Hydrocortisone vs Cortisone Acetate for Isolated ACTH Deficiency
For isolated ACTH deficiency, hydrocortisone 15-20 mg daily in divided doses (typically 10 mg upon awakening and 5 mg at noon) is the preferred glucocorticoid replacement because it best recreates the physiological diurnal cortisol rhythm, though cortisone acetate 25-37.5 mg daily in divided doses is an acceptable alternative that requires hepatic conversion to active hydrocortisone. 1, 2
Preferred Agent: Hydrocortisone
Hydrocortisone is the first-line glucocorticoid for secondary adrenal insufficiency because it most closely mimics physiological cortisol secretion when given in divided doses. 2
The standard maintenance regimen is 15-25 mg daily in 2-3 divided doses, with common schedules including 10 mg at 07:00 + 5 mg at 12:00 + 2.5 mg at 16:00, or simply 10 mg at 07:00 + 5 mg at 12:00. 1, 2
For patients with isolated ACTH deficiency specifically, lower doses (15-20 mg daily) are often sufficient, as these patients may have partial rather than complete cortisol deficiency. 2, 3
Research demonstrates that conventional full-dose replacement (20 mg twice daily) produces supraphysiological cortisol peaks in patients with partial ACTH deficiency, whereas lower doses (10 mg morning/5 mg afternoon) produce a 24-hour cortisol profile that most closely resembles healthy controls. 4, 5
Alternative Agent: Cortisone Acetate
Cortisone acetate 25-37.5 mg daily in divided doses is an acceptable alternative when hydrocortisone is unavailable or not tolerated. 1, 6
The typical dosing is 25 mg daily (mean 0.35 mg/kg) for replacement therapy in isolated ACTH deficiency. 3
Cortisone acetate is a pro-drug that requires hepatic conversion to active hydrocortisone, which may result in less predictable cortisol levels in patients with hepatic dysfunction. 1
Starting doses should be 20-30 mg for cortisone acetate, divided into two or three doses. 6
Critical Dosing Principles
The first dose must be taken immediately upon awakening (before 9 AM) to mimic the physiological morning cortisol peak. 2, 7
The last dose should be taken no later than 4-6 hours before bedtime to avoid insomnia and maintain the normal diurnal rhythm. 2, 7
Weight-adjusted dosing is preferred: approximately 0.30 mg/kg for hydrocortisone or 0.35 mg/kg for cortisone acetate. 3, 6
Mineralocorticoid Considerations
Patients with isolated ACTH deficiency (secondary adrenal insufficiency) do NOT require fludrocortisone because the renin-angiotensin-aldosterone system remains intact and mineralocorticoid production is preserved. 2, 3, 8
This is a critical distinction from primary adrenal insufficiency (Addison's disease), where fludrocortisone 50-200 µg daily is mandatory. 1, 6
Monitoring and Dose Adjustment
Clinical assessment is the primary monitoring tool—plasma ACTH and serum cortisol measurements are not useful for dose titration in patients on established replacement therapy. 2
Signs of over-replacement include weight gain, insomnia, peripheral edema, hypertension, and hyperglycemia. 2, 7
Signs of under-replacement include lethargy, morning nausea, poor appetite, weight loss, and persistent fatigue. 1, 2, 7
For patients with morning nausea or lack of appetite, waking earlier to take the first dose and then returning to sleep may relieve symptoms. 1, 7
Drug Interactions Requiring Dose Adjustment
CYP3A4 inducers increase hydrocortisone clearance and may require higher doses: phenytoin, carbamazepine, phenobarbital, rifampin, other antituberculosis drugs. 1, 2
CYP3A4 inhibitors decrease hydrocortisone clearance and may require dose reduction: grapefruit juice and licorice. 1, 2
Essential Patient Education
All patients must receive education on stress dosing: double or triple the usual dose during illness, fever, or physical stress. 1, 2
Patients should be prescribed a hydrocortisone 100 mg IM injection kit with self-injection training for emergency use during acute adrenal crisis. 1, 2
Every patient must wear a medical alert bracelet or necklace indicating adrenal insufficiency to trigger emergency stress-dose administration by healthcare providers. 1, 2
Patients need explicit instruction on when to seek immediate medical attention: severe vomiting, diarrhea, inability to take oral medications, or signs of impending adrenal crisis (severe weakness, confusion, hypotension). 9, 1
Common Pitfalls to Avoid
Never use synthetic long-acting glucocorticoids (prednisone, prednisolone, dexamethasone) as first-line therapy for chronic replacement in isolated ACTH deficiency—these agents have undesirable metabolic long-term effects and cannot recreate the diurnal cortisol rhythm. 6
Do not delay treatment in suspected acute adrenal crisis for diagnostic testing—if the patient presents with unexplained hypotension, collapse, or severe vomiting, give 100 mg IV hydrocortisone immediately plus rapid saline infusion. 1
Avoid starting thyroid hormone replacement before or simultaneously with glucocorticoid replacement in patients with concurrent hypothyroidism—corticosteroids must be started several days first to prevent precipitating adrenal crisis. 9, 1
Do not rely on electrolyte abnormalities to guide diagnosis or dosing—hyponatremia may be present but hyperkalemia is typically absent in secondary adrenal insufficiency. 1