What is the recommended treatment for a patient with lab work consistent with secondary adrenal insufficiency?

Treatment for Secondary Adrenal Insufficiency

Initiate hydrocortisone 15-25 mg daily in divided doses as glucocorticoid replacement therapy for confirmed secondary adrenal insufficiency. 1, 2

Standard Maintenance Dosing Regimen

The recommended approach is hydrocortisone 10 mg at 7:00 AM, 5 mg at 12:00 PM, and 2.5-5 mg at 4:00 PM to approximate physiological cortisol secretion. 2 This timing mimics the natural diurnal cortisol rhythm and optimizes symptom control throughout the day. 3

Alternative effective regimens include:

• 15 mg morning + 5 mg early afternoon (simplified two-dose regimen) 2
• 10 mg + 10 mg (twice daily) 2
• 10 mg + 5 mg + 5 mg (three times daily) 2

The total daily dose typically ranges from 15-25 mg, with most patients requiring 20-25 mg daily. 1, 4, 5 Real-world data shows 42.2% of patients receive 20 to <25 mg/day, though some require doses up to 30 mg/day. 6

Critical Distinction: No Mineralocorticoid Needed

Unlike primary adrenal insufficiency, secondary adrenal insufficiency does NOT require fludrocortisone (mineralocorticoid) replacement because the renin-angiotensin-aldosterone system remains intact. 1, 2 This is a crucial difference—adding fludrocortisone in secondary AI is unnecessary and potentially harmful. 7

Severity-Based Dosing Algorithm

Mild/Stable Outpatient

• Hydrocortisone 15-20 mg daily in divided doses (10 mg morning, 5-10 mg afternoon) 2
• Alternative: Prednisolone 4-5 mg daily (equivalent to 20-25 mg hydrocortisone) 1, 2

Moderate Symptoms (fatigue, nausea, weakness)

• Start at 2-3 times maintenance dose: 20-30 mg morning, 10-20 mg afternoon 1, 2
• Taper back to maintenance over 5-10 days as symptoms improve 2

Severe/Life-Threatening (hypotension, altered mental status, suspected adrenal crisis)

• Immediate IV hydrocortisone 100 mg bolus—never delay treatment for diagnostic testing 7, 1, 2
• Follow with IV normal saline infusion at 1 L/hour 7, 1
• Continue stress-dose IV hydrocortisone 200 mg/24 hours as continuous infusion or divided doses 7
• Taper to oral maintenance over 7-14 days after clinical stabilization 2

Stress Dosing Education (Mandatory)

All patients must be instructed to double or triple their hydrocortisone dose during febrile illness, infection, gastroenteritis, or minor physiological stress. 1, 2 This prevents adrenal crisis, which occurs at a rate of 6-8 episodes per 100 patient-years and carries significant mortality risk. 7

For major stress (surgery, severe infection, trauma):

• Hydrocortisone 100 mg IV immediately 1, 2
• Continue stress dosing until the acute event resolves 7
• Endocrine consultation is mandatory prior to any surgical procedure for stress-dose planning 1, 2

Drug Interactions Affecting Dosing

Medications that increase hydrocortisone requirements:

• Anti-epileptics (phenytoin, carbamazepine, barbiturates) 1, 2
• Rifampin and other antituberculosis drugs 1, 2
• Topiramate 1
• Etomidate 1, 2

Substances that decrease requirements (should be avoided):

• Grapefruit juice 1, 2
• Liquorice 1, 2

Patient Safety Measures

Every patient must:

• Wear a medical alert bracelet or necklace indicating adrenal insufficiency 1, 2
• Carry an emergency hydrocortisone 100 mg IM injection kit with self-injection training 1
• Receive written instructions on stress dosing and warning signs of adrenal crisis 1

Monitoring and Dose Optimization

Adjust dosing based on clinical symptoms rather than cortisol levels, as exogenous hydrocortisone confounds laboratory interpretation. 1 Signs of under-replacement include persistent fatigue, nausea, poor appetite, weight loss, and morning symptoms. 1 Signs of over-replacement include weight gain, hypertension, hyperglycemia, and cushingoid features. 3

If morning nausea persists, have the patient wake earlier to take the first hydrocortisone dose, then return to sleep. 1 This simple timing adjustment often relieves morning symptoms without increasing the total daily dose.

Critical Pitfall to Avoid

If treating concurrent hypothyroidism and adrenal insufficiency, always start hydrocortisone several days before initiating thyroid hormone replacement. 1, 2 Starting thyroid hormone first can precipitate acute adrenal crisis by increasing cortisol metabolism. 1

Mortality Context

Untreated or inadequately treated adrenal insufficiency carries a mortality risk ratio of 2.19 for men and 2.86 for women, with excess deaths from cardiovascular disease, infections, and malignancies. 7 Adrenal crisis accounts for 8.6% of hospitalizations in patients with chronic adrenal insufficiency, with documented deaths occurring during follow-up. 7 Proper glucocorticoid replacement and patient education on stress dosing are life-saving interventions.