What is the treatment for Cushing's syndrome caused by exogenous (external) corticosteroid therapy?

From the Guidelines

Exogenous Cushing syndrome due to immune checkpoint inhibitor therapy is best managed by initiating replacement therapy with hydrocortisone at a dose of 15-20 mg in divided doses, with titration to a maximum of 30 mg daily total dose for residual symptoms of adrenal insufficiency, as recommended by the American Society of Clinical Oncology guideline update 1. The management of exogenous Cushing syndrome due to immune checkpoint inhibitor therapy involves a step-wise approach based on the severity of symptoms.

• For patients with asymptomatic or mild symptoms (G1), consideration should be given to holding immune checkpoint inhibitor therapy until the patient is stabilized on replacement hormone, with endocrine consultation and initiation of replacement therapy with hydrocortisone at a dose of 15-20 mg in divided doses 1.
• For patients with moderate symptoms (G2), immune checkpoint inhibitor therapy should be held until the patient is stabilized on replacement hormone, with endocrine consultation and initiation of outpatient corticosteroid treatment at 2-3 times maintenance dose 1.
• For patients with severe symptoms (G3-4), inpatient management may be necessary, with initiation of IV stress dose steroids and normal saline, and tapering of stress dose corticosteroids down to oral maintenance doses over 5-7 days 1. Additional considerations include the use of fludrocortisone for primary adrenal insufficiency, with a starting dose of 0.05-0.1 mg/d, and the importance of patient education on stress dosing, emergency injectables, and medical alert bracelets or necklaces 1. The goal of treatment is to manage symptoms, prevent adrenal crisis, and improve quality of life, while minimizing the risks of over-replacement and other complications. Key principles of management include:
• Gradual tapering of immune checkpoint inhibitor therapy as needed
• Initiation of replacement therapy with hydrocortisone at a dose of 15-20 mg in divided doses
• Titration of hydrocortisone to a maximum of 30 mg daily total dose for residual symptoms of adrenal insufficiency
• Use of fludrocortisone for primary adrenal insufficiency
• Patient education on stress dosing, emergency injectables, and medical alert bracelets or necklaces
• Monitoring for adrenal insufficiency symptoms and recurrence of the underlying condition being treated.

From the FDA Drug Label

The same clinical findings of hyperadrenocorticism may be noted during long-term pharmacologic dose corticoid therapy administered in conventional daily divided doses. The diurnal rhythm of the HPA axis is lost in Cushing's disease, a syndrome of adrenocortical hyperfunction characterized by obesity with centripetal fat distribution, thinning of the skin with easy bruisability, muscle wasting with weakness, hypertension, latent diabetes, osteoporosis, electrolyte imbalance, etc

Cushing syndrome exogenous therapy can be caused by long-term pharmacologic dose corticosteroid therapy.

• Key points:
  • Exogenous corticosteroids can suppress adrenocorticoid activity.
  • The clinical findings of hyperadrenocorticism, such as those seen in Cushing's disease, may be noted during long-term pharmacologic dose corticoid therapy.
  • Alternate day therapy may be used to minimize certain undesirable effects, including pituitary-adrenal suppression and the Cushingoid state.
  • Prednisone is considered a short-acting corticosteroid and may be recommended for alternate day therapy 2

From the Research

Cushing Syndrome Exogenous Therapy

• Cushing syndrome is defined as a prolonged increase in plasma cortisol levels that is not due to a physiological etiology 3.
• The most frequent cause of Cushing syndrome is exogenous steroid use 3.
• Evaluation of patients with possible Cushing syndrome begins with ruling out exogenous steroid use 3, 4.

Treatment Options

• Management of Cushing syndrome begins with surgery to remove the source of excess endogenous cortisol production followed by medication that includes adrenal steroidogenesis inhibitors, pituitary-targeted drugs, or glucocorticoid receptor blockers 3, 5.
• Medical therapy to control hypercortisolism in adrenal Cushing's syndrome is currently not the first-line therapy, but can be important in certain clinical scenarios 6.
• Adrenal steroidogenesis inhibitors and glucocorticoid receptor blockers have been used for many years, including metyrapone, ketoconazole, and mifepristone 6, 7.

Medications Used

• Metyrapone and ketoconazole are most frequently used to suppress adrenal cortisol production via inhibition of steroidogenic enzymes 7.
• Etomidate can be used to rapidly reverse cortisol excess in patients with acute complications of hypercortisolism 6, 7.
• New drugs are being tested in prospective trials, including levoketoconazole, osilidrostat, and relacorilant 6.