What is the recommended steroid replacement therapy for a patient with secondary adrenal insufficiency, with or without a history of other endocrine disorders such as hypothyroidism?

Steroid Replacement in Secondary Adrenal Insufficiency

Recommended Glucocorticoid Replacement

For secondary adrenal insufficiency, initiate hydrocortisone 15-25 mg daily divided into 2-3 doses, with the first dose immediately upon awakening and the last dose at least 4-6 hours before bedtime to mimic physiological cortisol rhythm. 1, 2, 3

Standard Dosing Regimens

The most effective dosing schedules based on guideline recommendations include: 1, 2

• 10 mg at 07:00 + 5 mg at 12:00 + 2.5-5 mg at 16:00 (three-dose regimen) 1
• 15 mg at 07:00 + 5 mg at 12:00 (two-dose regimen) 1, 2
• 10 mg at 07:00 + 5 mg at 12:00 (alternative two-dose regimen) 1

Hydrocortisone is strongly preferred over other glucocorticoids because it best recreates the physiological diurnal cortisol rhythm. 2, 4

Alternative Glucocorticoid Options

If hydrocortisone is not tolerated or compliance is problematic, consider: 1

• Prednisolone 4-5 mg once daily in the morning 1
• Cortisone acetate 25-37.5 mg daily in divided doses (though less commonly used) 1

Prednisolone should only be considered when patients experience marked fluctuations in energy throughout the day or when hydrocortisone is not tolerated. 1

Critical Distinction: No Mineralocorticoid Needed

Patients with secondary adrenal insufficiency do NOT require fludrocortisone (mineralocorticoid replacement) because the renin-angiotensin-aldosterone system remains intact. 1, 2, 3 This is a crucial difference from primary adrenal insufficiency, where both glucocorticoid and mineralocorticoid replacement are necessary. 1, 5

Dosing Based on Clinical Severity

Mild Symptoms

• Start with physiologic replacement: hydrocortisone 15-20 mg daily in divided doses, typically 2/3 in the morning and 1/3 in early afternoon 6, 2

Moderate Symptoms

• Initiate at 2-3 times maintenance dosing: hydrocortisone 30-50 mg daily or prednisone 20 mg daily 6, 2
• Taper to physiologic maintenance (15-25 mg daily) over 5-10 days as symptoms improve 6

Severe Symptoms/Adrenal Crisis

• Immediate IV hydrocortisone 100 mg bolus, followed by 50-100 mg every 6-8 hours 6, 2, 3
• Aggressive fluid resuscitation with 3-4 L isotonic saline at initial rate of 1 L/hour 6
• Never delay treatment for diagnostic testing 1, 7, 6

Special Consideration: Concurrent Hypothyroidism

If the patient has both secondary adrenal insufficiency and hypothyroidism, always start corticosteroids several days before initiating thyroid hormone replacement. 7, 6 Starting thyroid hormone first can accelerate cortisol clearance and precipitate adrenal crisis. 2

Monitoring and Dose Adjustment

Clinical assessment is the primary monitoring tool—plasma ACTH and serum cortisol levels are not useful for dose adjustment in patients on established replacement therapy. 2, 7

Signs of Over-Replacement

• Weight gain 2
• Insomnia 2
• Peripheral edema 2
• Hypertension 2
• Hyperglycemia 2

Signs of Under-Replacement

• Lethargy 2
• Nausea and poor appetite 2
• Weight loss 2
• Increased pigmentation (in primary AI) 2

Drug Interactions Requiring Dose Adjustments

Medications That Increase Hydrocortisone Requirements

• Anti-epileptics and barbiturates 1, 2
• Antituberculosis medications 1, 2
• Antifungal drugs 1
• Etomidate 1, 2
• Topiramate 1, 2

Medications/Foods That Decrease Hydrocortisone Requirements

• Grapefruit juice 1, 2
• Liquorice 1, 2

Essential Patient Education

All patients with secondary adrenal insufficiency must receive comprehensive education on: 6, 2, 3

• Stress dosing protocol: Double or triple the dose during illness, fever, or physical stress 6
• Emergency injectable hydrocortisone 100 mg IM kit with self-injection training 6, 3
• Medical alert bracelet indicating adrenal insufficiency 6, 2, 3
• Warning signs of adrenal crisis: severe weakness, confusion, abdominal pain, hypotension 6

Perioperative Management

Major Surgery

• Hydrocortisone 100 mg IV at induction, followed by continuous infusion of 200 mg/24 hours 1
• Postoperatively: Continue 200 mg/24 hours IV while nil by mouth, then resume oral glucocorticoid at double the pre-surgical dose for 48 hours if recovery is uncomplicated 1

Minor Surgery

• Hydrocortisone 100 mg IM before procedure 6
• Double oral dose for 24 hours postoperatively 6

Common Pitfalls to Avoid

• Never use dexamethasone for chronic replacement therapy in secondary adrenal insufficiency—it lacks mineralocorticoid activity and doesn't mimic physiological cortisol rhythm 6
• Don't attempt diagnostic testing (morning cortisol, ACTH stimulation test) while patient is on active corticosteroid therapy—results will be unreliable 7, 6
• Don't delay treatment in suspected adrenal crisis to perform diagnostic procedures 1, 7, 6
• Don't start thyroid hormone replacement before corticosteroids in patients with multiple pituitary hormone deficiencies 7, 6, 2