What is the treatment for hypercortisolism?

Treatment of Hypercortisolism

Transsphenoidal surgery is the first-line treatment for Cushing's disease (pituitary source of hypercortisolism), while adrenal-directed surgery is indicated for adrenal causes, and medical therapy is used when surgery fails or is contraindicated. 1, 2

Treatment Based on Source of Hypercortisolism

Cushing's Disease (Pituitary Source)

• Transsphenoidal surgery (TSS) is the first-line treatment, with remission rates varying from 37% to 88% 1
• Repeat TSS may be considered for recurrent disease if tumor is evident on MRI, especially if the first surgery was not performed at a specialized center 1
• Radiation therapy can achieve biochemical control in approximately 80% of patients with persistent or recurrent disease 2

Adrenal Source

• Laparoscopic adrenalectomy for benign adenomas or open adrenalectomy with lymph node removal for suspected carcinomas 2

Ectopic ACTH Source

• Surgical removal of the ectopic tumor is first-line treatment 2
• Medical therapy or bilateral adrenalectomy are alternatives when surgery is not possible 2

Medical Therapy Options

First-Line Medical Therapy: Adrenal Steroidogenesis Inhibitors

• For mild disease with no visible tumor on MRI, ketoconazole, osilodrostat, or metyrapone are typically preferred 1
• For severe disease requiring rapid cortisol normalization, osilodrostat and metyrapone work within hours, while ketoconazole works within days 1, 3
• Etomidate is the only parenteral option for critically ill patients requiring rapid control of hypercortisolemia 4, 3

Ketoconazole

• Blocks multiple adrenal enzymes, normalizing UFC in 64.3% of patients 1
• Typical dose: 600-673.9 mg/day 1
• Monitor for hepatotoxicity (10-20% of patients), which is usually mild and reversible 1
• May cause hypogonadism and gynecomastia in men 1

Osilodrostat

• Recently approved adrenal steroidogenesis inhibitor with rapid action 1, 3
• Does not require liver function monitoring and doesn't cause hypogonadism in men 1

Metyrapone

• Inhibits 11β-hydroxylase, providing rapid control of cortisol levels 4, 3
• May be considered with precautions in selected pregnant women 1

Second-Line Medical Therapy Options

Cabergoline

• Can be used for mild disease; less effective but requires less frequent dosing 1
• May be preferred for patients with visible tumor due to potential for tumor shrinkage 1
• Should not be used in patients with history of bipolar or impulse control disorder 1

Pasireotide

• FDA-approved subcutaneous injection at 0.6 mg or 0.9 mg twice daily 5
• May cause tumor shrinkage but has high rate of hyperglycemia 1, 5
• Monitor for bradycardia and QT prolongation 5

Mifepristone (Glucocorticoid Receptor Antagonist)

• Improves hyperglycemia and weight gain associated with hypercortisolism 1
• Challenging to use as cortisol measurements are not reliable for dosing or safety monitoring 1, 3
• Should only be used by clinicians with extensive experience in Cushing's disease 1

Combination Therapy Approaches

• Consider combining ketoconazole with metyrapone to maximize adrenal blockade when monotherapy is ineffective 1
• Steroidogenesis inhibitor plus tumor-targeting agent (e.g., ketoconazole plus cabergoline) is rational if visible tumor is present 1
• Monitor for overlapping toxicities, particularly QTc prolongation 1

Bilateral Adrenalectomy (BLA)

• Consider BLA when medical therapy fails to control severe hypercortisolism 1, 3
• Results in immediate control of cortisol excess but requires lifelong glucocorticoid and mineralocorticoid replacement 2
• Provides long-term clinical improvement in BMI, diabetes, hypertension, and muscle weakness in >80% of patients 2

Monitoring During Treatment

• For adrenal-targeting agents, monitor ACTH levels as significant elevations may indicate tumor growth 1
• Perform MRI 6-12 months after initiating treatment and repeat every few years 1
• With steroidogenesis inhibitors, monitor for adrenal insufficiency due to overtreatment 1, 5
• For pasireotide, monitor fasting plasma glucose, HbA1c, liver tests, serum potassium and magnesium levels, and perform baseline ECG and gallbladder ultrasound 5

Pitfalls and Caveats

• Hypopituitarism is common after radiation therapy (25-50% of patients) and generally increases over time 2
• Escape phenomenon (loss of biochemical control) occurs in up to 23% of initially responsive patients on ketoconazole 1
• Preoperative medical therapy may make it difficult to assess surgical remission 1
• Patients treated with bilateral adrenalectomy require lifelong monitoring for pituitary hormone deficiencies 2