What is the treatment for Cushing's disease?

Treatment of Cushing's Disease

Transsphenoidal surgery (TSS) to resect the ACTH-secreting pituitary adenoma is the first-line treatment for Cushing's disease, achieving remission in approximately 78% of patients. 1

Primary Treatment: Surgical Resection

• TSS should be performed by an experienced pituitary neurosurgeon as the initial definitive treatment, with remission rates around 78% and long-term recurrence occurring in approximately 13% of patients over 10 years. 2
• Immediate postoperative cortisol levels help determine surgical success; low cortisol (<5 μg/dL) indicates likely remission and requires glucocorticoid replacement. 1
• Patients require lifelong surveillance for recurrence, as relapse can occur decades after initially successful surgery. 2, 3

Preoperative Medical Therapy (Selected Cases)

• Adrenal steroidogenesis inhibitors may be used preoperatively in patients with severe, life-threatening hypercortisolism to rapidly control metabolic, cardiovascular, infectious, or psychiatric complications before surgery. 1
• Osilodrostat and metyrapone provide rapid cortisol reduction within hours; ketoconazole acts within days. 1
• Preoperative therapy complicates postoperative assessment of surgical cure, as cortisol levels cannot reliably indicate remission. 1

Second-Line Treatment for Persistent or Recurrent Disease

Medical Therapy Options

For patients with persistent or recurrent disease after surgery, medical therapy should be individualized based on disease severity:

Adrenal Steroidogenesis Inhibitors (First Choice for Most Patients)

• Osilodrostat provides rapid, reliable cortisol reduction with 80% biochemical control and durable hypercortisolism control in 57% of patients, though it carries risks of hypocortisolism, hypokalemia, QTc prolongation, and hyperandrogenism in women. 1
• Ketoconazole achieves approximately 70% UFC normalization and is preferred for mild disease without visible tumor on MRI, but requires monitoring for hepatotoxicity and has multiple drug-drug interactions. 1
• Metyrapone normalizes UFC in approximately 70% of patients with rapid onset (hours), but causes hyperandrogenism and hypokalemia requiring monitoring. 1

Pituitary-Directed Medications

• Pasireotide (FDA-approved for Cushing's disease when surgery has failed or is not an option) achieves 15-26% UFC normalization with twice-daily dosing (0.6-0.9 mg) or 40% with monthly LAR formulation, but carries a very high risk of hyperglycemia requiring careful patient selection and should be avoided in patients with HbA1c >8%. 4, 1
• Cabergoline normalizes UFC in approximately 40% of patients and may shrink tumors in up to 50%, making it preferred for mild-to-moderate disease with residual tumor, though 25-40% experience treatment escape and it should be avoided in patients with bipolar disorder or impulse control issues. 1

Glucocorticoid Receptor Antagonist

• Mifepristone (FDA-approved for hyperglycemia associated with Cushing's syndrome) improves glycemia in 60% and blood pressure in 38% of patients, making it particularly useful for patients with diabetes, but cortisol levels remain elevated and only clinical features can assess for adrenal insufficiency, requiring specialized monitoring. 1

Severe Disease Management

• For severe, life-threatening hypercortisolism, combination therapy with multiple steroidogenesis inhibitors should be used to achieve rapid cortisol normalization. 1
• Etomidate (IV) provides very rapid cortisol control within hours for hospitalized ICU patients who cannot take oral medications, though it causes sedation. 1
• If severe hypercortisolism remains uncontrolled despite optimized medical therapy, bilateral adrenalectomy (BLA) should be performed to prevent further morbidity and mortality. 1, 5

Radiation Therapy

• Stereotactic radiosurgery (SRS) is the preferred radiation modality for persistent hypercortisolism after incomplete tumor resection, achieving biochemical control in 80% and durable control in 57% of patients, with tumor control in approximately 95%. 1
• SRS requires maintaining at least 3-5 mm distance from the optic chiasm with chiasm dose <8 Gy to prevent damage. 1
• Adjuvant medical therapy is mandatory during the latency period (months to years) until radiation achieves remission, with periodic withdrawal to assess treatment effect. 1
• Hypopituitarism occurs in 25-50% of patients after radiation and increases over time, requiring lifelong monitoring for pituitary hormone deficiencies. 1

Bilateral Adrenalectomy

• BLA provides immediate, definitive control of cortisol excess and should be considered earlier in patients with severe complications such as left ventricular hypertrophy and cirrhosis requiring rapid cortisol normalization. 1, 5
• BLA is recommended for females with Cushing's disease desiring pregnancy at many expert centers, as it provides definitive control without teratogenic medication risks. 1
• Laparoscopic BLA has a 10-18% complication rate and <1% mortality, with clinical improvement in BMI, diabetes, hypertension, and muscle weakness in >80% of patients. 1
• Lifelong glucocorticoid and mineralocorticoid replacement is required after BLA, and corticotroph tumor progression (Nelson's syndrome) occurs in 25-40% of patients after 5-10 years, necessitating lifelong pituitary MRI surveillance every 6 months initially. 1, 5

Critical Monitoring Considerations

• Multiple serial measurements of 24-hour urinary free cortisol (UFC) and late-night salivary cortisol (LNSC) are essential for monitoring treatment response, as single measurements are unreliable. 1
• All patients require lifelong surveillance for recurrence, treatment-related adverse effects, and development of hypopituitarism. 1, 6
• Common pitfall: Underestimating disease severity and delaying aggressive treatment, which allows progression of irreversible cardiovascular, metabolic, and psychiatric complications that may persist even after biochemical cure. 3, 7