What are the consequences of prolonged glucocorticoid (corticosteroid) therapy on the adrenal glands and how is it managed?

Prolonged Glucocorticoid Therapy Leads to Adrenal Insufficiency Through HPA Axis Suppression

Prolonged glucocorticoid therapy causes tertiary adrenal insufficiency through suppression of the hypothalamic-pituitary-adrenal (HPA) axis, leading to decreased ACTH production and subsequent bilateral adrenal atrophy, which can result in life-threatening adrenal crisis if not properly managed during periods of stress. 1

Mechanism of Adrenal Suppression

• Exogenous glucocorticoids (like prednisone, hydrocortisone) suppress the hypothalamus, reducing corticotropin-releasing hormone (CRH) production 1
• Decreased CRH leads to reduced ACTH secretion from the pituitary gland 1
• Without ACTH stimulation, the adrenal glands atrophy bilaterally, losing their ability to produce adequate cortisol 1
• This suppression can occur with glucocorticoid administration through any route: oral, inhaled, topical, intranasal, or intra-articular 1

Risk Factors for Developing Adrenal Insufficiency

• Dose: Prednisolone ≥5 mg daily (or equivalent) in adults or hydrocortisone-equivalent of 10-15 mg/m² daily in children 1
• Duration: Treatment for 1 month or longer significantly increases risk 1
• Administration timing: Glucocorticoids given in the morning (when natural cortisol is highest) cause less suppression 2
• Individual susceptibility: Varies between patients 1
• Concomitant medications: Drugs that affect CYP3A4 (like ketoconazole) can alter glucocorticoid metabolism 1

Clinical Manifestations of Adrenal Insufficiency

• Symptoms may be nonspecific: fatigue, weakness, anorexia, nausea, hypotension 1
• Laboratory findings: Low morning cortisol, low ACTH levels 1
• Adrenal crisis: Life-threatening emergency with hypotension, hyponatremia, hyperkalemia, hypoglycemia 1
• Increased mortality risk: Risk ratio for all-cause mortality is 2.19 for men and 2.86 for women 1

Diagnosis of Glucocorticoid-Induced Adrenal Insufficiency

• Morning cortisol levels are often insufficient to confirm or exclude the diagnosis 3
• ACTH stimulation test (Short Synacthen Test) is recommended 3
• Cortisol peak >500 nmol/L typically excludes adrenal insufficiency 3
• Testing is often based on clinical suspicion rather than routine screening, leading to underdiagnosis 4

Management During Stress and Surgery

For Adults:

• Major surgery: Hydrocortisone 100 mg IV at induction, followed by continuous infusion of 200 mg/24h until oral intake is possible 1
• Minor procedures with general anesthesia: Hydrocortisone 50 mg IV/IM at induction 1
• Minor procedures without general anesthesia: Double morning dose of hydrocortisone 1

For Children:

• Major surgery: Hydrocortisone 2 mg/kg at induction followed by weight-based continuous infusion 1
• Minor procedures with general anesthesia: Hydrocortisone 2 mg/kg IV/IM at induction 1
• Minor procedures without general anesthesia: Double morning dose of hydrocortisone 1

Prevention and Treatment of Adrenal Insufficiency

• Gradual tapering of glucocorticoids is essential to allow HPA axis recovery 2
• Avoid abrupt withdrawal of therapy to prevent adrenal crisis 2
• During stress (illness, surgery, trauma), increase glucocorticoid doses to mimic physiological stress response 1
• Patient education about symptoms of adrenal insufficiency and when to seek medical attention is crucial 4
• Recovery of the HPA axis may take months to years after glucocorticoid discontinuation 1, 4

Long-term Consequences and Monitoring

• Increased risk of cardiovascular, malignant, and infectious diseases 1
• Adrenal crises requiring hospital treatment occur about 6-8 times per 100 patient-years 1
• Monitor for symptoms of both glucocorticoid excess (Cushing syndrome) and insufficiency during treatment 1
• Consider bone health: calcium and vitamin D supplementation for patients on prolonged therapy 1
• Regular assessment of HPA axis function during tapering is recommended 5

Common Pitfalls and Caveats

• Inhaled corticosteroids can cause HPA axis suppression even at recommended doses 1
• Symptoms of adrenal insufficiency may be mistaken for the underlying disease being treated 4
• Dexamethasone is inadequate as glucocorticoid treatment in patients with primary adrenal insufficiency as it lacks mineralocorticoid activity 1
• Patients may require stress-dose steroids for up to 12 months after discontinuation of prolonged therapy 2
• Hyperglycemia is a common side effect of glucocorticoid stress dosing but is rarely associated with increased morbidity 1