What are the side effects of hydrocortisone (cortisol) in patients with adrenal insufficiency?

Side Effects of Hydrocortisone in Adrenal Insufficiency

When hydrocortisone is dosed appropriately at physiological replacement levels (15-25 mg daily), side effects are minimal, but over-replacement by even 5-10 mg above this range causes weight gain, insomnia, and peripheral edema as the primary adverse effects. 1

Side Effects from Over-Replacement (Most Common Clinical Problem)

Immediate Clinical Manifestations

• Weight gain is the most consistent early indicator of glucocorticoid over-replacement and should prompt immediate dose reduction 1
• Insomnia occurs particularly when doses are taken too late in the day or when total daily dose exceeds physiological needs 1
• Peripheral edema results from the mineralocorticoid effects of excess glucocorticoids 1
• These symptoms can appear with doses as low as 5-10 mg above the physiological range of 15-25 mg daily 1

Long-Term Complications from Chronic Over-Replacement

• Prolonged use produces posterior subcapsular cataracts and glaucoma with possible optic nerve damage 2
• Elevation of blood pressure, salt and water retention, and increased potassium excretion occur with average to large doses 2
• All corticosteroids increase calcium excretion, potentially leading to osteoporosis 2
• Enhanced establishment of secondary ocular infections due to fungi or viruses 2

Side Effects from Appropriate Physiological Replacement

Infection Risk

• Corticosteroids may mask signs of infection, and new infections may appear during their use 2
• Decreased resistance and inability to localize infection can occur even at replacement doses 2
• Patients on immunosuppressive doses are more susceptible to severe or fatal courses of chicken pox and measles 2
• Prophylaxis with varicella zoster immune globulin (VZIG) for chicken pox exposure or pooled intramuscular immunoglobulin (IG) for measles exposure may be indicated 2

Vaccination Considerations

• Patients should not be vaccinated against smallpox while on corticosteroid therapy 2
• Other immunization procedures should not be undertaken, especially at high doses, due to possible neurological complications and lack of antibody response 2

Tuberculosis Reactivation

• Close observation is necessary in patients with latent tuberculosis or tuberculin reactivity, as reactivation may occur 2
• During prolonged therapy, these patients should receive chemoprophylaxis 2

Monitoring Strategy to Detect Over-Replacement

Clinical assessment is the primary monitoring method, as plasma ACTH and serum cortisol are not useful parameters for dose adjustment. 1

Key Clinical Parameters to Monitor

• Patient weight trends (most important) 1
• Sleep quality and presence of insomnia 1
• Presence of peripheral edema 1
• General feelings of energy and mental concentration 1
• Daytime somnolence 1
• Blood pressure in supine and standing positions 3
• Salt cravings or lightheadedness (indicates mineralocorticoid status) 3

Critical Pitfall to Avoid

Do not compensate for under-replacement of mineralocorticoids by over-replacing glucocorticoids, as this leads to long-term adverse outcomes from glucocorticoid excess and continued predisposition to adrenal crises 1. All patients with primary adrenal insufficiency require fludrocortisone 0.05-0.2 mg daily in addition to appropriate glucocorticoid dosing 1.

Special Populations

Pregnancy

• Infants born of mothers who received substantial doses of corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism 2
• Higher fludrocortisone doses (up to 500 µg daily) may be needed in the last trimester when high progesterone levels counteract mineralocorticoids 3

Stress Situations

• Increased dosage of rapidly acting corticosteroids before, during, and after stressful situations is indicated to prevent adrenal crisis 2
• Patients should double their dose during minor illness and triple their dose during severe illness 4

Metabolic Effects from Suboptimal Dosing Regimens

• Most patients with adrenal insufficiency are imperfectly treated with standard hydrocortisone tablets, with 79%, 55%, and 45% of patients over- or under-treated at morning, afternoon, and midnight measurements respectively 5
• Fixed dosing (rather than weight-adjusted dosing) overexposes patients to cortisol by 6.3% and increases interpatient variability 6