For a 26‑year‑old woman with isolated ACTH deficiency already on physiologic hydrocortisone, should chronic replacement be with hydrocortisone or methylprednisolone, and what is the appropriate peri‑operative stress‑dose regimen?

Hydrocortisone for Chronic Replacement in Isolated ACTH Deficiency

For a 26-year-old woman with isolated ACTH deficiency, hydrocortisone 15–25 mg daily in divided doses is the definitive choice for chronic glucocorticoid replacement, not methylprednisolone. 1, 2

Why Hydrocortisone Over Methylprednisolone

Hydrocortisone is the only glucocorticoid that recreates the physiological diurnal cortisol rhythm and provides appropriate glucocorticoid activity at replacement doses. 2 Methylprednisolone is a synthetic intermediate-acting corticosteroid used for pharmacologic immunosuppression, not physiologic replacement. 3

Optimal Hydrocortisone Dosing Regimen

• Give 15–25 mg hydrocortisone daily in 2–3 divided doses, with the first dose immediately upon awakening and the last dose 4–6 hours before bedtime. 1, 2
• Common effective regimens include 10 mg at 07:00 + 5 mg at 12:00 + 2.5–5 mg at 16:00, or alternatively 15 mg at 07:00 + 5 mg at 12:00. 2
• The morning dose should be taken immediately upon waking to mimic the physiological cortisol peak. 2

Why Mineralocorticoid Replacement Is Not Needed

• Isolated ACTH deficiency is secondary (central) adrenal insufficiency, where the renin-angiotensin-aldosterone system remains intact; therefore, fludrocortisone is not required. 2, 4
• Mineralocorticoid production is maintained in secondary adrenal insufficiency because aldosterone secretion is primarily regulated by the renin-angiotensin system, not ACTH. 4

Peri-Operative Stress-Dose Protocol

For any surgery under general or regional anesthesia, give hydrocortisone 100 mg IV at induction, followed immediately by continuous infusion of 200 mg over 24 hours. 1, 5

Detailed Surgical Stress Dosing

• The 100 mg IV bolus at induction plus 200 mg/24-hour continuous infusion is preferred over intermittent bolus dosing because it maintains stable physiologic cortisol levels throughout the stress period. 1, 5
• If continuous infusion is not feasible, give hydrocortisone 50 mg IV or IM every 6 hours as an alternative. 1, 5
• Continue the 200 mg/24-hour infusion while the patient is NPO or experiencing postoperative nausea/vomiting. 1, 5

Post-Operative Tapering

• Once the patient tolerates oral intake and is hemodynamically stable, switch to oral hydrocortisone at double the usual maintenance dose (30–50 mg daily in divided doses). 1, 5
• Continue the doubled oral dose for 48 hours after uncomplicated surgery, or up to 1 week following major or complicated procedures. 1, 5
• Then taper back to the standard maintenance dose of 15–25 mg daily. 1

Physiologic Rationale

• During major surgical stress, cortisol requirements increase approximately five-fold to ~100 mg/day, compared to normal daily production of ~20 mg. 1, 5
• Continuous IV hydrocortisone infusion is the only administration method that consistently maintains cortisol concentrations within the physiologic stress range; intermittent bolus dosing produces peaks and troughs that may leave patients vulnerable to crisis. 5

Critical Patient Education and Safety Measures

All patients with isolated ACTH deficiency require comprehensive education on stress dosing, emergency management, and medical identification. 1, 2

Stress-Dosing for Illness

• During febrile illness, gastroenteritis, or other intercurrent illness, instruct the patient to double her usual oral hydrocortisone dose. 5, 2
• If the patient develops severe vomiting, diarrhea, or is unable to take oral medications, she must seek immediate medical care for IV hydrocortisone administration. 2

Emergency Preparedness

• Prescribe an emergency injectable hydrocortisone 100 mg IM kit and provide hands-on training in self-administration technique. 5, 2
• The patient must wear a medical alert bracelet or necklace indicating adrenal insufficiency to trigger stress-dose corticosteroids by emergency medical personnel. 1, 5, 2
• Provide a steroid emergency card to carry at all times. 2

Warning Signs of Impending Crisis

• Educate the patient to recognize early signs of adrenal crisis: severe weakness, confusion, marked hypotension, persistent nausea/vomiting, or altered mental status. 1
• If any of these symptoms develop, the patient should administer the emergency IM hydrocortisone injection and call 911 immediately. 1

Monitoring and Dose Adjustment

Clinical assessment is the primary monitoring tool; plasma ACTH and serum cortisol measurements are not useful for dose adjustment in patients on established replacement therapy. 2

Signs of Over-Replacement

• Weight gain, insomnia, peripheral edema, hypertension, and hyperglycemia indicate excessive glucocorticoid exposure and warrant dose reduction. 2

Signs of Under-Replacement

• Persistent lethargy, morning nausea, poor appetite, unintentional weight loss, and difficulty maintaining energy throughout the day suggest insufficient dosing and require dose increase. 2, 6
• If morning nausea is prominent, consider having the patient wake earlier to take the first hydrocortisone dose and then return to sleep. 2

Drug Interactions Requiring Dose Adjustments

Several medications alter hydrocortisone clearance and may necessitate dose adjustments. 2

Medications That Increase Hydrocortisone Requirements

• CYP3A4-inducing agents—including phenytoin, carbamazepine, phenobarbital, rifampin, other antituberculosis drugs, and barbiturates—accelerate hydrocortisone metabolism and may require higher replacement doses. 2

Medications That Decrease Hydrocortisone Requirements

• CYP3A4-inhibiting substances, particularly grapefruit juice and licorice, decrease hydrocortisone clearance and may necessitate dose reduction. 2

Critical Pitfall: Thyroid Hormone Co-Administration

If the patient develops concurrent hypothyroidism, glucocorticoid replacement must be started several days before initiating thyroid hormone therapy to prevent precipitating adrenal crisis. 1, 2

• Thyroid hormone accelerates cortisol clearance; starting levothyroxine before adequate glucocorticoid replacement can unmask or worsen adrenal insufficiency. 1, 2