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Cushing Syndrome

By

Ashley B. Grossman

, MD, University of Oxford; Fellow, Green-Templeton College

Last full review/revision Oct 2020| Content last modified Oct 2020
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In Cushing syndrome, the level of corticosteroids is excessive, usually due to taking corticosteroid drugs or overproduction by the adrenal glands.

  • Cushing syndrome usually results from taking corticosteroids to treat a medical disorder or from a tumor in the pituitary or adrenal gland that causes the adrenal glands to produce excessive corticosteroids.

  • Cushing syndrome can also result from tumors in other locations (such as the lungs).

  • People with Cushing syndrome usually develop excessive fat throughout the torso and have a large, round face and thin skin.

  • Doctors measure the level of cortisol and do other tests to detect Cushing syndrome.

  • Surgery or radiation therapy is often needed to remove a tumor.

The adrenal glands may overproduce corticosteroids because of a problem in the adrenal glands or because of too much stimulation from the pituitary gland, which controls the adrenal glands and other endocrine glands. An abnormality in the pituitary gland, such as a tumor, can cause the pituitary to produce large amounts of corticotropin, the hormone that controls the production of corticosteroids by the adrenal glands (a condition known as Cushing disease). Tumors outside the pituitary gland, such as small cell lung cancer or a carcinoid tumor in the lungs or elsewhere in the body, can produce corticotropin as well (a condition called ectopic corticotropin syndrome).

Sometimes a noncancerous tumor (adenoma) develops in the adrenal glands, which causes them to overproduce corticosteroids. Adrenal adenomas are extremely common. About 10% of all people have them by the age of 70. Only a small fraction of adenomas produce excess hormone, however. Cancerous tumors of the adrenal glands are very rare, but some of them also produce excess hormone.

Taking corticosteroids

Cushing syndrome can also develop in people who must take large doses of corticosteroids (such as prednisone or dexamethasone) because of a serious medical condition. Corticosteroids are often used to treat many inflammatory, allergic, and autoimmune disorders. Common examples include asthma, rheumatoid arthritis, systemic lupus erythematosus, many skin disorders, and numerous other conditions. Those who must take large doses have the same symptoms as those who produce too much of the hormone. The symptoms can occasionally occur even if the corticosteroids are inhaled, as for asthma, or are used topically for a skin condition.

In addition to causing Cushing syndrome, taking large doses of corticosteroids also can suppress the function of the adrenal glands. This suppression occurs because corticosteroids signal the hypothalamus and pituitary gland to stop producing the hormones that normally stimulate adrenal function. Thus, if the person abruptly stops taking corticosteroids, the body cannot restore adrenal function quickly enough, and temporary adrenal insufficiency (a condition similar to Addison disease) results. Also, when stress occurs, the body is not able to stimulate production of the additional corticosteroids that are needed.

Therefore, doctors never stop the use of corticosteroids abruptly if people have been taking them for more than 2 or 3 weeks. Instead, doctors gradually reduce (taper) the dose over weeks and sometimes months.

Also, the dose of corticosteroids may need to be increased in people who become ill or otherwise severely stressed while taking corticosteroids. Corticosteroid use may need to be resumed in people who become ill or otherwise severely stressed within weeks of having the corticosteroid tapered and stopped.

Cushing disease

Cushing disease is a term given specifically to Cushing syndrome caused by overstimulation of the adrenal glands, usually because of a pituitary tumor. In this disorder, the adrenal glands are overactive because the pituitary gland is overstimulating them, and not because the adrenal glands are abnormal. Symptoms of Cushing disease are similar to those of Cushing syndrome. Cushing disease is diagnosed by blood tests, or sometimes also with tests of urine and saliva. Cushing disease is treated with surgery or radiation to remove the pituitary tumor. If removal of the pituitary tumor can't be done or is unsuccessful, the adrenal glands can be removed surgically, or drugs can be given to reduce corticotropin production or block the production or effects of the excess cortisol on tissues.

Symptoms

Corticosteroids alter the amount and distribution of body fat. Excessive fat develops throughout the torso and may be particularly noticeable at the top of the back (sometimes called a buffalo hump). A person with Cushing syndrome usually has a large, round face (moon face). The arms and legs are usually slender in proportion to the thickened trunk. Muscles lose their bulk, leading to weakness. The skin becomes thin, bruises easily, and heals poorly when bruised or cut. Purple streaks that look like stretch marks (striae) may develop over the abdomen and chest. People with Cushing syndrome tend to tire easily.

Over time, high corticosteroid levels raise the blood pressure (hypertension), weaken bones (osteoporosis), and diminish resistance to infections. The risk of developing kidney stones and diabetes is increased, and mental disturbances, including depression and hallucinations, may occur. Women usually have an irregular menstrual cycle. Children with Cushing syndrome grow slowly and remain short. In some people, the adrenal glands also produce large amounts of male sex hormones ( testosterone and similar hormones), leading to increased facial and body hair, and balding in women.

Diagnosis

  • Measure the level of cortisol in the urine, saliva, and/or blood

  • Sometimes other blood and imaging tests

When doctors suspect Cushing syndrome, they measure the level of cortisol, the main corticosteroid hormone. Normally, cortisol levels are high in the morning and lower late in the day. In people who have Cushing syndrome, cortisol levels are usually very high throughout the day. Cortisol levels may be checked by testing the urine, the saliva, or the blood.

If the cortisol levels are high, doctors may recommend a dexamethasone suppression test in which doctors give a dose of dexamethasone at night or over several days and then measure the level of cortisol in the morning. Dexamethasone normally suppresses the secretion of corticotropin by the pituitary gland and should lead to suppression of cortisol secretion by the adrenal glands. If Cushing syndrome is caused by too much pituitary stimulation (Cushing disease), the blood level of cortisol will fall to some extent, although not as much as in people who do not have Cushing syndrome. A high corticotropin level further suggests overstimulation of the adrenal gland by the pituitary.

If Cushing syndrome has another cause, the level of cortisol will remain high after giving dexamethasone. If a tumor in the adrenal produces too much cortisol, the level of corticotropin from the pituitary is already suppressed, and dexamethasone does not decrease the blood level of cortisol. Sometimes, other types of tumors elsewhere in the body produce corticotropin-like substances that stimulate the adrenal to produce excess cortisol, but this stimulation is not suppressed by dexamethasone.

Imaging tests may be needed to determine the exact cause, including a computed tomography (CT) or magnetic resonance imaging (MRI) scan of the pituitary or adrenal glands and a chest x-ray or CT scan of the lungs or the abdomen. However, these tests may occasionally fail to find the tumor.

When overproduction of corticotropin is thought to be the cause, blood samples may sometimes need to be taken from the veins that drain the pituitary to see if that is the source.

Treatment

  • Diet high in protein and potassium

  • Drugs that decrease cortisol levels or block the effects of cortisol

  • Surgery or radiation therapy

Treatment depends on whether the problem is in the adrenal glands, the pituitary gland, or elsewhere.

If the problem is caused by taking corticosteroid drugs, doctors weigh the benefit of the drug against the harm of having Cushing syndrome. Some people need to continue taking the drug. If not, doctors gradually reduce (taper) the dose over weeks and sometimes months. During the tapering, the dose may need to be increased if people become ill or otherwise severely physically stressed. Even for weeks to months after corticosteroids have been stopped, people who become ill may need to resume taking the drug because their adrenal glands have not fully recovered from suppression by the corticosteroids.

The first step people can take in the treatment of Cushing syndrome is to support their general condition by following a diet that is high in protein and potassium. Sometimes, drugs that increase potassium or lower blood glucose (sugar) levels are necessary. Any increase in blood pressure needs to be treated, and such patients are also at increased risk of blood clots in their veins, so blood thinners may be used. These patients are also especially liable to infections which may be life-threatening.

Surgery or radiation therapy may be needed to remove or destroy a pituitary tumor. If available, proton beam therapy can be used.

Tumors of the adrenal glands (usually adenomas) can often be removed surgically. Both adrenal glands may have to be removed if these treatments are not effective, if a tumor is present in both adrenal glands, or if no tumor is present. People who have both adrenal glands removed, and many people who have part of their adrenal glands removed, must take corticosteroids for life.

Tumors outside the pituitary and adrenal glands that secrete excess hormones are usually surgically removed.

Certain drugs, such as metyrapone or ketoconazole, can lower cortisol levels and can be used while awaiting more definitive treatment such as surgery. Mifepristone, which can block the effects of cortisol, can also be used. People with mild cases of persistent or recurrent disease may benefit from the drug pasireotide, although this will tend to cause or worsen diabetes. Cabergoline may also occasionally be useful. Pasireotide and cabergoline decrease the ability of corticotropin to stimulate production of cortisol by the adrenal glands.

What Is Nelson Syndrome?

People who have both their adrenal glands removed as treatment for Cushing disease that did not resolve with surgery and/or radiation to the pituitary may develop Nelson syndrome.

In this disorder, the pituitary tumor that caused the Cushing disease continues to grow, producing large amounts of corticotropin and leading to darkening of the skin. The enlarging pituitary tumor may compress nearby structures in the brain, causing headaches and defects in vision.

Some experts believe that this compression may be prevented, at least in some people, by radiation therapy to the pituitary gland. If necessary, Nelson syndrome can be treated with radiation therapy or surgical removal of the pituitary gland.

Drugs Mentioned In This Article

Generic Name Select Brand Names
H.P. ACTHAR GEL
OZURDEX
NIZORAL
MIFEPREX
SIGNIFOR
No US brand name
METOPIRONE
RAYOS
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