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Cushing’s Syndrome

National Endocrine and Metabolic Diseases Information Service

What is Cushing’s Women with Cushing’s syndrome usually have excess hair growth on their face, neck, syndrome? chest, abdomen, and thighs. Their menstrual Cushing’s syndrome is a hormonal periods may become irregular or stop. Men U.S. Department disorder caused by prolonged exposure may have decreased fertility with diminished of Health and of the body’s tissues to high levels of the or absent desire for sex and, sometimes, Human Services cortisol. Sometimes called erectile dysfunction. hypercortisolism, Cushing’s syndrome is NATIONAL Other common signs and symptoms include INSTITUTES relatively rare and most commonly affects OF HEALTH adults aged 20 to 50. People who are obese • severe fatigue and have type 2 , along with poorly controlled blood glucose—also called blood • weak muscles sugar—and high blood pressure, have an • high blood pressure increased risk of developing the disorder. • high blood glucose What are the signs and • increased thirst and urination symptoms of Cushing’s • irritability, anxiety, or depression syndrome? • a fatty hump between the shoulders Signs and symptoms of Cushing’s syndrome Sometimes other conditions have many of vary, but most people with the disorder the same signs as Cushing’s syndrome, even have upper body obesity, a rounded face, though people with these disorders do not increased fat around the neck, and relatively have abnormally elevated cortisol levels. slender arms and legs. Children tend to be For example, polycystic ovary syndrome can obese with slowed growth rates. cause menstrual disturbances, weight gain beginning in adolescence, excess hair growth, Other signs appear in the skin, which and impaired insulin action and diabetes. becomes fragile and thin, bruises easily, Metabolic syndrome—a combination of and heals poorly. Purple or pink stretch problems that includes excess weight around marks may appear on the abdomen, thighs, the waist, high blood pressure, abnormal buttocks, arms, and breasts. The bones are levels of cholesterol and triglycerides in the weakened, and routine activities such as blood, and insulin resistance—also mimics bending, lifting, or rising from a chair may the symptoms of Cushing’s syndrome. lead to backaches and rib or spinal column fractures. What causes Cushing’s syndrome? Pituitary gland Cushing’s syndrome occurs when the CRH body’s tissues are exposed to high levels of ACTH cortisol for too long. Many people develop Cushing’s syndrome because they take glucocorticoids—steroid that are Adrenal chemically similar to naturally produced glands cortisol—such as for asthma, rheumatoid arthritis, lupus, and other Cortisol inflammatory diseases. Glucocorticoids are also used to suppress the immune system after transplantation to keep the body from rejecting the new or tissue. Other people develop Cushing’s syndrome because their bodies produce too much cortisol. Normally, the production of The hypothalamus sends CRH to the pituitary, which responds by secreting ACTH. ACTH then causes the cortisol follows a precise chain of events. adrenals to release cortisol into the bloodstream. First, the hypothalamus, a part of the about the size of a small sugar cube, sends corticotropin-releasing hormone (CRH) One of cortisol’s most important jobs is to the . CRH causes the to help the body respond to stress. For pituitary to secrete adrenocorticotropin this reason, women in their last 3 months hormone (ACTH), which stimulates the of pregnancy and highly trained athletes adrenal glands. When the adrenals, which normally have high levels of the hormone. are located just above the kidneys, receive People from depression, the ACTH, they respond by releasing cortisol alcoholism, malnutrition, or panic disorders into the bloodstream. also have increased cortisol levels. Cortisol performs vital tasks in the body When the amount of cortisol in the blood is including adequate, the hypothalamus and pituitary release less CRH and ACTH. This process • helping maintain blood pressure and ensures the amount of cortisol released by cardiovascular function the adrenal glands is precisely balanced to • reducing the immune system’s meet the body’s daily needs. However, if inflammatory response something goes wrong with the adrenals or the regulating switches in the pituitary gland • balancing the effects of insulin, which or hypothalamus, cortisol production can breaks down glucose for energy go awry. • regulating the metabolism of proteins, carbohydrates, and fats

2 Cushing’s Syndrome Pituitary Adenomas Adrenal Tumors Pituitary adenomas cause 70 percent of In rare cases, an abnormality of the adrenal Cushing’s syndrome cases,1 excluding those glands, most often an adrenal tumor, causes caused by glucocorticoid use. These benign, Cushing’s syndrome. Adrenal tumors are or noncancerous, tumors of the pituitary four to five times more common in women gland secrete extra ACTH. Most people than men, and the average age of onset with the disorder have a single adenoma. is about 40. Most of these cases involve This form of the syndrome, known as noncancerous tumors of adrenal tissue called Cushing’s disease, affects women five times adrenal adenomas, which release excess more often than men. cortisol into the blood. Ectopic ACTH Syndrome Adrenocortical carcinomas—adrenal cancers—are the least common cause of Some benign or, more often, cancerous Cushing’s syndrome. With adrenocortical tumors that arise outside the pituitary can carcinomas, cancer cells secrete excess produce ACTH. This condition is known levels of several adrenocortical hormones, as ectopic ACTH syndrome. Lung tumors including cortisol and adrenal androgens, cause more than half of these cases, and men a type of male hormone. Adrenocortical are affected three times more often than carcinomas usually cause very high hormone women. The most common forms of ACTH- levels and rapid development of symptoms. producing tumors are small cell lung cancer, which accounts for about 13 percent of all Familial Cushing’s Syndrome lung cancer cases,2 and carcinoid tumors— Most cases of Cushing’s syndrome are not small, slow-growing tumors that arise from inherited. Rarely, however, Cushing’s hormone-producing cells in various parts syndrome results from an inherited tendency of the body. Other less common types to develop tumors of one or more endocrine of tumors that can produce ACTH are glands. Endocrine glands release hormones thymomas, pancreatic islet cell tumors, into the bloodstream. With primary and medullary carcinomas of the thyroid. pigmented micronodular adrenal disease, children or young adults develop small cortisol-producing tumors of the adrenal glands. With multiple endocrine neoplasia type 1 (MEN1), hormone-secreting tumors of the parathyroid glands, pancreas, and pituitary develop; Cushing’s syndrome in MEN1 may be due to pituitary, ectopic, or adrenal tumors.

1Nieman LK, Ilias I. Evaluation and treatment of Cushing’s syndrome. The Journal of American . 2005;118(12):1340–1346. 2Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. Journal of Clinical . 2006;24:4539–4544.

3 Cushing’s Syndrome How is Cushing’s However, a late-night or bedtime saliva sample can be obtained at home, then syndrome diagnosed? tested to determine the cortisol level. Diagnosis is based on a review of a person’s Diagnostic ranges vary, depending on medical history, a physical examination, the measurement technique used. and laboratory tests. X rays of the adrenal or pituitary glands can be useful in locating • Low-dose dexamethasone suppression tumors. test (LDDST). In the LDDST, a person is given a low dose of dexamethasone, a Tests to Diagnose synthetic glucocorticoid, by mouth every Cushing’s Syndrome 6 hours for 2 days. is collected before dexamethasone is administered No single lab test is perfect and usually and several times on each day of the several are needed. The three most common test. A modified LDDST uses a one­ tests used to diagnose Cushing’s syndrome time overnight dose. are the 24-hour urinary free cortisol test, measurement of midnight plasma cortisol or Cortisol and other glucocorticoids signal late-night salivary cortisol, and the low-dose the pituitary to release less ACTH, dexamethasone suppression test. Another so the normal response after taking test, the dexamethasone-corticotropin­ dexamethasone is a drop in blood and releasing hormone test, may be needed urine cortisol levels. If cortisol levels to distinguish Cushing’s syndrome from do not drop, Cushing’s syndrome is other causes of excess cortisol. suspected. • 24-hour urinary free cortisol level. In The LDDST may not show a drop in this test, a person’s urine is collected cortisol levels in people with depression, several times over a 24-hour period alcoholism, high estrogen levels, acute and tested for cortisol. Levels higher illness, or stress, falsely indicating than 50 to 100 micrograms a day for an Cushing’s syndrome. On the other adult suggest Cushing’s syndrome. The hand, drugs such as phenytoin and normal upper limit varies in different phenobarbital may cause cortisol levels laboratories, depending on which to drop, falsely indicating that Cushing’s measurement technique is used. is not present in people who actually have the syndrome. For this reason, • Midnight plasma cortisol and late- usually advise their patients night salivary cortisol measurements. to stop taking these drugs at least The midnight plasma cortisol test 1 week before the test. measures cortisol concentrations in the blood. Cortisol production is normally suppressed at night, but in Cushing’s syndrome, this suppression doesn’t occur. If the cortisol level is more than 50 nanomoles per liter (nmol/L), Cushing’s syndrome is suspected. The test generally requires a 48-hour hospital stay to avoid falsely elevated cortisol levels due to stress.

4 Cushing’s Syndrome • Dexamethasone-corticotropin-releasing Tests to Find the Cause hormone (Crh) test. Some people of Cushing’s Syndrome have high cortisol levels but do not develop the progressive effects of Once Cushing’s syndrome has been Cushing’s syndrome, such as muscle diagnosed, other tests are used to find the weakness, fractures, and thinning of exact location of the abnormality that leads the skin. These people may have to excess cortisol production. The choice of pseudo-Cushing’s syndrome, a condition test depends, in part, on the preference of the sometimes found in people who have endocrinologist or the center where the test depression or anxiety disorders, drink is performed. excess alcohol, have poorly controlled • Crh stimulation test. The CRH diabetes, or are severely obese. test, without pretreatment with Pseudo-Cushing’s does not have the dexamethasone, helps separate people same long-term effects on health with pituitary adenomas from those as Cushing’s syndrome and does with ectopic ACTH syndrome or not require treatment directed at adrenal tumors. As a result of the the endocrine glands. CRH injection, people with pituitary The dexamethasone-CRH test rapidly adenomas usually experience a rise distinguishes pseudo-Cushing’s in blood levels of ACTH and cortisol from mild cases of Cushing’s. This because CRH acts directly on the test combines the LDDST and a pituitary. This response is rarely seen CRH stimulation test. In the CRH in people with ectopic ACTH syndrome stimulation test, an injection of CRH and practically never in those with causes the pituitary to secrete ACTH. adrenal tumors. Pretreatment with dexamethasone • high-dose dexamethasone suppression prevents CRH from causing an increase test (hDDST). The HDDST is the in cortisol in people with pseudo­ same as the LDDST, except it uses Cushing’s. Elevations of cortisol during higher doses of dexamethasone. This this test suggest Cushing’s syndrome. test helps separate people with excess production of ACTH due to pituitary adenomas from those with ectopic ACTH-producing tumors. High doses of dexamethasone usually suppress cortisol levels in people with pituitary adenomas but not in those with ectopic ACTH-producing tumors.

5 Cushing’s Syndrome • radiologic imaging: direct taken to confirm the correct position of visualization of the endocrine glands. the tubes. Often CRH, the hormone Imaging tests reveal the size and shape that causes the pituitary to release of the pituitary and adrenal glands and ACTH, is given during this test to help determine if a tumor is present. improve diagnostic accuracy. The most common imaging tests are Levels of ACTH in the petrosal sinuses the computerized tomography (CT) are measured and compared with scan and magnetic resonance imaging ACTH levels in a forearm vein. Higher (MRI). A CT scan produces a series of levels of ACTH in the sinuses than in x-ray pictures giving a cross-sectional the forearm vein indicate a pituitary image of a body part. MRI also adenoma. Similar levels of ACTH in produces images of internal organs the petrosal sinuses and the forearm but without exposing patients to suggest ectopic ACTH syndrome. ionizing radiation. Imaging procedures are used to find How is Cushing’s a tumor after a diagnosis has been made. Imaging is not used to make syndrome treated? the diagnosis of Cushing’s syndrome Treatment depends on the specific reason because benign tumors are commonly for excess cortisol and may include , found in the pituitary and adrenal radiation, chemotherapy, or the use of glands. These tumors, sometimes cortisol-inhibiting drugs. If the cause is called incidentalomas, do not produce long-term use of glucocorticoid hormones hormones in quantities that are to treat another disorder, the doctor will harmful. They are not removed unless gradually reduce the dosage to the lowest blood tests show they are a cause of dose adequate for control of that disorder. symptoms or they are unusually large. Once control is established, the daily dose Conversely, pituitary tumors may not of glucocorticoid hormones may be doubled be detectable by imaging in almost half and given on alternate days to lessen side of people who ultimately need pituitary effects. In some cases, noncorticosteroid surgery for Cushing’s syndrome. drugs can be prescribed. • Petrosal sinus sampling. This test is Pituitary Adenomas not always required, but in many cases, Several are available to treat the it is the best way to distinguish pituitary ACTH-secreting pituitary adenomas of from ectopic causes of Cushing’s Cushing’s disease. The most widely used syndrome. Samples of blood are drawn treatment is surgical removal of the tumor, from the petrosal sinuses—veins that known as transsphenoidal adenomectomy. drain the pituitary––by inserting tiny Using a special microscope and fine tubes through a vein in the upper thigh instruments, the surgeon approaches the or groin region. A local anesthetic and pituitary gland through a nostril or an mild sedation are given, and x rays are opening made below the upper lip. Because this procedure is extremely delicate, patients are often referred to centers specializing in

6 Cushing’s Syndrome this type of surgery. The success, or and metyrapone. Each drug has its own cure, rate of this procedure is more than side effects that doctors consider when 80 percent when performed by a surgeon prescribing medical for individual with extensive experience. If surgery fails or patients. only produces a temporary cure, surgery can be repeated, often with good results. Ectopic ACTH Syndrome To cure the overproduction of cortisol After curative pituitary surgery, the caused by ectopic ACTH syndrome, all production of ACTH drops two levels below of the cancerous tissue that is secreting normal. This drop is natural and temporary, ACTH must be eliminated. The choice and patients are given a synthetic form of of cancer treatment—surgery, radiation, cortisol such as hydrocortisone or prednisone chemotherapy, immunotherapy, or a to compensate. Most people can stop this combination of these treatments—depends replacement therapy in less than 1 or 2 years, on the type of cancer and how far it has but some must be on it for life. spread. Because ACTH-secreting tumors If transsphenoidal surgery fails or a patient may be small or widespread at the time of is not a suitable candidate for surgery, diagnosis, making them difficult to locate is another possible and treat directly, cortisol-inhibiting drugs treatment. Radiation to the pituitary are an important part of treatment. In gland is given over a 6-week period, with some cases, if other treatments fail, surgical improvement occurring in 40 to 50 percent removal of the adrenal glands, called of adults and up to 85 percent of children. bilateral adrenalectomy, may replace drug Another technique, called stereotactic therapy. radiosurgery or gamma knife radiation, can be given in a single high-dose treatment. Adrenal Tumors It may take several months or years Surgery is the mainstay of treatment for before people feel better from radiation benign and cancerous tumors of the adrenal treatment alone. Combining radiation glands. Primary pigmented micronodular with cortisol-inhibiting drugs can help adrenal disease and the inherited Carney speed recovery. complex––primary tumors of the heart that can lead to endocrine overactivity Drugs used alone or in combination to and Cushing’s syndrome––require surgical control the production of excess cortisol are removal of the adrenal glands. ketoconazole, mitotane, aminoglutethimide,

7 Cushing’s Syndrome Hope through Research Points to Remember Several components of the National • Cushing’s syndrome is a disorder Institutes of Health (NIH) conduct and caused by prolonged exposure of support research on Cushing’s syndrome the body’s tissues to high levels of and other disorders of the endocrine system, the hormone cortisol. including the National Institute of Diabetes and Digestive and Diseases, the

• Typical signs and symptoms of National Institute of Child Health and Cushing’s syndrome include upper Human Development (NICHD), the body obesity, a rounded face, skin National Institute of Neurological Disorders that bruises easily and heals poorly, and Stroke, the National Cancer Institute, weakened bones, excess body hair and the National Center for Research growth and menstrual irregularities Resources. in women, and decreased fertility in men. NIH-supported scientists are conducting intensive research into the normal and • Cushing’s syndrome is caused by abnormal function of the major endocrine exposure to glucocorticoids, which glands and the many hormones of the are used to treat inflammatory endocrine system. Researchers continue to diseases, or by the body’s study the effects of excess cortisol, including overproduction of cortisol, most its effect on brain structure and function. often due to tumors of the pituitary To refine the diagnostic process, studies are gland or lung. under way to assess the accuracy of existing • Several tests are usually needed screening tests and the effectiveness of new to diagnosis Cushing’s syndrome, imaging techniques to evaluate patients with including urine, blood, and saliva ectopic ACTH syndrome. Researchers are tests. Other tests help find the also investigating jugular vein sampling as cause of the syndrome. a less invasive alternative to petrosal sinus • Treatment depends on the specific sampling. Research into treatment options reason for excess cortisol and includes study of a new drug to treat the may include surgery, radiation, symptoms of Cushing’s syndrome caused chemotherapy, or the use of by ectopic ACTH secretion. cortisol-inhibiting drugs. Studies are under way to understand the causes of benign endocrine tumor formation, such as those that cause most cases of Cushing’s syndrome. In a few pituitary adenomas, specific gene defects have been identified and may provide important clues to understanding tumor formation. Endocrine factors may also play a role. Increasing evidence suggests that tumor formation is a multistep process. Understanding the basis of Cushing’s syndrome will yield new approaches to therapy.

8 Cushing’s Syndrome The NIH supports research related to The following organizations may also be able Cushing’s syndrome at medical centers to assist with certain types of information: throughout the United States. Scientists American Association of are also treating patients with Cushing’s Neurological Surgeons syndrome at the NIH Clinical Center 5550 Meadowbrook Drive in Bethesda, MD. Physicians who are Rolling Meadows, IL 60008 interested in referring an adult patient Phone: 1–888–566–AANS (2267) may contact Lynnette Nieman, M.D., at or 847–378–0500 NICHD, 10 Center Drive, Room 1–3140, Email: [email protected] Bethesda, MD 20892–1109, or by phone Internet: www.NeurosurgeryToday.org at 301–496–8935. Physicians interested in To locate a board-certified neurosurgeon: referring a child or adolescent may contact www.neurosurgerytoday.org/findaneuro Constantine Stratakis, M.D., D.Sc., at NICHD, 10 Center Drive, Room 1–3330, Cushing’s Support and research Bethesda, MD 20892–1103, or by phone at Foundation, Inc. 301–402–1998. 65 East India Row, Suite 22B Boston, MA 02110 For More Information Phone and Fax: 617–723–3674 Email: [email protected] The following articles about Cushing’s syndrome Internet: www.CSRF.net can be found in medical libraries, some college and university libraries, and through interlibrary Pituitary Network Association loan in most public libraries. P.O. Box 1958 Thousand Oaks, CA 91358 Labeur M, Arzt E, Stalla GK, Páez-Pereda Phone: 805–499–9973 M. New perspectives in the treatment of Fax: 805–480–0633 Current Drug Targets— Cushing’s syndrome. Email: [email protected] Immune, Endocrine & Metabolic Disorders . Internet: www.pituitary.org 2004;4:335–342. Lin D, Loughlin K. Diagnosis and management of surgical adrenal diseases. . 2005;66:476–483. Newell-Price J, Bertagna X, Grossman A, Nieman L. Cushing’s syndrome. The Lancet. 2006;367:1605–1617. Nieman L, Ilias I. Evaluation and treatment of Cushing’s syndrome. The American Journal of Medicine. 2005;118:1340–1346.

9 Cushing’s Syndrome You may also find additional information about this National Endocrine topic by visiting MedlinePlus at www.medlineplus.gov. and Metabolic Diseases This publication may contain information about medications used to treat a health condition. When Information Service this publication was prepared, the NIDDK included the most current information available. Occasion- 6 Information Way ally, new information about medication is released. Bethesda, MD 20892–3569 For updates or for questions about any medications, Phone: 1–888–828–0904 please contact the U.S. Food and Drug Administra- Fax: 703–738–4929 tion at 1–888–INFO–FDA (463–6332), a toll-free call, or visit their website at www.fda.gov. Consult your Email: [email protected] doctor for more information. Internet: www.endocrine.niddk.nih.gov The National Endocrine and Metabolic Diseases Information Service is an information dissemination service of the National Institute The U.S. Government does not endorse or favor any specific commercial product or company. Trade, of Diabetes and Digestive and Kidney Diseases proprietary, or company names appearing in this (NIDDK). The NIDDK is part of the National document are used only because they are considered Institutes of Health (NIH), which is part of the necessary in the context of the information provided. U.S. Department of Health and Human Services. If a product is not mentioned, the omission does not mean or imply that the product is unsatisfactory. The NIDDK conducts and supports biomedical research. As a public service, the NIDDK has established information services to increase knowledge and understanding about health and disease among patients, health care professionals, and the public. Publications produced by the NIDDK are carefully reviewed by both NIDDK scientists and outside experts. This publication was reviewed by George Chrousos, M.D., Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH.

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U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health NIH Publication No. 08–3007 July 2008