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What is Cushing syndrome?

Cushing syndrome is a group of signs and symptoms caused by abnormally high levels of cortisol (hypercortisolism). Cortisol is produced by the outer layer of the adrenal glands, called the cortex. Cortisol is a steroid hormone that breaks down fat and protein and stimulates liver glucose production. It helps the body react to physical and emotional stress, helps to regulate blood pressure, to control inflammation, and can affect cardiovascular function. The adrenal glands are located at the top of each kidney and are part of the endocrine system, a network of glands that produce hormones. The adrenal cortex produces the steroid hormones cortisol, aldosterone and the adrenal androgens, primarily dehydroepiandrosterone (DHEA).

Production of cortisol is controlled through a feedback system in the endocrine system involving the adrenal glands, the pituitary gland, and the hypothalamus, a gland in the lower part of the brain. When the cortisol level is low, the hypothalamus produces corticotropin-releasing hormone (CRH). This stimulates the pituitary gland, located below it, to produce adrenocorticotropic hormone (ACTH), also called corticotropin, which then stimulates the adrenal glands to produce and release cortisol. When the cortisol level is high, production of CRH and ACTH decrease.

Common causes of this relatively rare condition are:

  • Prolonged glucocorticoid therapy (iatrogenic Cushing syndrome) -- a result of taking glucocorticoids-steroid hormones that are chemically similar to natural cortisol, such as anti-inflammatory medications like prednisone prescribed for asthma, rheumatoid arthritis, lupus, and other inflammatory diseases. Such hormones may also be taken after an organ transplant to suppress the immune system and prevent organ rejection.
  • Cushing disease -- caused by a pituitary gland that produces too much of the hormone ACTH, which then signals the adrenal glands to produce cortisol. Cushing disease, a form of Cushing syndrome, occurs in about 40% of cases and is the most common cause of excess endogenous cortisol production by the adrenal glands. It is caused by a pituitary tumor (adenoma) that secretes ACTH.
  • An adrenal gland tumor or adrenal hyperplasia can cause the adrenal gland to overproduce cortisol.
  • A tumor in another part of the body such as the pancreas, lung, or thyroid can produce ACTH (called "ectopic" ACTH production because it is produced somewhere other than the pituitary gland).

Cushing syndrome can affect anyone, but it is most frequently seen in adults between the ages of 20 to 50 years and is 3 times more common in women than men. It is estimated that there are two new cases per million people each year. Rarely, a person may have an inherited gene mutation, such as Multiple Endocrine Neoplasia Type 1 or MEN-1, which increases the risk of developing tumors throughout the endocrine system, including pituitary and adrenal tumors. People who are obese and have type 2 diabetes along with poorly controlled blood glucose are at increased risk for Cushing syndrome.

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About Cushing Syndrome
  • Signs and Symptoms

    Signs and symptoms associated with Cushing syndrome vary but frequently include:

    • Obesity in the torso (central obesity) with thinner arms and legs
    • A large rounded face (moon face)
    • Increased fat in the neck and shoulder area (Buffalo hump)
    • Thirst and excessive urination
    • Visual problems caused by glaucoma or cataracts
    • Increased susceptibility to infections
    • Thin, fragile skin that bruises easily and heals slowly
    • Pinkish streaks that look like stretch marks on the abdomen, thighs, and buttocks
    • Muscle weakness
    • Decreased endurance
    • Osteoporosis
    • High blood pressure
    • Increased blood sugar
    • Headaches, backaches
    • Mental symptoms (confusion to psychosis)
    • Children with Cushing syndrome tend to be obese, develop slowly, and may remain short.
    • Women may have excess hair on their face and chest and menstrual irregularities.
    • Men may have decreased sexual desire or impotence.
  • Tests

    Laboratory Tests
    No single laboratory test is ideal to diagnose Cushing syndrome and more than one is often used. Since cortisol levels change over the course of a day, a single cortisol result from a blood sample drawn at most times of the day is of little value. Testing for Cushing syndrome is typically done in two stages. Initial tests are used to verify that there is excess cortisol present. The second set of tests is used to determine the cause of the increased cortisol: pituitary, adrenal, or other.

    Initial tests to diagnosis Cushing syndrome
    The three most common tests are measurement of midnight plasma cortisol or late-night salivary cortisol, 24-hour urinary free cortisol test, and the dexamethasone suppression screening test.

    • Midnight plasma cortisol and late-night salivary cortisol measurements: Normally, cortisol production is suppressed at midnight but in Cushing syndrome, this does not happen. Therefore, an elevated blood (plasma) level at midnight suggests Cushing syndrome. Blood is the preferred sample, but this usually requires a hospital stay. Alternatively, a saliva sample can be collected late at night at home and then tested. It is recommended that a sample be collected three nights in a row. If only a single sample is collected and tested, the test should be repeated if the result is outside the established reference range, to confirm the results and to avoid false positives.
    • 24-hour urine cortisol: 24-hour urine cortisol (or urine free cortisol, UFC) is often used to evaluate overall cortisol production. One out of four 24-hour urine samples may be normal and other testing may have to be performed. Like the midnight cortisol test, it is recommended that this test be repeated if results are abnormal, to avoid false positives.
    • Dexamethasone suppression screening test: Dexamethasone is a synthetic steroid that mimics cortisol in the feedback inhibition of corticotropin-releasing hormone (CRH) and adrenocorticotropin hormone (ACTH) production. A normal response to dexamethasone is suppression of cortisol secretion.

      Dexamethasone can be used in different dosages for different purposes as a diagnostic test. One version involves giving a fairly low dose (1 mg) at bedtime to prevent the rise in ACTH and cortisol that normally occurs during sleep. Between 8 and 9 am the next morning, a blood sample is drawn and the cortisol level is measured. In healthy individuals, the level will be low (suppressed); in those with Cushing syndrome, the level will not be suppressed.

      Less commonly, a different approach involves giving 0.5 mg every 6 hours for two days and collecting a 24-hour urine sample on the second day for urine free cortisol. As with the overnight version, in healthy persons, urine free cortisol should be suppressed to very low levels, while high levels will continue to be present in those with Cushing syndrome.

    If one of these tests shows an increased cortisol level, then it is likely that cortisol levels are not varying normally. Additional testing is then ordered to help determine the reason for the increased level.

    Follow-up tests

    • Corticotrophin releasing hormone (CRH) stimulation test: The CRH stimulation test is used once Cushing syndrome has been diagnosed, to discern people with a pituitary condition from those with adrenal tumors and people with tumors outside the pituitary that produce ACTH (called ectopic ACTH). For this test, ACTH levels are measured at baseline. CRH is then injected and cortisol and ACTH levels are measured at timed intervals after the injection, for example, at 30 and 60 minutes. The normal response is a peak in ACTH levels followed by a peak in cortisol levels. Most people with Cushing syndrome caused by adrenal tumors or ACTH-secreting tumors outside the endocrine system do not respond to CRH.
    • High-dose dexamethasone suppression test (HDDST): This test is similar to the low-dose version. A higher dose of dexamethasone can be given to distinguish between an ACTH-producing pituitary tumor and other causes of Cushing syndrome. High doses of dexamethasone usually suppress cortisol levels in people with pituitary tumors but not in those with ACTH-producing tumors outside the endocrine system.
    • Dexamethasone-corticotropin-releasing hormone test: Some people may have pseudo-Cushing syndrome, sometimes found in people who are severely obese, drink excess alcohol, have poorly controlled diabetes, or have depression or anxiety disorders. Pseudo-Cushing does not have the same long-term health effects as Cushing syndrome or require hormone treatment. People with pseudo-Cushing can have a high cortisol level but do not develop the progressive effects of the syndrome, such as muscle weakness, bone fractures, or thinning skin. The dexamethasone-CRH test rapidly distinguishes pseudo-Cushing from mild cases of Cushing. This test combines the Dexamethasone suppression screening test and a CRH stimulation test (see above). An elevation of cortisol during this test suggest Cushing syndrome, while a level that does not rise suggests pseudo-Cushing.
    • Petrosal sinus sampling: This test is usually combined with a CRH stimulation test. ACTH levels may be measured in samples obtained through a catheter placed in the neck to draw blood from the inferior petrosal sinuses, veins that carry blood away from the pituitary gland. The level of ACTH in the petrosal sinuses is compared with the level in the forearm vein. A higher level of ACTH in the sinuses indicates a pituitary tumor. If the levels in the sinuses and forearm are about the same, it suggests the ACTH is produced by a tumor outside of the pituitary gland.

    Some general laboratory tests that may be performed include:

    Non-Laboratory Tests

    • Computed tomography (CT) – scan of the chest, particularly the lung, and abdomen; may be used to help locate adrenal, pituitary, and other ectopic tumors 
    • Magnetic resonance imaging (MRI) – sometimes ordered to help evaluate pituitary and adrenal glands for the presence of a tumor
    • Ultrasound
    • Octreotide scan – a drug called octreotide, similar to somatostatin, is labeled with a radioactive tag and injected into the person tested; the radioactive drug attaches to receptors on the hormone-producing tumor, allowing detection with a radiologic scan.

    For more on these, visit the web site

  • Treatment

    Treating Cushing syndrome requires identifying and then removing, blocking, or minimizing the body's exposure to excess cortisol. The type(s) of treatment depends on the cause:

    • If the source is a single benign adrenal tumor, then the affected gland may be surgically removed. In many cases, this will reduce cortisol to normal or near normal levels.
    • If an ACTH-producing pituitary tumor (Cushing disease) is the cause of Cushing syndrome, then removal of the tumor will often resolve the excess cortisol. This is typically performed by a neurosurgeon. Likewise, ACTH-producing tumor(s) located outside the endocrine system (ectopic) may require surgery. If removal is not possible, then medical treatment with radiation therapy or chemotherapy may be attempted.
    • Cushing syndrome is recognized as a side effect of having to treat certain conditions with high doses of corticosteroids. Typically, healthcare practitioners try to avoid prescribing high doses and long-term use of these types of drugs. When possible, healthcare providers will usually try to reduce the dose or stop use of the medication as soon as the patient's condition allows, to alleviate the signs and symptoms associated with Cushing syndrome.
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