What is the recommended approach for tapering corticosteroids (e.g. prednisone) in a patient with drug-induced Cushing's syndrome to avoid adrenal insufficiency?

Tapering Corticosteroids in Drug-Induced Cushing's Syndrome

Gradual tapering over at least 1 month is essential to prevent life-threatening adrenal crisis, as abrupt discontinuation in patients with drug-induced Cushing's syndrome causes secondary adrenal insufficiency due to prolonged HPA axis suppression. 1, 2

Understanding the Clinical Context

Drug-induced Cushing's syndrome results from exogenous corticosteroid exposure through any route—oral, inhaled, topical, or intranasal—and invariably suppresses the hypothalamic-pituitary-adrenal (HPA) axis 3, 4, 5, 6. The duration and degree of HPA suppression depends on the dose, potency, duration of therapy, and individual susceptibility 2. Patients who receive corticosteroids for more than 14 days are at significant risk for HPA axis suppression and require gradual dose reduction rather than abrupt cessation 1.

The critical danger is that these patients have developed iatrogenic secondary adrenal insufficiency—their adrenal glands have atrophied and cannot produce cortisol when the exogenous steroid is withdrawn 7, 2. This creates a life-threatening vulnerability to adrenal crisis during the tapering period and for up to 12 months after complete discontinuation 8, 2.

Tapering Protocol

Initial Dose Reduction Phase

Decrease the initial dose in small increments at appropriate intervals over at least 1 month until reaching the lowest dose that maintains adequate clinical response 1, 8. The FDA label for prednisone explicitly states that dosage requirements are variable and must be individualized, but emphasizes that if long-term therapy is to be stopped, withdrawal must be gradual rather than abrupt 8.

• Reduce the dose by approximately 10-25% every 1-2 weeks during the initial tapering phase 1
• Monitor carefully for signs of adrenal insufficiency (fatigue, weakness, nausea, vomiting, hypotension) and signs of disease recurrence at each dose reduction 1, 2
• The reduction should not be too rapid to avoid precipitating adrenal crisis or recurrence of the underlying condition 1

Transition to Physiologic Replacement

Once you reach approximately prednisone 5-7.5 mg daily (or equivalent), transition to hydrocortisone for physiologic replacement therapy 1. This is critical because:

• Hydrocortisone allows recreation of the diurnal cortisol rhythm, which is essential for HPA axis recovery 7
• The typical physiologic replacement dose is hydrocortisone 15-25 mg daily in divided doses (10 mg at 7 AM, 5 mg at noon, 2.5-5 mg at 4 PM) 9, 1
• Alternative regimens include 15+5 mg or 10+10 mg depending on individual response 7

Assessing HPA Axis Recovery

Do not attempt diagnostic testing for HPA axis recovery until the patient has been on stable physiologic replacement (hydrocortisone 15-20 mg daily) for at least 3 months 7, 2. Testing while on higher doses or other corticosteroids yields false results 7.

• After 3 months of physiologic replacement, perform a morning cortisol and ACTH measurement 7
• If morning cortisol is <250 nmol/L (<9 μg/dL) with low ACTH, continue replacement and retest in 3 months 7
• If morning cortisol is indeterminate (250-500 nmol/L or 9-18 μg/dL), perform a cosyntropin stimulation test 7
• A peak cortisol >500-550 nmol/L (>18-20 μg/dL) indicates HPA axis recovery 7, 1

HPA axis suppression may persist for up to 12 months after discontinuation of prolonged glucocorticoid therapy 8, 2. During this entire recovery period, patients remain vulnerable to adrenal crisis during stress and require stress-dose coverage 8.

Critical Safety Measures During Tapering

Stress Dosing Education

All patients must be educated to double or triple their glucocorticoid dose during illness, fever, or physical stress 7, 1. This is non-negotiable because:

• Even mild illness can precipitate adrenal crisis in patients with suppressed HPA axis 9
• Patients need written instructions on when and how to increase doses 7
• Prescribe an emergency injectable hydrocortisone 100 mg IM kit with self-injection training 7, 1

Medical Alert Identification

Patients must wear a medical alert bracelet or necklace indicating adrenal insufficiency/steroid dependence 7, 1, 10. This triggers emergency personnel to administer stress-dose corticosteroids if the patient presents with unexplained hypotension or altered mental status 7.

Monitoring Parameters

• Assess clinical symptoms at each dose reduction: energy level, appetite, weight, blood pressure (including orthostatic measurements) 1, 10
• Check electrolytes periodically, watching for hyponatremia (which occurs in 90% of adrenal insufficiency cases) 7
• Monitor for signs of over-replacement (weight gain, insomnia, edema) versus under-replacement (fatigue, nausea, weight loss) 7, 1

Common Pitfalls to Avoid

Never stop corticosteroids abruptly—this can be fatal 1, 8. Even patients who appear clinically well may have complete HPA axis suppression 2.

Do not attempt to "test" adrenal function by stopping steroids and checking cortisol levels 7. This approach risks precipitating adrenal crisis. Instead, taper to physiologic replacement first, maintain for 3 months, then test 7, 2.

Avoid tapering too quickly based on resolution of Cushingoid features 1, 2. The physical manifestations of Cushing's syndrome may resolve before HPA axis recovery occurs 2.

Do not confuse glucocorticoid withdrawal syndrome with adrenal insufficiency 2. Withdrawal symptoms (myalgia, arthralgia, malaise) can occur even with adequate cortisol levels and may require slower tapering, not higher doses 8, 2.

If the patient requires surgery or develops acute illness during the tapering period or within 12 months of stopping steroids, immediately reinstitute stress-dose corticosteroids 9, 1, 8. For major surgery, give hydrocortisone 100 mg IV just before anesthesia, then 100 mg every 6 hours until able to eat and drink 9, 1.

Special Considerations

Drug Interactions

Be aware that certain medications can affect the tapering process 7:

• Drugs that increase hydrocortisone requirements: anti-epileptics, rifampin, phenytoin, carbamazepine 7
• Drugs that decrease requirements: macrolide antibiotics, itraconazole, ritonavir (which can cause severe Cushing's syndrome even with inhaled steroids) 7, 4
• Avoid grapefruit juice and licorice, which potentiate corticosteroid effects 9, 7

Concurrent Hypothyroidism

If the patient has both adrenal insufficiency and hypothyroidism, corticosteroids must be started several days before initiating thyroid hormone replacement 7, 1. Starting thyroid hormone first can precipitate adrenal crisis by increasing cortisol metabolism 7.

Perioperative Management

Endocrine consultation is mandatory prior to any surgery or invasive procedure for stress-dose planning 7, 1. All patients on glucocorticoid therapy for longer than 1 month who will undergo surgery need perioperative glucocorticoid coverage 1.