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Cushing's syndrome.

Cushing's syndrome is an endocrine, or hormonal, disorder. Although symptoms vary from person to person, most patients have upper-body obesity, severe fatigue and muscle weakness, high blood pressure, backache, elevated blood sugar, easy bruising, and bluish-red stretch marks on the skin. In women, there may be increased growth of facial and body hair, and menstrual periods may become irregular or stop completely.

Cushing's syndrome is caused by prolonged exposure of the body's tissues to high levels of the hormone cortisol. For this reason, the disorder is sometimes called hypercortisolism."

Cortisol is normally produced by the adrenal glands, located just above the kidneys. It belongs to a class of hormones called glucocorticoids, which affect almost every organ and tissue in the body. Scientists think that cortisol has possibly hundreds of effects in the body. Among its vital tasks, cortisol:

* helps maintain blood pressure and cardiovascular function;

* helps slow the immune system's inflammatory response;

* helps balance the effects of insulin in breaking down sugar for energy; and

* helps regulate the metabolism of proteins, carbohydrates, and fats.

One of cortisol's most important jobs is to help the body respond to stress. In fact, the adrenal glands naturally produce more cortisol during stress. High levels of the hormone normally occur in women during the last 3 months of pregnancy and in highly trained athletes. Increased cortisol levels also are found in people suffering from depression, alcoholism, malnutrition, and panic disorders.

To understand the different ways that cortisol production can go wrong, it helps to look at how hormones normally do their work. Endocrine glands differ from other organs in the body because they release hormones into the bloodstream. Hormones travel through the blood, instructing cells in other parts of the body to release another hormone or to perform a specific function. Among the major endocrine glands are the thyroid, parathyroid, thymus, pituitary, and adrenals. Together, they play a major role in growth, metabolism, reproduction, and overall health.

The leaders in this carefully balanced performance are the brain's hypothalamus and the pituitary gland, a bean-sized organ at the base of the brain. First, the hypothalamus sends releasing hormones" to the pituitary gland. The pituitary responds by secreting other hormones that regulate growth, thyroid function, and sex hormones such as estrogen and testosterone. One of the pituitary's main duties is to secrete ACTH (adrenocorticotropin), a hormone that stimulates the adrenal glands. When the adrenals receive the pituitary's signal in the form of ACTH, they respond by producing cortisol. Completing the cycle, cortisol then signals the pituitary to lower secretion of ACTH.

Normally, the amount of cortisol released by the adrenals is precisely balanced to meet the body's daily needs. If something goes wrong during this process-for example, with the adrenals, or their regulating switches in the brain (the pituitary gland or the hypothalamus) -cortisol production can go awry.

Causes

Exposure to too much cortisol can occur for different reasons. A common cause of elevated cortisol is the long-term use of glucocorticoid hormones such as prednisone for the treatment of inflammatory illnesses like rheumatoid arthritis. People who have taken these hormones for a long time may develop the symptoms of Cushing's syndrome, for example, the rounded or "moon face" and muscle weakness.

Elevated levels of cortisol can also be traced to abnormalities of the pituitary gland or the adrenal glands. High cortisol production also can be caused by tumor cells that release ACTH, in turn signaling the adrenals to overproduce cortisol. Each of these causes is discussed in more detail below.

Pituitary Adenomas

Most cases of Cushing's syndrome are caused by benign, or noncancerous tumors of the pituitary gland called adenomas, which secrete increased amounts of ACTH. Most patients have a single adenoma. This form of the syndrome, known as "Cushing's disease," afflicts more women than men. Adenomas are unlikely to spread; rarely, however, some pituitary tumors have the features of cancer, including the ability to spread.

Ectopic ACTH Syndrome

About 17 percent of Cushing's syndrome cases are due to the production of ACTH by various types of potentially malignant tumors that arise in different parts of the body. By far, the most common form of ACTH-producing tumor is oat cell, or small cell, lung cancer, which accounts for about 25 percent of all lung cancer cases. Other, less common types of cancer that can produce ACTH are thymomas, carcinoid tumors, pancreatic islet cell tumors, and medullary carcinomas of the thyroid.

Adrenal Tumors

In about 15 percent of patients with Cushing's syndrome, the cause can be traced to an abnormality of the adrenal glands, most often an adrenal tumor. In about one-half of these cases, the tumors are noncancerous growths of adrenal tissue, called adrenal adenomas, which release excess cortisol into the blood.

Adrenocortical carcinomas, or adrenal cancers, are the least common cause of Cushing's syndrome, accounting for about 7 percent of cases. They tend to occur in children. Cancer cells secrete excess levels of several adrenal cortical hormones, causing cortisol and adrenal androgen levels to remain elevated. Adrenal carcinomas also can be marked by very high hormone levels and rapid development of symptoms.

Incidence

Cushing's syndrome is relatively rare. It affects about 10 people per million population every year, or approximately 1 in 5,000 hospital admissions, with most cases occurring between the ages of 20 and 50 years.

About 70 percent of reported cases are diagnosed with pituitary adenomas that overproduce ACTH (Cushing's disease). This form of the syndrome affects more women than men at a ratio of 5:1.

The ectopic ACTH syndrome, caused by ACTH-producing tumors, is responsible for about 17 percent of the cases of Cushing's syndrome. Of these, over 50 percent are due to lung tumors, with a 3:1 ratio of males to females.

Adrenal tumors account for the remainder of cases, occurring in about two per million population annually. The average age of onset is about 40 years.

Symptoms

There is no single symptom shared by all patients with Cushing's syndrome, although some features of the disorder occur more often than others.

Obesity

The most common symptom is weight gain, with rounding of the face and increased fat in the neck and above the collar bone, while the arms and legs tend to stay thin. Obesity associated with poor growth is most common in children.

Skin

Skin changes also are common in Cushing's syndrome. The cheeks redden as the skin becomes thin, making the blood vessels more visible. The thin, fragile skin breaks easily, and ulcers may arise from minor injury. The ulcers may persist for a long time because of poor wound healing. Easy bruising and bluish-red stretch marks, which often appear on the abdomen, thighs, buttocks, arms, armpits, and breasts, result from weakened connective tissue. Connective tissue not only provides the supportive framework of the body and its internal organs, but it is a major structural component of arteries and veins as well as the skin.

Excess Hair Growth

In women, excess hair growth, or hirsutism, often appears on the face, neck, chest, abdomen, and thighs. It occurs in about 80 percent of women with Cushing's syndrome.

Menstrual Disorders

Menstrual Disorders are common. Periods become irregular and often stop. In men, there is decreased fertility with diminished or absent libido.

High Blood Pressure

Blood pressure above the normal range, or hypertension, occurs in 85 percent of Cushing's patients. More than 50 percent of patients have elevated diastolic pressure, and practically all patients have elevated systolic pressure. High blood pressure is associated with increased atherosclerosis, a buildup of fat in the arteries.

Muscle and Bone Weakness

Severe fatigue and weak, fragile muscles are characteristic of Cushing's syndrome. Backache is common due to osteoporosis, a weakening of the bones resulting from decreased bone mass. In Cushing's syndrome, rib fractures are frequent, and vertebral (spinal column) compression fractures may occur during routine activities such as bending, lifting, or rising from a chair.

High Blood Sugar

High blood sugar, or hyperglycemia, is seen in 80 percent of patients with Cushing's syndrome following the oral glucose tolerance test. However, diabetes mellitus occurs in less than 20 percent of people with Cushing's syndrome, and usually only in those with a family history of the disorder.

Diagnosis

The diagnosis of Cushing's syndrome is based on a review of the patient's medical history, physical examination, laboratory tests, and often x-ray exams of the adrenal or pituitary glands. The aim of these tests is first to determine whether excess levels of cortisol are present and then to establish the cause.

24-Hour Urinary Free Cortisol Level

This is the most specific test for diagnosing Cushing's syndrome. The patient's urine is collected over a 24-hour period and then tested for the amount of cortisol. Levels higher than 100 micrograms a day for an adult suggest Cushing's syndrome. (Persons suffering from depression or alcoholism, who tend to produce higher than normal levels of cortisol, may need further testing to confirm a diagnosis of Cushing's syndrome.)

Once Cushing's syndrome has been diagnosed, it is important to determine its cause. Various other tests are used to find the abnormality that leads to excess cortisol production. The choice of test depends in part on the preference of the endocrinologist or the center where the test is performed. Two very specialized tests that may be used are described below.

Dezamethasone Suppression Test

In this test, dexamethasone, a synthetic cortisol, is given by mouth every 6 hours for a period of 4 days. For the first 2 days, low doses of dexamethasone are given, and for the last 2 days, higher doses are given. The normal response after taking dexamethasone is a drop in blood and urine cortisol levels. Depending on the cause of Cushing's syndrome, different responses of cortisol to dexamethasone are obtained. The dexamethasone suppression test helps to distinguish patients with pituitary adenomas from those with ACTH- or cortisol-producing tumors.

The dexamethasone test can produce false-positive results in response to depression, alcohol abuse, high estrogen levels, acute illness, and stress. Conversely, drugs such as phenytoin and phenobarbital may cause false results in response to dexamethasone suppression. For this reason, patients should stop taking these drugs for at least 1 week before the test is performed.

CRH Stimulation Test

The corticotropin-releasing hormone (CRH) stimulation test is a relatively new diagnostic tool that also may be used to identify the cause of Cushing's syndrome. Patients with pituitary adenomas, after receiving an injection of CRH, usually have a rise in blood levels of ACTH and cortisol. This response is rarely seen in patients with ectopic ACTH syndrome and practically never in patients with cortisol-secreting adrenal tumors.

Direct Visualization of Endocrine Glands

Doctors use different imaging tools to reveal the size and shape of the pituitary and adrenal glands. The most common are the CT (computerized tomography) scan and MRI (magnetic resonance imaging). A CT scan produces a series of x-ray pictures giving a cross-sectional image of a body part. MRI also produces images of the internal organs of the body but without exposing the patient to ionizing radiation. A CT scan or MRI of the pituitary gland may help determine if a tumor is present, causing an overproduction of ACTH. Occasionally, doctors use a special radioisotope procedure, known as the iodocholesterol scan, to view the adrenal glands. If these tests do not establish the source of ACTH, some centers are experienced in performing catheterization procedures that sample the blood leaving the pituitary gland to determine if the pituitary is the source of high ACTM.

Treatment

Treatment of Cushing's syndrome depends on the specific reason for cortisol overproduction. If the cause is long-term use of glucocorticoid hormones to treat another disorder, the doctor will gradually reduce the dosage until the symptoms are under control. Once control is established, the daily dose will be doubled and given on alternate days.

Pituitary Adenomas

Several therapies are available to treat the ACTH-secreting pituitary adenomas of Cushing's disease. The most widely used treatment is removal of the tumor by surgery, known as transsphenoidal adenomectomy. Using a special microscope and very fine instruments, the surgeon approaches the pituitary gland through a nostril or an opening made in the bridge of the nose. Because this is an extremely delicate procedure, patients are often referred to centers specializing in this type of surgery. The success, or cure, rate of this procedure is over 80 percent. When surgery fails, it is usually because the CT scan or MRI is unable to identify the small adenoma. After pituitary surgery, there is a natural but temporary drop in the production of ACTH, so patients must be given a synthetic glucocorticoid hormone called hydrocortisone. Most patients can stop this replacement therapy in less than I year.

For patients in whom transsphenoidal surgery has failed or who are not suitable candidates for surgery, radiotherapy is another possible treatment. Radiation to the pituitary gland is given over a period of 6 weeks, with improvement occurring in 40 to 50 percent of adults and up to 80 percent of children. It may take several months before patients feel better from radiation treatment alone. However, the combination of radiation and the drug mitotane (Lysodren[registered trade mark]) can help speed recovery. Mitotane suppresses cortisol production and lowers plasma and urine hormone levels. Treatment with mitotane alone can be successful in 30 to 40 percent of patients. Other drugs used alone or in combination to control the production of excess cortisol are aminoglutethimide, metyrapone, and ketoconazole. Like all drugs, each has its own set of side effects that doctors consider when prescribing therapy for individual patients.

Ectopic ACTH Syndrome

To cure the overproduction of cortisol caused by ectopic ACTH syndrome, it is necessary to eliminate all of the cancerous tissue that is secreting ACTH. The choice of cancer treatment-surgery, radiotherapy, chemotherapy, immunotherapy, or a combination of these treatments-depends on the type of cancer and how far it has spread. Since ACTH-secreting tumors (for example, small cell lung cancer) may be very small or widespread at the time of diagnosis, cortisol-inhibiting drugs like mitotane form an important part of treatment. In some cases, if pituitary surgery is not successful, surgical removal of the adrenal glands (bilateral adrenalectomy) may take the place of drug therapy.

Recently, researchers have found that a glucocorticoid antagonist, RU 486, is effective in fighting the excessive effects of cortisol that cause Cushing's syndrome. RU 486 is stiff an investigational drug, however, and its use is limited to clinical trials.

Adrenal Tumors

Surgery is the mainstay of treatment for benign as well as cancerous tumors of the adrenal glands.

Research in Cushing's Syndrome

The National Institutes of Health (NIH) is the biomedical research arm of the Federal Government. It is one of seven health agencies of the Public Health Service, which is part of the U.S. Department of Health and Human Services. Several components of NIH-the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Child Health and Human Development (NICHD), the National Institute of Neurological Disorders and Stroke, and the National Cancer Institute-conduct and support research on Cushing's syndrome and other disorders of the endocrine system.

NIH-supported scientists are conducting intensive research into the normal and abnormal function of the major endocrine glands and the many hormones of the endocrine system. One important NIDDK-supported study by Dr. Wylie W. Vale and colleagues at the Salk Institute for Biological Studies in La Jolla California, led to the identification of corticotropin-releasing hormone (CRH), which instructs the pituitary gland to release ACTH. This finding enabled Dr. George P Chrousos and coworkers at the NICHD to develop the CRH stimulation test, which is increasingly being used to identify the cause of Cushing's syndrome. Using the dexamethasone suppression test, doctors are able to diagnose the cause of Cushing's syndrome in 80 percent of patients. With the CRH stimulation test alone, they can accurately diagnose the cause in 85 percent of cases. By using the dexamethasone suppression test and CRH stimulation test together, they are able to diagnose Cushing's syndrome with 98 percent accuracy, according to a recent NIH study.

NIH scientists are continuing their efforts to improve the diagnosis and treatment of Cushing's syndrome. Current research is targeted not only at identifying new hormones, but also understanding their precise functions. Researchers also are focusing on the role of receptors, which are large complex molecules either on the surface of or within target cells to which hormones must attach to be effective.

One goal of future research is to find ways to cure Cushing's syndrome without surgery. For example, it may be possible to destroy pituitary tumors selectively by binding a hormone like CRH, which precisely targets pituitary tissue, with a tumor-killing toxin or monoclonal antibody.

Current NIH Studies

Scientists are treating patients with Cushing's syndrome at the NIH Warren Grant Magnuson Clinical Center in Bethesda, Maryland. Physicians who are interested in referring a patient with Cushing's syndrome may contact Dr. George P. Chrousos, Developmental Endocrinology Branch, NICHD, Building 10, Room 1ON262, Bethesda, Maryland 20892, telephone (301) 496-4686.

Suggested Reading

The following materials can be found in medical libraries, many college and university libraries, and through interlibrary loan in most public libraries.
 Forsham, Peter H. and Tyrrell, J. Blake, "Cushing's
 Syndrome," in Current Diagnosis, edited by
 Rex B. Conn. Philadelphia, W.B. Saunders Company,
 1985, pp 863-867.
 Chrousos, George P, "Cushing's Syndrome," in
 Conn's Current Therapy, edited by Robert E. Rakel.
 Philadelphia, W.B. Saunders Company, Philadelphia,
 1987, pp 495-498.
 Kohler, Peter O., ed. Clinical Endocrinology, New
 York, John Wiley & Sons, 1986.
 Braunwald, Eugene et al., eds. Hanison's Principles
 of Internal Medicine, 11th edition, New York,
 McGraw-Hill Book Company, 1987, pp 1760
- 1764.
 NCI Research Report.- Cancer of the Lung. Prepared
 by the Office of Cancer Communications, National
 Cancer Institute, NIH Publication No. 86-526.
 Other Resources
 National Cushing's Association
 4620 1/2 Van Nuys Boulevard
 Sherman Oaks, California 91403
 (818) 788-9235 or (818) 788-9239
 Andrea Hecht, President


This fact sheet was written by Eileen K. Corrigan of NIDDK's Office of Health Research Reports. The draft was reviewed by Dr. George P Chrousos, National Institute of Child Health and Human Development, and by Dr. Richard Horton, University of Southern California Medical Center.

This fact sheet is not copyrighted. Readers are encouraged to duplicate and distribute as many copies as needed. Single copies may be obtained from the Office of Health Research Reports, NIDDK, Building 31, Room 9A04, Bethesda, Maryland 20892, (301) 496-3583.
COPYRIGHT 1989 National Institute of Diabetes & Digestive & Kidney Diseases
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 1989, Gale Group. All rights reserved. Gale Group is a Thomson Corporation Company.

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Title Annotation:NIDDK Fact Sheet
Publication:Pamphlet by: National Institute of Diabetes & Digestive & Kidney Diseases
Article Type:pamphlet
Date:Apr 1, 1989
Words:3062
Previous Article:Familial multiple endocrine neoplasia type 1.
Next Article:Addison's disease.
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