What are the treatment options for reducing cortisol levels in patients with Cushing's disease?

Treatment Options for Reducing Cortisol Levels in Cushing's Disease

Transsphenoidal surgery is the first-line treatment for Cushing's disease, with medical therapy reserved for patients with persistent or recurrent disease after surgery, those awaiting definitive treatment, or when surgery is contraindicated. 1, 2

First-Line Treatment Approach

• Selective transsphenoidal adenomectomy should be performed by an experienced pituitary surgeon, with remission rates varying from 37% to 88% 1, 2
• Early post-operative remission is associated with successful identification of the adenoma during surgery, while factors predicting long-term remission include younger age, smaller adenoma size, and absence of cavernous sinus invasion 2
• Lifelong follow-up is essential as recurrence can occur up to 15 years after apparent surgical cure 2

Medical Therapy Options for Persistent or Recurrent Disease

Adrenal Steroidogenesis Inhibitors

• Ketoconazole, osilodrostat, or metyrapone are recommended as first-line medical therapies for controlling hypercortisolism, with osilodrostat and metyrapone working within hours and ketoconazole within days 1
• Ketoconazole is the most commonly used drug due to its rapid action, but requires monitoring for hepatotoxicity 3, 4
• Metyrapone effectively reduces cortisol levels but may increase androgen and mineralocorticoid production, requiring careful monitoring 3
• Etomidate can be used for rapid reversal of severe hypercortisolism in acute settings, such as psychosis 3

Pituitary-Directed Medications

• Cabergoline (dopamine agonist) can be used for mild disease and may be preferred for patients with visible tumors due to potential tumor shrinkage 1, 5
• Pasireotide (somatostatin analog) is FDA-approved for Cushing's disease when surgery has failed or is not an option, though it requires monitoring for hyperglycemia 1, 5
• Pituitary-directed drugs have the advantage of acting at the source of the disease 5

Glucocorticoid Receptor Antagonists

• Mifepristone is recommended for improving hyperglycemia and weight gain associated with hypercortisolism, and is FDA-approved for Cushing's syndrome with glucose metabolism impairment when surgery is not indicated 1, 5
• Should only be used by clinicians with extensive experience in Cushing's disease management 1

Combination Therapy Approaches

• When monotherapy is ineffective, combining ketoconazole with metyrapone can maximize adrenal blockade 1, 4
• Combination of pituitary-directed drugs (pasireotide and/or cabergoline) with low-dose ketoconazole is a rational approach to achieve biochemical control 3
• Monitor for overlapping toxicities with combination therapies, particularly QTc prolongation and drug-drug interactions 4

Radiation Therapy Options

• Radiation therapy is indicated for recurrent disease not amenable to curative surgery 2
• Options include stereotactic radiotherapy, fractionated proton beam therapy, and gamma knife radiosurgery 2
• Achieves biochemical control in approximately 80% of patients but may cause hypopituitarism in 25-50% of patients 1, 2

Bilateral Adrenalectomy

• Consider bilateral adrenalectomy when medical therapy fails to control severe hypercortisolism 1
• Provides immediate control of cortisol excess but requires lifelong glucocorticoid and mineralocorticoid replacement 1
• Results in long-term clinical improvement in BMI, diabetes, hypertension, and muscle weakness in >80% of patients 1

Monitoring During Treatment

• For adrenal-targeting agents, monitor ACTH levels as significant elevations may indicate tumor growth 4
• Perform MRI 6-12 months after initiating treatment and repeat every few years 4, 1
• With steroidogenesis inhibitors, monitor for adrenal insufficiency due to overtreatment 1
• For pasireotide, perform baseline ECG and gallbladder ultrasound 1

Important Pitfalls and Caveats

• When using combination therapies, monitor for potential overlapping toxicities, particularly QTc prolongation 4
• Preoperative medical therapy may make it difficult to assess surgical remission 1
• The "escape phenomenon" occurs in up to 23% of initially responsive patients on ketoconazole 1
• With adrenal-targeting agents, tumor growth may occur due to ACTH-cortisol feedback interruption, requiring careful monitoring 4