What is Cushing's disease (Cushing's syndrome)?

From the Guidelines

Cushing's disease should be managed with a multidisciplinary approach, prioritizing accurate diagnosis, careful treatment selection, and long-term management to optimize patient outcomes, as outlined in the 2021 consensus guideline update 1. The primary treatment for Cushing's disease is transsphenoidal surgery to remove the pituitary tumor, which is successful in 70-80% of cases. If surgery fails or isn't possible, medication options include steroidogenesis inhibitors like ketoconazole (400-1200 mg/day), metyrapone (500-6000 mg/day), or mitotane (2-6 g/day), or pituitary-directed drugs like pasireotide (600-900 μg twice daily) 1. Key considerations for diagnosis and management include:

• Measuring 24-hour urinary free cortisol, late-night salivary cortisol, and low-dose dexamethasone suppression test to diagnose Cushing's syndrome
• Confirming the pituitary source with high-dose dexamethasone suppression test and pituitary MRI
• Using algorithms for diagnosis of Cushing's syndrome and management of Cushing's disease, as presented in the consensus guideline update 1 Radiation therapy may be used as a secondary treatment, though effects can take years to develop, and bilateral adrenalectomy is a last resort that requires lifelong glucocorticoid and mineralocorticoid replacement 1. Long-term monitoring is essential as recurrence can occur, and untreated disease leads to significant morbidity including cardiovascular disease, osteoporosis, and increased mortality 1.

From the Research

Definition and Causes of Cushing Disease

• Cushing disease is defined as a prolonged increase in plasma cortisol levels that is not due to a physiological etiology 2.
• It is primarily caused by a pituitary adenoma, which leads to excessive secretion of adrenocorticotropin-hormone (ACTH) and consequently cortisol 2, 3.
• The estimated incidence of Cushing syndrome due to endogenous overproduction of cortisol ranges from 2 to 8 per million people annually 2.

Symptoms and Diagnosis of Cushing Disease

• Cushing syndrome is associated with hyperglycemia, protein catabolism, immunosuppression, hypertension, weight gain, neurocognitive changes, and mood disorders 2.
• Characteristic symptoms 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 2.
• Diagnosis involves ruling out exogenous steroid use, followed by screening for elevated cortisol using a 24-hour urinary free cortisol test, late-night salivary cortisol test, or dexamethasone suppression test 2.

Treatment Options for Cushing Disease

• First-line therapy for Cushing syndrome due to endogenous overproduction of cortisol is surgery to remove the causative tumor 2, 3.
• Medical therapy is used to control hypercortisolism in patients whose disease persists or recurs after pituitary surgery, and may include steroidogenesis inhibitors, centrally acting agents, and glucocorticoid receptor antagonists 4, 5, 6.
• Bilateral adrenalectomy is a second-line treatment option that offers immediate control of hypercortisolism, but requires lifelong glucocorticoid and mineralocorticoid replacement therapy and carries the risk of developing Nelson's syndrome 3.
• Radiation therapy may also be used in patients who are not responsive to surgery and medication 2, 3.