What are the treatment options for Cushing's syndrome?

From the Guidelines

The first-line treatment for Cushing syndrome caused by pituitary adenomas (Cushing disease) is transsphenoidal surgery to remove the tumor, as recommended by the most recent consensus guideline 1. This approach is supported by the latest evidence, which suggests that selective adenomectomy is the treatment of choice for Cushing disease, with a strong recommendation and moderate-quality evidence 1.

Key Considerations

• The treatment of Cushing syndrome depends on its underlying cause, with different approaches for ACTH-dependent and ACTH-independent cases.
• For ACTH-dependent Cushing syndrome caused by pituitary adenomas, transsphenoidal surgery is the preferred initial treatment.
• Medical therapies, such as metyrapone and ketoconazole, may be used to reduce cortisol levels in patients awaiting surgery or as an adjunct to other treatments, but their use is limited due to potential adverse effects 1.
• Bilateral adrenalectomy is reserved for severe refractory Cushing disease or life-threatening emergencies, due to the risk of Nelson syndrome 1.

Treatment Options

• Transsphenoidal surgery: the first-line treatment for Cushing disease, with a strong recommendation and moderate-quality evidence 1.
• Medical therapies: may be used to reduce cortisol levels, but with careful consideration of potential adverse effects and limited long-term efficacy 1.
• Bilateral adrenalectomy: reserved for severe refractory Cushing disease or life-threatening emergencies, with a strong recommendation and low-quality evidence 1.

Monitoring and Follow-up

• Patients require careful monitoring of cortisol levels, electrolytes, and blood pressure during treatment.
• Medical therapy may cause side effects, including hepatotoxicity, hypokalemia, and gastrointestinal distress.
• After successful treatment, patients often need temporary glucocorticoid replacement therapy as the hypothalamic-pituitary-adrenal axis recovers.

From the FDA Drug Label

14 CLINICAL STUDIES 14. 1 Cushing's Syndrome An uncontrolled, open-label, 24-week, multicenter clinical study was conducted to evaluate the safety and efficacy of mifepristone in the treatment of endogenous Cushing's syndrome.

The study enrolled 50 subjects with clinical and biochemical evidence of hypercortisolemia despite prior surgical treatment and radiotherapy Mifepristone treatment was started in all patients at a dose of 300 mg once a day The study protocol allowed an increase in dose to 600 mg after 2 weeks, and then by additional 300 mg increments every 4 weeks to a maximum of 900 mg per day for patients <60 kg, or 1200 mg per day for patients >60 kg, based on clinical tolerance and clinical response Individual patients showed varying degrees of improvement in Cushing's syndrome manifestations such as cushingoid appearance, acne, hirsutism, striae, psychiatric symptoms, and excess total body weight

Mifepristone Therapy for Cushing's Syndrome

• Mifepristone is used in the treatment of endogenous Cushing's syndrome.
• The initial dose is 300 mg once a day, with possible increases to 600 mg after 2 weeks, and then by additional 300 mg increments every 4 weeks.
• The maximum dose is 900 mg per day for patients <60 kg, or 1200 mg per day for patients >60 kg, based on clinical tolerance and clinical response.
• Mifepristone has been shown to improve Cushing's syndrome manifestations such as cushingoid appearance, acne, hirsutism, striae, psychiatric symptoms, and excess total body weight 2.

From the Research

Cushing Syndrome Therapy

• The primary treatment for Cushing's disease is transsphenoidal surgery to remove the ACTH-secreting adenoma 3.
• Pituitary surgery is the first line therapy for removal of the ACTH-secreting adenoma, with high post-operative remission rates in experienced hands 3.
• Medical therapy may have either a primary or adjunctive role if the patient cannot safely undergo surgery, if surgery fails, or if the tumor recurs 4.
• Medical therapies for Cushing's disease include steroidogenesis inhibitors, such as mitotane, metyrapone, ketoconazole, and aminoglutethimide, which are the agents of choice for medical therapy of Cushing's disease 4.
• Novel medical therapies, such as osilodrostat and levoketoconazole, are being developed and have shown increased efficacy and better tolerability in clinical trials 5.
• Radiation therapy and bilateral adrenalectomy may be appropriate for patients not responsive to surgery and medication 6, 7.
• Management of Cushing syndrome begins with surgery to remove the source of excess endogenous cortisol production, followed by medication, which may include adrenal steroidogenesis inhibitors, pituitary-targeted drugs, or glucocorticoid receptor blockers 7.

Treatment Options

• Transsphenoidal surgery: the primary treatment for Cushing's disease 3.
• Medical therapy: may have either a primary or adjunctive role, including steroidogenesis inhibitors and novel therapies 5, 4.
• Radiation therapy: may be appropriate for patients not responsive to surgery and medication 6, 7.
• Bilateral adrenalectomy: may be appropriate for patients not responsive to surgery and medication 6, 7.

Factors Affecting Treatment Outcome

• Tumor size and invasiveness: patients with small, non-invasive tumors have the highest chance for cure 3.
• Visibility of the tumor on pre-operative MRI: tumor visibility on MRI increases the chances of successful surgery 3.
• Experience of the surgeon: high-volume pituitary neurosurgeons have higher success rates 3.