Practice Essentials

Cushing 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 symptoms

The 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.

Diagnosis
On 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

Testing
Laboratory 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 tests
Perform 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

Procedures
Inferior 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.

Management
Treatment 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.
Pharmacotherapy
Medications used in the management of Cushing syndrome include the following:

Somatostatin analogs (eg, pasireotide)

Adrenal steroid inhibitors (eg, metyrapone, ketoconazole, aminoglutethimide,

mifepristone)

Surgical option
Remove 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.