What are the current treatment options for hypercortisolism?

Treatment Options for Hypercortisolism

For hypercortisolism, adrenal steroidogenesis inhibitors (osilodrostat, metyrapone, or ketoconazole) should be used as first-line medical therapy, with osilodrostat preferred for its highest efficacy, while severe cases require rapid normalization with these agents or bilateral adrenalectomy if medical therapy fails. 1

Treatment Selection Based on Disease Severity

Mild Hypercortisolism

• Ketoconazole, osilodrostat, or metyrapone are typically preferred for patients with mild disease and no visible tumor on MRI 1
• Cabergoline may be used for mild disease, though it is less effective and has a slower onset of action, requiring less frequent dosing 1
• For mild-to-moderate disease with residual tumor, cabergoline or pasireotide may be preferred due to potential for tumor shrinkage, though pasireotide carries a high risk of hyperglycemia requiring critical patient selection 1

Severe Hypercortisolism

• Rapid normalization of cortisol is the most important goal in severe disease 1
• Osilodrostat and metyrapone produce response within hours, while ketoconazole works within a few days 1
• Etomidate can be used for hospitalized patients unable to take oral medications, as it works rapidly 1, 2
• If hypercortisolism is very severe and not responsive to optimized medical therapy including combinations, bilateral adrenalectomy should be considered to avoid worsening outcomes 1

Specific Medication Options

Adrenal Steroidogenesis Inhibitors (First-Line)

• Osilodrostat: Highest efficacy based on prospective clinical trials, rapid onset within hours 1, 3
• Metyrapone: Rapid onset within hours, not limited by liver function monitoring, no hypogonadism in men 1, 3
• Ketoconazole: Effective within days, favored for ease of dose titration, though often under-dosed due to hepatotoxicity concerns 1, 3
• Etomidate: For severe cases requiring hospitalization and rapid control 1
• Mitotane: Available for cortisol reduction 1

Tumor-Targeting Agents

• Pasireotide: Can provide tumor shrinkage but causes high rates of hyperglycemia requiring weekly glucose monitoring for 2-3 months 1, 4
• Cabergoline: Slower onset, useful for mild disease or when tumor shrinkage desired, contraindicated in bipolar or impulse control disorders 1

Glucocorticoid Receptor Antagonist

• Mifepristone: Improves hyperglycemia and weight gain specifically, but challenging to use due to lack of reliable biochemical markers for monitoring cortisol levels 1
• Should only be used by clinicians with extensive experience in Cushing's disease, as cortisol measurements are unreliable for dosing and safety monitoring 1
• Often worsens hypokalemia and has long half-life requiring several days of stress-dose glucocorticoid replacement if adrenal insufficiency develops 1

Combination Therapy Strategies

When to Use Combinations

• Combination therapy should be used when monotherapy is not effective or to allow lower doses of individual drugs 1
• For patients with persistent hypercortisolism even during trough periods, combination therapy is strongly recommended to maximize adrenal blockade 3

Effective Combination Regimens

• Ketoconazole plus metyrapone: Maximizes adrenal blockade when monotherapy insufficient 1, 3
• Steroidogenesis inhibitor plus tumor-targeting agent (e.g., ketoconazole plus cabergoline): Rational combination especially if visible tumor present 1, 3
• Triple therapy: Cabergoline, pasireotide, plus ketoconazole or metyrapone, ketoconazole plus mitotane for severe cases 1, 3

Combination Therapy Precautions

• Risk for potentiating adverse effects such as QTc prolongation must be considered 1

Surgical Management

Bilateral Adrenalectomy

• Laparoscopic bilateral adrenalectomy can rapidly decrease circulating cortisol levels to allow patients with rapidly progressive disease to begin definitive treatment in a timely manner 1
• Should be considered as rescue therapy when severe hypercortisolism is not responsive to optimized medical therapy 1
• Replacement glucocorticoid therapy will be needed to prevent adrenal insufficiency 1

Special Clinical Contexts

Paraneoplastic Cushing's Syndrome (Ectopic ACTH)

• Hypercortisolism represents a significant barrier to effective cancer treatment because it increases risk for therapy-induced complications 1
• Mortality of patients with small cell lung cancer and Cushing's syndrome is high after chemotherapy induction due to severe opportunistic infections 1
• Venous thromboembolism risk is approximately 2% without surgery and 4% after surgery due to increased clotting factors 1
• Treatment of hypercortisolism must be initiated prior to chemotherapy or surgery to permit more-effective cancer treatment with less risk 1

Pregnancy Considerations

• Cabergoline should not be used in patients with bipolar or impulse control disorder but may be preferred in young women desiring pregnancy 1
• Metyrapone may be considered with precautions in selected pregnant women, using higher cortisol target of 1.5 × upper limit of normal 1

Cyclic Cushing's Syndrome

• Block-and-replace regimen may be particularly useful to maintain stable cortisol levels 3
• This involves complete blockade of cortisol production with steroidogenesis inhibitors while simultaneously providing glucocorticoid replacement 3
• Multiple, periodic, sequential late-night salivary cortisol measurements are useful for longitudinal surveillance 3

Critical Monitoring Requirements

Adrenal Steroidogenesis Inhibitors

• Monitor for adrenal insufficiency (weakness, fatigue, anorexia, nausea, vomiting, hypotension, hyponatremia, hypoglycemia) 4
• Regular monitoring for treatment efficacy with multiple serial tests of urinary free cortisol and late-night salivary cortisol 3
• Morning cortisol values may be especially pertinent in patients taking higher medication doses in the evening 3

Ketoconazole-Specific Monitoring

• Liver function tests should be regularly monitored, but treatment does not necessarily have to be discontinued if liver enzymes are mildly elevated yet stable 1, 3

Pasireotide-Specific Monitoring

• Glycemic monitoring should be done every week for the first 2-3 months and periodically thereafter, as well as over the first 2-4 weeks after any dose increase 4
• Nearly all patients develop worsening glycemia in the first two weeks of treatment 4
• Baseline ECG recommended with monitoring for QTc interval effects 4
• Hypokalemia and hypomagnesemia must be corrected prior to administration and monitored periodically 4

Clinical Parameters

• Weight, glycemia, and blood pressure should be monitored as key clinical symptoms and comorbidities 3

Common Pitfalls and How to Avoid Them

• Avoid under-dosing ketoconazole due to fear of hepatotoxicity; liver function tests should be monitored but mild stable elevations do not require discontinuation 1, 3
• Do not use mifepristone without extensive experience in Cushing's disease management, as cortisol level monitoring is unreliable 1
• Ensure intensive optimization of anti-diabetic therapy before starting pasireotide in patients with uncontrolled diabetes, as those with HbA1c >8% are at higher risk of severe hyperglycemia and ketoacidosis 4
• Avoid glucocorticoid over-replacement when using block-and-replace regimens to prevent inducing iatrogenic Cushing's syndrome 3
• Recognize that severe hypercortisolism is a medical emergency requiring specific and prompt combined medical and surgical intervention 2