What is the diagnosis and treatment for Cushing's syndrome (Hypercortisolism)?

From the Guidelines

Cushing's syndrome should be treated based on the underlying cause, with surgery, radiation therapy, or medications like ketoconazole (400-1200 mg/day) being considered, and lifelong monitoring is crucial to prevent serious complications. The treatment approach depends on whether the condition is exogenous, resulting from prolonged use of corticosteroid medications, or endogenous, caused by a tumor producing excessive cortisol 1. For endogenous Cushing's syndrome, identifying the source of excessive cortisol production, such as a pituitary tumor, adrenal tumor, or ectopic tumor, is critical for determining the appropriate treatment strategy.

Treatment Options

• Surgery: Transsphenoidal surgery for pituitary tumors or adrenalectomy for adrenal tumors can be effective treatments for Cushing's syndrome, with the goal of removing the source of excessive cortisol production 1.
• Radiation Therapy: For cases where surgery is not possible or has failed, radiation therapy, including fractionated proton beam radiotherapy, can be considered, especially in pediatric patients with recurrent Cushing disease 2.
• Medications: Ketoconazole (400-1200 mg/day), metyrapone (250-750 mg every 4 hours), or mifepristone (300-1200 mg/day) can be used to block cortisol production or effects, although their use in children is limited due to potential adverse effects and the importance of normalizing childhood growth and puberty 3.

Diagnostic Approach

• Elevated levels of cortisol in 24-hour urine tests are indicative of Cushing syndrome, and further tests, such as imaging studies and adrenal vein sampling, may be necessary to determine the source of excessive cortisol production 1.
• The presence of elevated ACTH levels suggests that the excessive cortisol secretion is not coming from the adrenal gland, pointing towards pituitary or ectopic tumors as potential sources 1.

Importance of Early Diagnosis and Treatment

Early diagnosis and treatment of Cushing's syndrome are crucial to prevent serious complications such as osteoporosis, diabetes, and cardiovascular disease, which can result from the disruptive effects of excess cortisol on normal metabolic processes 1, 3, 2. Lifelong monitoring is necessary for patients with Cushing's syndrome, even after successful treatment, to manage potential long-term effects and adjust treatment as needed.

From the FDA Drug Label

Adverse Reactions Associated with Unapproved Uses Ketoconazole has been used in high doses for the treatment of advanced prostate cancer and for Cushing’s syndrome when other treatment options have failed. The FDA drug label does not provide direct information to fully answer the question about Cushing's syndrome. However, ketoconazole is mentioned to have been used in high doses for the treatment of Cushing’s syndrome when other treatment options have failed, although this use is not approved by the FDA 4.

• Metyrapone is used as a diagnostic test, with urinary 17-OHCS measured as an index of pituitary ACTH responsiveness, and it may also suppress biosynthesis of aldosterone, resulting in a mild natriuresis [5] [6]. The information provided in the drug labels does not directly support a conclusion about the use of these medications for Cushing's syndrome.

From the Research

Definition and Causes of Cushing's Syndrome

• Cushing's syndrome is defined as a prolonged increase in plasma cortisol levels that is not due to a physiological etiology 7.
• The most frequent cause of Cushing's syndrome is exogenous steroid use, but endogenous overproduction of cortisol can also occur, with an estimated incidence of 2 to 8 per million people annually 7.
• Cushing's disease, caused by an adrenocorticotrophin (ACTH) secreting pituitary adenoma, is the commonest cause of endogenous hypercortisolism and occurs in approximately 60% to 70% of patients with Cushing's syndrome due to endogenous cortisol production 8, 7.

Clinical Presentation and Diagnosis

• Cushing's syndrome is associated with hyperglycemia, protein catabolism, immunosuppression, hypertension, weight gain, neurocognitive changes, and mood disorders 7.
• Characteristic presentations include skin changes such as facial plethora, easy bruising, and purple striae, as well as metabolic manifestations like hyperglycemia, hypertension, and excess fat deposition in the face, back of the neck, and visceral organs 7.
• Screening tests for Cushing's syndrome include the overnight dexamethasone suppression test, the low-dose dexamethasone suppression test, late night salivary cortisol, and 24-hour urinary free cortisol test 8, 7, 9, 10.
• Plasma ACTH measurement and imaging procedures such as MRI and bilateral inferior petrosal sinus sampling are used to confirm the diagnosis and identify the source of excess cortisol production 8, 7, 9, 10.

Management and Treatment

• The management of Cushing's syndrome depends on the exact knowledge of its various causes, and the choice of treatment depends on the underlying cause of the syndrome 8, 7, 9.
• First-line therapy for Cushing's syndrome due to endogenous overproduction of cortisol is surgery to remove the causative tumor, followed by medication that includes adrenal steroidogenesis inhibitors, pituitary-targeted drugs, or glucocorticoid receptor blockers 8, 7.
• Radiation therapy and bilateral adrenalectomy may be considered for patients who are not responsive to surgery and medication 8, 7.
• Medical treatment with agents that inhibit adrenal steroidogenesis, such as metyrapone, ketoconazole, mitotane, and etomidate, can be used in preparation for surgery, when an operation has been unsuccessful, or when the effects of radiotherapy are being awaited 8.