What are the considerations for initiating hydrocortisone (cortisol) therapy for chronic primary adrenal insufficiency (Addison's disease)?

From the Guidelines

For chronic adrenal insufficiency, start hydrocortisone at a total daily dose of 15-25 mg divided into 2-3 doses, with the largest dose (typically 10-15 mg) given in the morning upon waking, a smaller dose (5-10 mg) at midday, and if using a three-dose regimen, the smallest dose (2.5-5 mg) in the early evening before 6 PM, as recommended by the most recent guidelines 1. This dosing regimen mimics the natural cortisol rhythm, with higher levels in the morning and lower levels in the evening.

Key Considerations

• Patients should be instructed to double or triple their dose during times of illness, injury, or significant stress, and to have an emergency injection kit containing 100 mg hydrocortisone for severe illness or inability to take oral medication 1.
• Regular monitoring is essential, with clinical assessment for signs of under-replacement (fatigue, weight loss, hyperpigmentation) or over-replacement (weight gain, hypertension, glucose intolerance) 1.
• Patients should wear a medical alert bracelet and carry information about their condition 1.
• Hydrocortisone is preferred over longer-acting steroids like prednisone because its shorter half-life better mimics natural cortisol secretion patterns, reducing the risk of metabolic side effects from prolonged glucocorticoid exposure 1.

Dosing Regimens

• The dosing regimen should be individualized based on the patient's specific needs and response to treatment 1.
• The total daily dose of hydrocortisone should be divided into 2-3 doses, with the largest dose given in the morning and the smallest dose given in the evening 1.
• Patients should be instructed to adjust their dose based on their symptoms and response to treatment, and to seek medical attention if they experience any signs of adrenal crisis 1.

From the FDA Drug Label

DOSAGE & ADMINISTRATION Dosage depends on the severity of the disease and the response of the patient. In Addison’s disease, the combination of fludrocortisone acetate tablets with a glucocorticoid such as hydrocortisone or cortisone provides substitution therapy approximating normal adrenal activity with minimal risks of unwanted effects. Fludrocortisone acetate tablets are preferably administered in conjunction with cortisone (10 mg to 37. 5 mg daily in divided doses) or hydrocortisone (10 mg to 30 mg daily in divided doses).

The recommended dosage of hydrocortisone for chronic adrenal insufficiency, specifically Addison's disease, is 10 mg to 30 mg daily in divided doses 2.

• The dose should be continually monitored and adjusted as necessary based on the patient's response and signs of disease exacerbation or remission.
• Hydrocortisone should be administered in conjunction with fludrocortisone acetate tablets.

From the Research

Starting Hydrocortisone for Chronic Adrenal Insufficiency

• The daily glucocorticoid replacement dose of hydrocortisone (HC) for chronic adrenal insufficiency is recommended to be 15 to 25 mg, with a midpoint of 20 mg, in divided doses for otherwise healthy individuals 3.
• However, a daily glucocorticoid replacement dose of 4.3 to 26 mg/d HC with a midpoint of 15 mg/d is predicted from current measurements of daily cortisol production rates and oral HC bioavailability, suggesting that higher HC doses may result in glucocorticoid overtreatment and associated long-term adverse outcomes 3.
• The Endocrine Society Guidelines recommend once-daily fludrocortisone and hydrocortisone (15-25 mg/d) or cortisone acetate replacement (20-35 mg/d) applied in two to three daily doses in adults with primary adrenal insufficiency 4.
• Novel strategies to replicate the cortisol rhythm using hydrocortisone infusion pumps and oral modified release hydrocortisone have been developed and confirmed to offer benefits to patients with adrenal insufficiency, including improved quality of life and reduced infections 5.
• The management of adrenal insufficiency requires life-long glucocorticoid substitution therapy, as well as stress adaptation to prevent adrenal crises, and the use of various glucocorticoid formulations, including short-acting, intermediate, long-acting, and novel modified-release hydrocortisone 6.

Dosage and Administration

• Hydrocortisone dosing should be individualized, and patients should be educated about stress dosing and equipped with a steroid card and glucocorticoid preparation for parenteral emergency administration 4.
• The use of hydrocortisone infusion pumps and oral modified release hydrocortisone may be reserved for patients with metabolic complications, very poor quality of life, and difficult-to-treat congenital adrenal hyperplasia 5.

Special Considerations

• Adrenal insufficiency can be a rare but potentially devastating side effect of immune checkpoint inhibitor therapy, and prompt diagnosis is of the utmost importance 7.
• Liberal use of early morning/8 am cortisol screening should be implemented as a standard part of clinical workup in acute onset of fatigue, hypotension, fever, weakness, weight loss, dehydration, oral intolerance, gastrointestinal upset, hyponatremia, and hyperkalemia 7.