What is the best glucocorticoid (cortisol) replacement therapy for adrenal insufficiency (Addison's disease)?

From the Guidelines

The best glucocorticoid replacement therapy for adrenal insufficiency is typically hydrocortisone, administered in a regimen that mimics the body's natural cortisol rhythm, with a total daily dose of 15-25 mg, as recommended by the most recent and highest quality study 1. Recommended regimen:

• Total daily dose: 15-25 mg of hydrocortisone
• Divided into 2-3 doses:
  • 50-60% of the daily dose upon waking (e.g., 10-15 mg)
  • 25-30% in the early afternoon (e.g., 5-7.5 mg)
  • 15-20% in the early evening if using a 3-dose regimen (e.g., 2.5-5 mg) Timing is crucial: The largest dose should be taken immediately upon waking, the second dose around lunchtime, and the third dose (if used) no later than 4-6 PM to avoid sleep disturbances. Patients should be instructed to adjust their dose during times of stress, illness, or surgery, typically doubling or tripling their usual dose for short periods, as suggested by 1 and 1. Hydrocortisone is preferred because:

1. It closely resembles natural cortisol
2. It has a short half-life, allowing for more physiological dosing
3. It has both glucocorticoid and mineralocorticoid effects, which can be beneficial in primary adrenal insufficiency Regular monitoring of symptoms and occasional cortisol day curves can help fine-tune the dosage and timing for individual patients, as noted in 1 and 1. Patients should always carry emergency hydrocortisone for injection and wear medical alert identification. Some key points to consider:

• Patients with a history of adrenal crisis are more vulnerable to future episodes, and should be closely monitored, as reported in 1.
• The incidence of adrenal crisis in patients with primary and secondary adrenal insufficiency is significant, with a reported incidence of 8.3 per 100 replacement years, as noted in 1.
• Patients with comorbidities, such as asthma and diabetes, are more susceptible to adrenal crisis, and should be managed accordingly, as suggested by 1.

From the Research

Glucocorticoid Replacement Therapy for Adrenal Insufficiency

The best glucocorticoid replacement therapy for adrenal insufficiency (Addison's disease) is a topic of ongoing research and debate.

• The Endocrine Society Guidelines recommend a daily glucocorticoid replacement dose of 15 to 25 mg with a midpoint of 20 mg of hydrocortisone (HC) (alternatively 3 to 5 mg prednisolone) in divided doses in otherwise healthy individuals with AI 2.
• However, some studies suggest that this dose may be too high and result in glucocorticoid overtreatment, leading to long-term adverse outcomes 2.
• Modified-release hydrocortisone treatments that mimic the physiological circadian pattern of cortisol secretion have been shown to be more effective than conventional glucocorticoid replacement therapies in improving metabolic outcomes and quality of life 3.
• Current treatment strategies have been shown to fail to maintain or normalize metabolism and quality of life in patients with adrenal insufficiency, highlighting the need for improved treatment regimens 4.

Treatment Regimens

• A study of 1166 patients with primary and secondary AI found significant heterogeneity in the type, dose, frequency, and timing of glucocorticoid replacement, with most patients receiving hydrocortisone 5.
• The most common dose range was 20 to <25 mg/day, but 12.6% of patients were receiving doses of ≥30 mg/day 5.
• Patients with primary AI received higher replacement doses than those with secondary AI 5.

Future Directions

• There is a need for further research to determine the optimal glucocorticoid replacement regimen for patients with adrenal insufficiency, taking into account individual patient needs and symptoms 2, 6.
• New modes of replacement that aim to mimic normal glucocorticoid physiology are being developed, with a focus on improving health-related quality of life, metabolic profile, and mortality in patients with adrenal insufficiency 6.