insufficiency cases) 1, 3
• Do not rely on electrolyte abnormalities alone—hyperkalemia is absent in secondary adrenal insufficiency, and hyponatremia may be mild or absent 1, 3
• Repeat morning (8 AM) paired ACTH and cortisol to verify the pattern 3

Assess for Underlying Causes

• Detailed medication history including any glucocorticoid exposure (oral, inhaled, topical, injected) that could cause iatrogenic secondary adrenal insufficiency 1, 3
• Consider immune checkpoint inhibitor therapy as a cause of hypophysitis if relevant 2, 3
• In isolated ACTH deficiency, consider testing for anti-pituitary antibodies, though this is rare 5

Common Pitfalls to Avoid

• Do not assume adrenal insufficiency is ruled out based on normal electrolytes alone—secondary AI typically does not cause hyperkalemia since mineralocorticoid function is preserved 1, 3
• Do not perform testing while patient is on corticosteroids—wait until weaned off or opt for empiric replacement and test for ongoing need at 3 months 1
• Do not start thyroid hormone replacement before or simultaneously with glucocorticoid replacement if both deficiencies are present—always start corticosteroids several days before thyroid hormone to prevent precipitating adrenal crisis 1, 6

If ACTH Stimulation Test Confirms Adrenal Insufficiency

Immediate Management

• Initiate hydrocortisone 15-20 mg daily in divided doses (typically 10 mg at 7 AM and 5-10 mg at noon or early afternoon) 1, 6
• Secondary adrenal insufficiency does NOT require mineralocorticoid (fludrocortisone) replacement since the renin-angiotensin-aldosterone system remains intact 1

Patient Education (Critical)

• All patients need education on stress dosing (doubling or tripling doses during illness, fever, or physical stress) 1, 6
• Provide emergency injectable hydrocortisone 100 mg IM kit with self-injection training 1
• Medical alert bracelet or necklace indicating adrenal insufficiency is mandatory to trigger stress-dose corticosteroids by emergency personnel 2, 1, 6

Endocrine Consultation

• Early endocrinology referral is appropriate for optimization of replacement therapy and long-term management 2, 3
• Consultation is particularly important before surgery or high-stress treatments 2