What is the best management approach for Cushing's disease?

Management of Cushing's Disease

Transsphenoidal surgery (TSS) by an experienced neurosurgeon at a Pituitary Tumor Center of Excellence is the first-line treatment for Cushing's disease, with remission rates of approximately 80% for microadenomas and 60% for macroadenomas. 1

Diagnostic Approach

• Initial screening should include late-night salivary cortisol (LNSC) and/or 24-hour urinary free cortisol (UFC) measurements to establish hypercortisolism 1
• Dexamethasone suppression test (DST) can also be used, especially if LNSC is not feasible 1
• After confirming hypercortisolism, measure ACTH levels to differentiate ACTH-dependent from ACTH-independent causes 1
• Pituitary MRI should be performed in ACTH-dependent cases; lesions <6mm should be further evaluated with inferior petrosal sinus sampling (IPSS) 1

Surgical Management

• Surgery should be performed at specialized centers by experienced pituitary neurosurgeons 1
• Remission is typically defined as postoperative serum cortisol <55 nmol/L (<2 μg/dL) 1
• Patients in remission require glucocorticoid replacement until hypothalamic-pituitary-adrenal (HPA) axis recovery 1
• Complication rates are low (<5%) and include new-onset hypopituitarism, diabetes insipidus, CSF leak, and venous thromboembolism 1
• Lifelong monitoring for recurrence is essential, as recurrence rates range from 5-35% 1

Medical Therapy

Medical therapy is indicated for:

• Patients with persistent or recurrent disease after surgery 1
• Patients awaiting effects of radiation therapy 1
• Patients who are not surgical candidates 1

Adrenal Steroidogenesis Inhibitors

• First-line medical therapy due to reliable effectiveness 1
• Options include:
  • Ketoconazole: 400-1200 mg/day PO, normalizes UFC in ~65% of patients initially 1
  • Osilodrostat: 2-7 mg/day BID PO, normalizes UFC in 86% of patients, FDA-approved for CD when surgery is not an option or not curative 1
  • Metyrapone: 500 mg/day to 6 g/day, normalizes UFC in ~70% of patients 1

Pituitary-Directed Therapies

• Pasireotide: Somatostatin receptor ligand, 0.3-0.9 mg/mL BID, normalizes UFC in 15-26% of patients 1, 2
• Cabergoline: Dopamine agonist, useful for mild disease, less effective but requires less frequent dosing 1

Glucocorticoid Receptor Antagonist

• Mifepristone: Blocks glucocorticoid receptor action, improves glucose metabolism and weight 1
• Cannot monitor with cortisol levels; requires clinical monitoring for adrenal insufficiency 1

Treatment Selection Based on Disease Severity

Mild Disease

• For patients with mild disease and no visible tumor on MRI, ketoconazole, osilodrostat, or metyrapone are typically preferred 1
• Cabergoline may be used for mild CD but has slower onset of action 1

Severe Disease

• Rapid normalization of cortisol is the primary goal 1
• Osilodrostat and metyrapone work within hours, ketoconazole within days 1
• Etomidate (IV) can be used for hospitalized patients unable to take oral medications 1
• Combinations of steroidogenesis inhibitors may be necessary 1
• If medical therapy fails despite optimization, bilateral adrenalectomy should be considered 1

Monitoring Treatment Response

• Response should be assessed using clinical improvement and biochemical endpoints 1
• UFC and LNSC are commonly used to monitor treatment efficacy 1
• Consider changing treatment if cortisol levels remain elevated after 2-3 months on maximum tolerated doses 1
• If cortisol is reduced but not normalized with some clinical improvement, combination therapy can be considered 1

Combination Therapy Approaches

• Ketoconazole with metyrapone or osilodrostat to maximize adrenal blockade 1
• Ketoconazole plus cabergoline or pasireotide when visible tumor is present 1
• Triple therapy with cabergoline, pasireotide, and ketoconazole in resistant cases 1

Pediatric Considerations

• Medical therapy in children should be limited to normalizing cortisol levels in preparation for surgery or while awaiting response to radiotherapy 1
• Metyrapone and ketoconazole have limited long-term use in children due to adverse effects 1
• Bilateral adrenalectomy should be reserved for severe refractory cases or life-threatening emergencies 1

Long-term Follow-up

• Lifelong monitoring for recurrence is required 1
• LNSC can detect recurrence earlier than other tests 1
• Annual evaluation should be performed after HPA axis recovery 1

By following this evidence-based approach to managing Cushing's disease, clinicians can optimize outcomes and minimize the substantial morbidity and mortality associated with chronic hypercortisolism.