At what time should a 3rd dose of hydrocortisone (cortisol replacement) be administered in an adrenal insufficiency patient to limit effects on sleep?

Timing of Third Hydrocortisone Dose in Adrenal Insufficiency

The third dose of hydrocortisone should be administered no later than 4-6 hours before bedtime (typically around 14:00h or 2:00 PM) to avoid insomnia and sleep disturbances. 1, 2

Physiological Rationale

The timing recommendation is based on mimicking physiological cortisol secretion patterns, which naturally decline throughout the day:

• Physiological cortisol follows a distinct diurnal pattern with peak levels in early morning (05:00-08:00h), intermediate levels in the afternoon, low levels in the evening, and a cortisol-free interval at night 3
• Administering glucocorticoids too late in the day disrupts this natural rhythm and directly causes insomnia 1
• The short elimination half-life of hydrocortisone (approximately 1.5 hours) means that afternoon dosing still allows clearance before bedtime if timed appropriately 3

Specific Dosing Algorithm for Three-Dose Regimens

When using a three-dose hydrocortisone regimen (total daily dose 15-25 mg):

• First dose: Upon awakening, before 9:00 AM (largest portion, typically 10 mg) 1, 4
• Second dose: Midday around 12:00 PM (typically 5 mg) 5
• Third dose: Early afternoon at 14:00h/2:00 PM (typically 5 mg) 1, 2, 5

Critical timing rule: The final dose must not be taken later than 4-6 hours before the patient's intended bedtime 1, 2

Clinical Considerations

For Standard Sleep Schedules

• If a patient goes to bed at 22:00h (10:00 PM), the latest acceptable time for the third dose would be 16:00-18:00h (4:00-6:00 PM) 1
• However, 14:00h (2:00 PM) is the recommended standard timing to provide adequate safety margin and better mimic physiological patterns 1, 2

For Night Shift Workers

• Dosing schedules should be adjusted according to the patient's sleep-wake pattern 1, 2
• The first dose should be taken upon awakening before work, with subsequent doses timed relative to their shifted circadian schedule 1

Signs of Improper Timing

Over-replacement indicators (suggesting doses too high or too late):

• Insomnia is a key sign of glucocorticoid excess or inappropriate timing 1, 2, 4
• Weight gain and peripheral edema 1, 2

Under-replacement indicators (suggesting inadequate dosing):

• Lethargy, nausea, poor appetite, weight loss 1, 2

Common Pitfalls to Avoid

• Do not allow patients to take the third dose in the late afternoon or evening (after 16:00-18:00h), as this is the most common cause of glucocorticoid-induced insomnia 1
• Do not use a three-dose regimen if compliance is problematic—consider switching to a two-dose regimen (morning and early afternoon only) or single morning dose instead 2
• For patients working long shifts who need sustained coverage, a divided dose regimen with the third dose at 14:00h is specifically useful, but timing discipline is essential 2

Alternative Considerations

If a patient experiences persistent sleep disturbances despite proper timing:

• Consider switching to a two-dose regimen (larger morning dose with single afternoon dose at 14:00h) 1, 2
• Evaluate for over-replacement and consider dose reduction 1, 2
• For patients with marked energy fluctuations, a single morning dose may be preferable 2