Hydrocortisone Versus Methylprednisolone for the Treatment of Glucocorticoid-Induced Adrenal Insufficiency

Glucocorticoids in supraphysiological doses are the most frequent cause of adrenal insufficiency due to the suppression of the hypothalamic-pituitary-adrenal (HPA) axis.

In cases of confirmed adrenal insufficiency, current guidelines recommend replacement therapy with physiological doses of short- and intermediate-acting glucocorticoids to prevent adrenal crises without inhibiting HPA axis recovery.

While hydrocortisone is the most commonly used short-acting glucocorticoid, methylprednisolone is widely prescribed in Slovenia.

Because methylprednisolone lacks mineralocorticoid effects, it appears to be a particularly suitable choice for patients with glucocorticoid-induced adrenal insufficiency, where mineralocorticoid secretion is not impaired.

This randomized, prospective, open-label interventional study will primarily evaluate non-inferiority regarding HPA axis recovery after 12 months, with a long-term assessment at 24 months.

Patients will undergo testing at baseline, 3, 6,12, 18, 24 months (or until HPA axis recovery), including laboratory tests, short ACTH tests, body composition measurements, and quality of life questionnaires.

Inclusion criteria

• Age over 18 years.
• Suspected adrenal insufficiency due to receiving supraphysiological doses of methylprednisolone for more than 4 weeks.
• Receiving methylprednisolone 4 mg for at least the last 4 weeks.
• Morning cortisol lower than 300 nmol/L.
• Inadequate result of a short ACTH test performed on a physiological dose of methylprednisolone (cortisol rise after 30 min under 470 nmol/L AND after 60 min under 500 nmol/L).
• No further indication for treating the underlying disease, and retreatment with glucocorticoids is not expected in the next 2 years.
• Consent to participate in the research.

Exclusion criteria

• Known organic disease of the pituitary-adrenal axis.
• Body mass over 130 kg.
• Advanced comorbidities.
• Advanced heart failure (NYHA IV).
• Chronic kidney disease IV, eGFR under 30 ml/min.
• Liver cirrhosis.
• Active malignant disease.
• Immune deficiencies.
• Planned major surgery during the study duration.
• Receiving drugs affecting cortisol metabolism or interfering with cortisol measurements (e.g., systemic estrogens, strong inducers or inhibitors of CYP3A4).
• Conditions affecting cortisol metabolism (pregnancy, liver disease, nephrotic syndrome).
• Alcohol dependence syndrome (consuming more than 21 units of alcohol per week).
• Shift (night) work.
• Presence of comorbidities with an expected life expectancy of less than 3 years.