What is the management of hypercortisolism (Cushing's syndrome)?

From the Guidelines

For patients with severe cortisol excess, the most effective management strategy is to rapidly normalize cortisol levels using steroidogenesis inhibitors such as osilodrostat and metyrapone, which can show response within hours, or ketoconazole, which works within a few days, as recommended by the most recent guideline update 1.

Management Approach

The management of cortisol excess, particularly in the context of Cushing's syndrome, requires a tailored approach based on the severity of the disease and the underlying cause.

• For severe disease, the primary goal is to quickly normalize cortisol levels to prevent further complications.
• Medications like osilodrostat, metyrapone, and ketoconazole are preferred due to their rapid action.
• In cases where hypercortisolism is very severe and not responsive to medical therapy, bilateral adrenalectomy (BLA) should be considered to avoid worsening outcomes, as indicated by the latest consensus guidelines 1.

Medical Therapy

Medical therapy plays a crucial role in managing cortisol excess when surgery is not feasible or as a bridge to surgery.

• Steroidogenesis inhibitors are the mainstay of medical treatment, with options including:
  • Osilodrostat
  • Metyrapone
  • Ketoconazole
• For pituitary-dependent Cushing's disease, additional options may include pasireotide or cabergoline.
• Mifepristone can be used to block cortisol receptors but requires careful management due to potential side effects and the challenge of monitoring its efficacy, as noted in recent guidelines 1.

Monitoring and Adjustment

Regular monitoring of cortisol levels, electrolytes, and blood pressure is essential during treatment to adjust medication doses and prevent complications.

• The goal of treatment is to normalize cortisol production while minimizing side effects.
• Untreated hypercortisolism can lead to significant metabolic complications, cardiovascular disease, and increased mortality, emphasizing the importance of effective management strategies, as highlighted by recent studies 1.

From the FDA Drug Label

Mifepristone is a cortisol receptor blocker indicated to control hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing's syndrome who have type 2 diabetes mellitus or glucose intolerance and have failed surgery or are not candidates for surgery The management of cortisol levels involves the use of mifepristone, a cortisol receptor blocker, to control hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing's syndrome.

• The recommended starting dose is 300 mg orally once daily.
• The dose of mifepristone may be increased in 300 mg increments to a maximum of 1200 mg once daily but should not exceed 20 mg/kg per day.
• Increases in dose should not occur more frequently than once every 2-4 weeks.
• Decisions about dose increases should be based on a clinical assessment of tolerability and degree of improvement in Cushing's syndrome manifestations 2

From the Research

Management of Cortisol

• The management of cortisol levels is crucial in treating Cushing's syndrome, a condition associated with serious morbidity and increased mortality 3.
• Medical therapy is often required when surgery is unsuccessful or contraindicated, and it involves the use of adrenal-blocking agents, neuromodulatory drugs, and glucocorticoid receptor antagonists 3, 4.
• Adrenal-blocking drugs, such as ketoconazole and metyrapone, suppress adrenal cortisol production via inhibition of steroidogenic enzymes, but chronic treatment can be limited by side effects like hepatotoxicity and increased androgen and mineralocorticoid production 3, 5.

Treatment Options

• Etomidate can be used to rapidly reverse cortisol excess in patients with acute complications of hypercortisolism, such as psychosis 3, 6.
• Combination therapy with drugs that target the corticotropic adenoma, such as pasireotide and cabergoline, and low-dose ketoconazole may be a rational approach to achieve biochemical control in Cushing's disease 3.
• Mifepristone, a glucocorticoid receptor antagonist, can improve clinical aspects of Cushing's disease, but its use is limited by difficulties in monitoring its efficacy and safety 5, 6.

Severe Hypercortisolism

• Severe hypercortisolism is a life-threatening condition that requires rapid normalization of cortisol concentrations and aggressive treatment of associated complications 6.
• Adrenal steroidogenesis inhibitors, such as etomidate, ketoconazole, and metyrapone, are commonly used as first-line treatment for severe hypercortisolemia due to their rapid action and good efficacy and safety profile 6.
• Bilateral adrenalectomy may be indicated as a life-saving measure when medical therapies fail, are unavailable, or contraindicated 6.