Cushing syndrome

Cushing syndrome results from chronic exposure to excess glucocorticoids, which disrupts normal metabolic and immune functions. The most common endogenous cause is an ACTH-secreting pituitary adenoma, termed Cushing disease, accounting for about 70% of cases. Other causes include ectopic ACTH production by tumors (e.g., small-cell lung cancer) and primary adrenal disorders such as adrenal adenomas or carcinomas. Exogenous glucocorticoid therapy is the most frequent overall cause, often prescribed for inflammatory or autoimmune conditions. The excess cortisol leads to central obesity, insulin resistance, hypertension, and osteoporosis, among other effects.

Patients typically present with a characteristic phenotype: moon facies, buffalo hump, supraclavicular fat pads, and purple striae. However, the presentation can be variable, and mild cases may be mistaken for metabolic syndrome. Diagnosis involves screening tests such as the 24-hour urinary free cortisol, late-night salivary cortisol, and the 1-mg dexamethasone suppression test. Once hypercortisolism is confirmed, further testing—including plasma ACTH levels, CRH stimulation, and inferior petrosal sinus sampling—helps determine the etiology. Imaging (MRI of the pituitary, CT of the adrenals) localizes the lesion. Early diagnosis is critical because untreated Cushing syndrome is associated with increased cardiovascular morbidity and mortality.

The treatment approach depends on the underlying cause. For Cushing disease, transsphenoidal surgery to remove the pituitary adenoma is the first-line therapy, with remission rates of 70–90% in expert centers. Adrenal tumors are treated with unilateral adrenalectomy, while ectopic ACTH syndrome requires resection of the primary tumor when feasible. When surgery is not possible or fails, medical therapy with steroidogenesis inhibitors (e.g., ketoconazole, metyrapone, osilodrostat) or glucocorticoid receptor antagonists (mifepristone) may be used. Radiation therapy is reserved for persistent or recurrent pituitary disease. With successful treatment, symptoms gradually improve, but patients may experience adrenal insufficiency and require long-term glucocorticoid replacement. Prognosis is generally good if the cause is benign and treated early, but persistent hypercortisolism carries a 4–5-fold increased mortality risk.

Beyond the classic presentation, Cushing syndrome has several lesser-known facets. Cyclic Cushing syndrome is a rare variant where cortisol secretion fluctuates, making diagnosis challenging and requiring repeated testing. Pseudo-Cushing syndrome, often due to alcohol dependence or depression, mimics the condition but resolves with treatment of the underlying cause. In children, the most common cause is iatrogenic (glucocorticoid therapy), and growth retardation is a prominent feature. Harvey Cushing himself described the syndrome in a 1912 paper, but it was not until 1932 that he linked it to a pituitary basophil adenoma. The condition has been reported in animals, particularly dogs and horses, where it is known as hyperadrenocorticism. Additionally, the use of topical or inhaled glucocorticoids can occasionally cause Cushing syndrome, a fact often overlooked in clinical practice.

ACTH

Adrenocorticotropic hormone, produced by the pituitary gland, stimulates cortisol secretion from the adrenal cortex.

Cushing disease

Cushing syndrome caused by an ACTH-secreting pituitary adenoma.

Ectopic ACTH syndrome

ACTH production from a non-pituitary tumor, often small-cell lung cancer.

Dexamethasone suppression test

A test that evaluates cortisol suppression after administration of dexamethasone, used to diagnose hypercortisolism.

Inferior petrosal sinus sampling

A procedure to measure ACTH levels in veins draining the pituitary, distinguishing pituitary from ectopic sources.