What is the recommended treatment for an adult patient with suspected or confirmed Cushing's syndrome?

Treatment of Cushing's Syndrome

For adult patients with confirmed Cushing's syndrome, unilateral adrenalectomy is the definitive treatment when caused by a unilateral cortisol-secreting adrenal mass with clinical symptoms, and minimally-invasive surgery should be performed when feasible. 1

Treatment Algorithm Based on Etiology

Endogenous Cushing's Syndrome with Clinical Symptoms

Surgical resection is first-line therapy for all etiologies of endogenous Cushing's syndrome. 1, 2

• Unilateral cortisol-secreting adrenal masses: Perform unilateral adrenalectomy of the affected gland using minimally-invasive surgery when feasible 1
• Pheochromocytomas and aldosterone-secreting adenomas: Adrenalectomy should be performed, with MIS preferred when feasible 1
• Suspected adrenocortical carcinoma (ACC): Resection is recommended, though surgical approach (laparoscopic vs. open) remains controversial 1

Mild Autonomous Cortisol Secretion (MACS)

For patients with cortisol-secreting lesions without overt Cushing's symptoms (formerly called subclinical Cushing's):

• Younger patients with progressive metabolic comorbidities (diabetes, hypertension, cardiovascular events, vertebral fractures) attributable to cortisol excess can be considered for adrenalectomy after shared decision-making 1
• Patients managed non-surgically should undergo annual clinical screening for new or worsening comorbidities 1
• Important caveat: MACS has low risk of progression to overt Cushing's syndrome but still contributes to significant medical comorbidity 1

Medical Therapy for Endogenous Cushing's Syndrome

When surgery is not an option, has failed, or while awaiting definitive treatment:

First-Line Medical Agents: Adrenal Steroidogenesis Inhibitors

The Endocrine Society recommends adrenal steroidogenesis inhibitors as first-line medical therapy, with ketoconazole, osilodrostat, or metyrapone as preferred agents. 3

• Osilodrostat: 2-7 mg twice daily orally; 86% achieve urinary free cortisol (UFC) normalization in Phase 3 studies; provides rapid response within hours 3, 4
• Ketoconazole: 400-1200 mg/day orally divided twice daily; approximately 65% achieve UFC normalization 3
• Metyrapone: 500 mg/day to 6 g/day; approximately 70% achieve UFC normalization with rapid decrease typically within the first month 3

Disease Severity-Based Selection

• Mild disease: Ketoconazole, osilodrostat, or metyrapone are preferred 3
• Moderate disease with residual tumor: Cabergoline or pasireotide may be preferred due to potential for tumor shrinkage 3
• Severe disease: Osilodrostat and metyrapone provide response within hours, making rapid cortisol normalization achievable 3

Glucocorticoid Receptor Blocker

• Mifepristone: Blocks cortisol action at the glucocorticoid receptor; 60% achieve ≥25% reduction in glucose area under the curve after 24 weeks 3
• Critical monitoring caveat: Cortisol levels remain elevated with mifepristone, so only clinical features can assess treatment response 3, 5

Treatment of Exogenous (Iatrogenic) Cushing's Syndrome

Immediately discontinue the causative glucocorticoid if medically feasible, followed by gradual tapering to prevent adrenal insufficiency. 3, 5

Discontinuation Protocol

• Stop all sources of exogenous glucocorticoids: oral, injectable, inhaled, and topical preparations 3
• Taper gradually rather than abrupt cessation to avoid precipitating adrenal crisis, as the HPA axis remains suppressed 3
• Consider switching to lower-dose inhaled steroids or alternative medications if complete discontinuation is not possible 3

Management of Complications During Tapering

Hypertension management:

• Use spironolactone 25-50 mg daily or eplerenone 50-100 mg daily as first-line therapy, as these mineralocorticoid receptor antagonists directly counteract cortisol's mechanism of causing hypertension 3, 5

Hyperglycemia management:

• Initiate metformin as first-line therapy, or consider GLP-1 receptor agonists or DPP-4 inhibitors 3, 5
• Monitor blood glucose closely during taper as insulin requirements will decrease 5

Osteoporosis prevention:

• Prescribe calcium 1000-1500 mg daily and vitamin D 800-1000 IU daily immediately for patients who received prednisone >7.5 mg daily for >3 months 3, 5

Monitoring During Tapering

• Assess body weight to track resolution of central obesity 3, 5
• Monitor blood pressure at each visit 3, 5
• Check fasting glucose or HbA1c every 4-8 weeks 3, 5
• Monitor serum potassium if on mineralocorticoid antagonists, at each dose reduction (every 2-4 weeks) 3, 5
• Measure morning cortisol level once daily dose reaches physiologic range (≤5 mg prednisone) to assess HPA axis recovery 3, 5
• Continue stress-dose coverage until HPA axis recovery is confirmed, which may take up to 12 months after prolonged high-dose therapy 3, 5

Monitoring Treatment Outcomes

• Use multiple serial tests of both UFC and late-night salivary cortisol (LNSC) to monitor treatment outcomes 3
• UFC average requires 2-3 collections, and LNSC requires ≥2 on consecutive days 3

Common Pitfalls to Avoid

• Do not assume all Cushing's syndrome is exogenous: Rule out endogenous causes before attributing symptoms solely to medication 5
• Avoid abrupt glucocorticoid cessation: This can precipitate life-threatening adrenal crisis 3
• Do not use live vaccines until HPA axis recovery is confirmed: Immunosuppression persists during tapering 5
• Recognize that MACS does not progress to overt Cushing's: However, it still causes significant metabolic morbidity requiring intervention in select patients 1