What are the side effects of excessive glucocorticoids (GCs), specifically 5 or 10mg above physiological levels, in patients with primary adrenal insufficiency?

Side Effects of Glucocorticoid Over-Replacement in Primary Adrenal Insufficiency

Excessive glucocorticoid dosing—even 5-10 mg above physiological levels—causes weight gain, insomnia, and peripheral edema as the primary clinical manifestations of over-replacement in patients with primary adrenal insufficiency. 1

Immediate Clinical Signs of Over-Replacement (5-10 mg Above Physiological)

The consensus guidelines identify three cardinal symptoms that appear with glucocorticoid excess above the physiological range of 15-25 mg hydrocortisone equivalent daily: 1

• Weight gain - This is the most consistent early indicator of over-replacement and should prompt immediate dose reduction 1
• Insomnia - Particularly when doses are taken too late in the day or total daily dose exceeds physiological needs 1, 2
• Peripheral edema - Results from the mineralocorticoid effects of excess glucocorticoids 1

Long-Term Consequences of Chronic Over-Replacement

Musculoskeletal Effects

Bone loss represents the most serious long-term morbidity from chronic glucocorticoid excess. 3 The FDA label specifically warns that:

• Corticosteroids decrease bone formation and increase bone resorption through effects on calcium regulation (decreasing absorption, increasing excretion) and inhibition of osteoblast function 3
• Reduced protein matrix of bone occurs secondary to increased protein catabolism 3
• Reduced sex hormone production contributes to osteoporosis development at any age 3
• All interventions for bone protection should be initiated in any patient receiving the equivalent of 5 mg of prednisone (25 mg hydrocortisone) for at least 3 months 3

Cardiovascular and Metabolic Effects

• Sodium retention with resultant edema and potassium loss may occur, requiring caution in patients with congestive heart failure, hypertension, or renal insufficiency 3
• Increased blood glucose concentrations may develop, potentially requiring adjustment of antidiabetic agents 3

Neuropsychiatric Effects

The FDA label documents a spectrum of psychiatric manifestations: 3

• Euphoria, insomnia, mood swings, and personality changes 3
• Severe depression to frank psychotic manifestations 3
• Aggravation of existing emotional instability or psychotic tendencies 3

Ophthalmic Effects

• Elevated intraocular pressure may develop in some individuals 3
• If steroid therapy continues for more than 6 weeks, intraocular pressure monitoring is recommended 3

Gastrointestinal Effects

• Increased risk of peptic ulcer perforation, with signs of peritoneal irritation potentially being minimal or absent 3
• Enhanced risk in patients with active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and nonspecific ulcerative colitis 3

Clinical Context: Physiological Dosing Range

Understanding what constitutes "over-replacement" requires knowing the physiological baseline: 1

• Normal adrenal function produces 5-10 mg of cortisol per m² of body surface area per day 1
• This translates to an oral replacement dose of 15-25 mg hydrocortisone daily 1
• Prednisolone equivalent is 4-5 mg daily 2, 4
• Therefore, 5-10 mg above physiological levels means 30-35 mg hydrocortisone or 9-15 mg prednisolone daily

Monitoring Strategy for Over-Replacement

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

• Patient weight trends (most objective early indicator) 1
• Sleep quality and timing of sleep onset 1
• Presence of peripheral edema 1
• General feelings of energy and "get up and go" 1
• Mental concentration and daytime somnolence 1

Critical Pitfall to Avoid

Do not compensate for under-replacement of mineralocorticoids by over-replacing glucocorticoids. 4 This practice leads to:

• Long-term adverse outcomes from glucocorticoid excess 4
• Continued predisposition to adrenal crises from inadequate mineralocorticoid replacement 4
• All patients with primary adrenal insufficiency require fludrocortisone 0.05-0.2 mg daily in addition to appropriate glucocorticoid dosing 4, 5

Quality of Life Impact

Even under established replacement therapy with individually adjusted glucocorticoid doses that avoid over-replacement, patients with chronic adrenal insufficiency experience impairment in daily life activities and higher numbers of sick days. 6 However, when over-replacement is avoided, the frequency of glucocorticoid side effects remains low. 6