Practice EssentialsCushing syndrome is caused by prolonged exposure to elevated levels of either endogenous glucocorticoids or exogenous glucocorticoids. Endogenous glucocorticoid overproduction or hypercortisolism that is independent of ACTH is usually due to a primary adrenocortical neoplasm (usually an adenoma but rarely a carcinoma). Bilateral micronodular hyperplasia and macronodular hyperplasia are rare causes of Cushing syndrome.Signs and symptomsThe following are signs and symptoms of Cushing syndrome: Weight gain, especially in the face, supraclavicular region, upper back, and torso Skin changes (eg, purple stretch marks, easy bruising, signs of skin thinning) Hirsutism Progressive proximal muscle weakness Menstrual irregularities/amenorrhea Infertility Decreased libido Impotence Psychological problems (eg, depression, cognitive dysfunction, emotional lability) New-onset or worsening of hypertension and diabetes mellitus Difficulty with wound healing, increased infections Osteopenia, osteoporotic fractures Growth retardation (in children) Other signs and symptoms associated with Cushing disease include the following: Patients with an ACTH-producing pituitary tumor: Headaches, polyuria, nocturia, visual problems, or galactorrhea Patients with tumor mass effect on the anterior pituitary: Hyposomatotropism, hypothyroidism, hyperprolactinemia or hypoprolactinemia, hypogonadism Patients with an adrenal carcinoma (as underlying cause of Cushing syndrome): Rapid onset of symptoms of glucocorticoid excess in conjunction with virilization in women or feminization in men See Clinical Presentation for more detail.DiagnosisOn examination, general findings of Cushing syndrome may include the following: General: Cervical, thoracic, and/or central obesity Dermatologic: Facial plethora, violaceous striae, ecchymoses, telangiectasias, purpura, cutaneous atrophy, facial lanugo Cardiovascular and renal [1] : Hypertension, edema Gastroenterologic: Peptic ulceration with or without symptoms Endocrinologic: Galactorrhea, signs of hypothyroidism (eg, slow reflex relaxation) Genitourinary: Decreased testicular volume Musculoskeletal: Proximal muscle weakness, kyphosis, height loss, bone pain Neuropsychological: Fatigue Ophthalmologic: Visual-field defects (often bitemporal), blurred vision in the presence of large ACTH-producing pituitary tumors that impinge on optic chiasma Patients in adrenal crisis may exhibit the following on examination: Hypotension Abdominal pain Vomiting Mental confusion Hypoglycemia Hyperkalemia, hyponatremia Metabolic acidosis TestingLaboratory studies used in the evaluation of patients with suspected Cushing syndrome include the following: Urinary free cortisol (UFC) levels Low-dose dexamethasone suppression tests Evening serum and salivary cortisol levels Dexamethasonecorticotropin-releasing hormone test CBC count Glucose levels Electrolyte panel Note that acute illness activates the hypothalamic-pituitary-adrenal (HPA) axis, resulting in increases in ACTH and cortisol. Therefore, do not perform laboratory workup for Cushing syndrome in acutely ill subjects.If concern for adrenal carcinoma exists, measurements of adrenal androgen production, such as serum dehydroepiandrosterone sulfate [DHEAS], and 24-hour urinary 17-ketosteroid measurements may be helpful. Imaging testsPerform imaging studies after the biochemical evaluation has been performed. Radiologic studies that may be helpful in patients with Cushing syndrome include the following: Abdominal CT scanning: When primary adrenal problem or suspected ectopic ACTH production suspected; presence of large adrenal mass may be adrenal carcinoma Pituitary contrast-enhanced MRI: When pituitary source of excess ACTH suspected Chest CT scanning: In patients with suspected ectopic ACTH production Octreotide scintigraphy: May detect ectopic ACTH tumors ProceduresInferior petrosal sinus sampling (IPSS) by an experienced interventional radiologist is useful in distinguishing a pituitary source from an ectopic source of ACTH. However, this study should not be used to establish the diagnosis of Cushing syndrome. See Workup for more detail.ManagementTreatment of Cushing syndrome is directed by the primary cause of the syndrome. In general, therapy should reduce the cortisol secretion to normal to reduce the risk of comorbidities associated with hypercortisolism. The treatment for exogenous Cushing syndrome is gradual withdrawal of glucocorticoid. PharmacotherapyMedications used in the management of Cushing syndrome include the following: Somatostatin analogs (eg, pasireotide) Adrenal steroid inhibitors (eg, metyrapone, ketoconazole, aminoglutethimide, mifepristone) Surgical optionRemove a culprit tumor, if possible. The treatment of choice for endogenous Cushing syndrome is surgical resection of the causative tumor. The primary therapy for Cushing disease is transsphenoidal surgery, and the primary therapy for adrenal tumors is adrenalectomy. Other surgical interventions include the following: Pituitary irradiation Bilateral adrenalectomy Unilateral adrenalectomy Resection of carcinomas Patients with endogenous Cushing syndrome who undergo resection of pituitary, adrenal, or ectopic tumors should receive stress doses of glucocorticoid in the intraoperative and immediate postoperative period. Also, in the event of pituitary destruction or bilateral adrenalectomy, lifelong glucocorticoid replacement is necessary. Lifelong mineralocorticoid replacement is also necessary in patients who undergo bilateral adrenalectomy. See Treatment and Medication for more detail.