What is a better replacement dose for secondary adrenal insufficiency, hydrocortisone (cortisol) 10 mg in the morning and 5 mg at noon or prednisolone (generic name) 5 mg in the morning?

Hydrocortisone 10 mg + 5 mg is Better for Secondary Adrenal Insufficiency

For maintenance replacement in secondary adrenal insufficiency, hydrocortisone 10 mg in the morning and 5 mg at noon is the preferred regimen over prednisolone 5 mg once daily. This recommendation is based on superior physiologic mimicry, safety data showing increased mortality with prednisolone in primary adrenal insufficiency, and guideline consensus favoring hydrocortisone as first-line therapy 1, 2.

Why Hydrocortisone is Preferred

Physiologic Replacement

• Hydrocortisone provides more physiologic cortisol replacement with its shorter half-life allowing better approximation of the normal diurnal rhythm when given in divided doses 3, 4, 5.
• The 10 mg morning + 5 mg noon regimen delivers approximately two-thirds of the total dose in the morning, mimicking the physiological cortisol peak 1.
• Prednisolone's longer half-life (12-36 hours) makes it impossible to replicate the natural cortisol rhythm, leading to sustained supraphysiologic levels followed by inadequate coverage 4, 5.

Safety Concerns with Prednisolone

• In primary adrenal insufficiency, prednisolone is associated with significantly higher mortality (adjusted HR 2.92 vs 1.90 for hydrocortisone, p=0.0020) 2.
• While this mortality difference was not statistically significant in secondary adrenal insufficiency specifically, the overall trend toward increased risk with prednisolone (HR 1.76 vs 1.69) raises concerns about long-term safety 2.
• The American College of Endocrinology specifically warns that prednisolone 5 mg daily can lead to iatrogenic Cushing's syndrome over time if used inappropriately 1.

Guideline Recommendations

• Current guidelines recommend hydrocortisone 15-20 mg daily in divided doses as the standard of care for adrenal insufficiency 6, 7.
• The typical maintenance regimen is 10 mg morning, 5 mg afternoon (around noon or 2 pm), with optional 5 mg evening dose if needed 7, 3.
• When prednisolone is used, guidelines recommend 4-5 mg daily (equivalent to hydrocortisone 16-20 mg), preferably split as 3 mg morning + 1-2 mg at 2 pm—not as a single 5 mg morning dose 1.

Critical Dosing Considerations

The Regimen You're Considering is Actually Appropriate

• Hydrocortisone 10 mg morning + 5 mg noon (total 15 mg/day) represents proper maintenance dosing, not stress dosing 1, 7, 3.
• The American College of Endocrinology clarifies that "10 mg morning and 5 mg afternoon" is often confused with stress-dose protocols, but this is actually a standard maintenance regimen when used as the total daily dose 1.
• Stress dosing would involve doubling this regimen (20 mg + 10 mg) for minor illness 8, 7.

Timing Matters

• The afternoon hydrocortisone dose should be given no later than 2-4 pm to avoid sleep disruption 1, 7.
• Never give the afternoon dose within 4-6 hours of bedtime 1.

Prednisolone 5 mg Once Daily is Suboptimal

• A single morning dose of prednisolone 5 mg provides no cortisol coverage in the afternoon/evening, when physiologic cortisol levels should still be measurable 4, 5.
• If prednisolone must be used, the dose should be split (3 mg morning + 1-2 mg at 2 pm) to provide better coverage 1.
• Prednisolone 5 mg is equivalent to hydrocortisone 20 mg—higher than the typical maintenance requirement of 15-20 mg daily 8, 9.

Monitoring and Adjustment

Clinical Assessment is Key

• Monitor for signs of under-replacement: lethargy, nausea, weight loss, postural hypotension 1, 8.
• Monitor for signs of over-replacement: weight gain, insomnia, peripheral edema, cushingoid features 1, 4.
• Plasma cortisol levels are not useful for monitoring adequacy of replacement therapy 3, 4.

Patient Education Requirements

• All patients need education on stress dosing: double the usual dose for minor illness (febrile illness, gastroenteritis) 8, 7.
• Provide emergency hydrocortisone injection kit (100 mg) for self-administration during severe illness or vomiting 8, 7.
• Medical alert bracelet/card is mandatory 8, 7.

Common Pitfalls to Avoid

Don't Confuse Maintenance with Stress Dosing

• The regimen "hydrocortisone 10-5-5 mg" mentioned in perioperative guidelines refers to a baseline maintenance dose, not stress dosing 6.
• During stress, this baseline is doubled (20-10-10 mg) for 48 hours to 1 week post-surgery 6.

Prednisolone is Not Interchangeable

• Prednisolone lacks the mineralocorticoid activity that hydrocortisone provides at physiologic doses 7.
• While this is less critical in secondary adrenal insufficiency (where mineralocorticoid function is preserved), it represents another reason hydrocortisone is preferred 6.

Individual Variation Exists

• Pharmacokinetic studies show that even with optimized hydrocortisone dosing (10+5+5 mg), approximately 54% of patients remain over- or under-treated at some point in the day 3.
• Some patients may require adjustment to 10+5 mg (total 15 mg) or 10+5+5 mg (total 20 mg) based on clinical response 7, 3.