What is the management approach for a patient with low Adrenocorticotropic hormone (ACTH) levels?

Management of Low ACTH Levels

Low ACTH with low cortisol is diagnostic of secondary adrenal insufficiency and requires lifelong glucocorticoid replacement therapy with hydrocortisone 15-25 mg daily in divided doses, along with mandatory patient education on stress dosing and medical alert identification. 1, 2

Diagnostic Confirmation

Before initiating treatment, confirm the diagnosis with:

• Morning (8 AM) paired measurements of serum cortisol and plasma ACTH to establish the pattern of secondary adrenal insufficiency (low ACTH with low cortisol) 3, 2
• Basic metabolic panel to assess for hyponatremia, which occurs in 90% of newly diagnosed cases, though hyperkalemia is typically absent in secondary adrenal insufficiency 3, 2
• ACTH stimulation test if morning cortisol falls in the indeterminate range (5-18 mcg/dL or 140-500 nmol/L): administer 0.25 mg cosyntropin IV or IM with cortisol measured at baseline, 30, and 60 minutes—peak cortisol <18 mcg/dL (<500 nmol/L) confirms adrenal insufficiency 3, 2

Evaluate for Underlying Etiology

Once secondary adrenal insufficiency is confirmed, investigate the cause:

• Assess other pituitary hormones: TSH, free T4, LH, FSH, testosterone (males) or estradiol (premenopausal females) to identify hypopituitarism 4, 1
• MRI of the brain with pituitary/sellar cuts if multiple endocrine abnormalities are present, or if patient has new severe headaches or vision changes 4, 1
• Review medication history for exogenous corticosteroids (prednisone, inhaled fluticasone), opioids, or immune checkpoint inhibitors that can cause iatrogenic secondary adrenal insufficiency 4, 3, 5

Critical pitfall: Patients on corticosteroids will have suppressed morning cortisol and ACTH—this is expected iatrogenic suppression, not a new diagnosis. Do not attempt diagnostic testing until corticosteroids have been discontinued with adequate washout time. 3

Treatment Algorithm Based on Severity

Grade 1: Asymptomatic or Mild Symptoms

• Initiate hydrocortisone 10-20 mg orally in the morning and 5-10 mg in early afternoon to mimic physiological cortisol rhythm 4, 1, 2
• Alternative regimens include hydrocortisone 15+5 mg, 10+10 mg, or 10+5+5 mg depending on symptom patterns 3
• If concurrent hypothyroidism exists, start corticosteroids several days before initiating levothyroxine to prevent precipitating adrenal crisis 4, 1
• Consider endocrine consultation for optimization 1

Grade 2: Moderate Symptoms (Able to Perform ADLs)

• Initiate outpatient treatment at 2-3 times maintenance dose: hydrocortisone 30-50 mg total daily or prednisone 20 mg daily 3, 2
• Taper stress-dose corticosteroids down to maintenance doses over 5-10 days once symptoms stabilize 1

Grade 3-4: Severe Symptoms or Adrenal Crisis

• Immediate treatment with IV hydrocortisone 100 mg bolus (or dexamethasone 4 mg if diagnosis uncertain and stimulation testing still needed) 4, 3, 2
• Infuse 0.9% normal saline at 1 L/hour (at least 2 liters total) for volume resuscitation 4, 2
• Never delay treatment for diagnostic procedures if patient is clinically unstable with suspected adrenal crisis 3, 2
• Taper stress-dose corticosteroids down to maintenance doses over 7-14 days after discharge 4, 1

Mandatory Patient Education and Safety Measures

All patients with secondary adrenal insufficiency require:

• Stress dosing education: Double or triple usual dose during illness, fever, injury, or significant physical stress 3, 2, 5
• Emergency injectable hydrocortisone 100 mg IM kit with self-injection training for use during vomiting, severe illness, or inability to take oral medications 3, 2, 5
• Medical alert bracelet or necklace indicating adrenal insufficiency to trigger stress-dose corticosteroids by emergency medical services 4, 1, 2
• Endocrine consultation prior to surgery or any procedure for stress-dose planning 4, 1

Important Medication Considerations

• CYP3A4 inducers (anticonvulsants, rifampin, barbiturates) increase cortisol clearance and may require higher replacement doses 3
• CYP3A4 inhibitors (grapefruit juice, liquorice) decrease cortisol clearance and may require lower doses—patients should avoid these 3
• Hydrocortisone is preferred over long-acting steroids (dexamethasone, betamethasone) because it allows recreation of diurnal cortisol rhythm 3, 6

Long-Term Monitoring

• Annual review with assessment of health, well-being, weight, blood pressure, and serum electrolytes 3
• Periodic screening for new autoimmune disorders, particularly hypothyroidism, as autoimmune conditions frequently coexist 3
• Follow free T4 (not TSH) for thyroid hormone replacement titration in patients with concurrent central hypothyroidism, as TSH is unreliable 4, 1

Critical distinction: Secondary adrenal insufficiency does NOT require mineralocorticoid (fludrocortisone) replacement because the renin-angiotensin-aldosterone system remains intact—only glucocorticoid replacement is needed. 3, 5, 7