Endocrine Resource Center
IntroductionCushing's syndrome is a hormonal disorder caused by prolonged exposure of the body's tissues to high levels of the hormone cortisol. Sometimes called "hypercortisolism," it is relatively rare and most commonly affects adults aged 20 to 50. An estimated 10 to 15 of every million people are affected each year.
What Are the Symptoms?Symptoms vary, but most people have upper body obesity, rounded face, increased fat around the neck, and thinning arms and legs. Children tend to be obese with slowed growth rates.
Other symptoms appear in the skin, which becomes fragile and thin. It bruises easily and heals poorly. Purplish pink stretch marks may appear on the abdomen, thighs, buttocks, arms and breasts. The bones are weakened, and routine activities such as bending, lifting or rising from a chair may lead to backaches, rib and spinal column fractures.
Most people have severe fatigue, weak muscles, high blood pressure and high blood sugar. Irritability, anxiety and depression are common.
Women usually have excess hair growth on their faces, necks, chests, abdomens, and thighs. Their menstrual periods may become irregular or stop. Men have decreased fertility with diminished or absent desire for sex.
What Causes Cushing's Syndrome?Cushing's syndrome occurs when the body's tissues are exposed to excessive levels of cortisol for long periods of time. Many people suffer the symptoms of Cushing's syndrome because they take glucocorticoid hormones such as prednisone for asthma, rheumatoid arthritis, lupus or other inflammatory diseases.
Others develop Cushing's syndrome because of overproduction of cortisol by the body. Normally, the production of cortisol follows a precise chain of events. First, the hypothalamus, a part of the brain which is about the size of a small sugar cube, sends corticotropin releasing hormone (CRH) to the pituitary gland. CRH causes the pituitary to secrete ACTH (adrenocorticotropin), a hormone that stimulates the adrenal glands. When the adrenals, which are located just above the kidneys, receive the ACTH, they respond by releasing cortisol into the bloodstream.
Cortisol performs vital tasks in the body. It helps maintain blood pressure and cardiovascular function, reduces the immune system's inflammatory response, balances the effects of insulin in breaking down sugar for energy, and regulates the metabolism of proteins, carbohydrates, and fats. One of cortisol's most important jobs is to help the body respond to stress. For this reason, women in their last 3 months of pregnancy and highly trained athletes normally have high levels of the hormone. People suffering from depression, alcoholism, malnutrition and panic disorders also have increased cortisol levels.
When the amount of cortisol in the blood is adequate, the hypothalamus and pituitary release less CRH and ACTH. This ensures that the amount of cortisol released by the adrenal glands is precisely balanced to meet the body's daily needs. However, if something goes wrong with the adrenals or their regulating switches in the pituitary gland or the hypothalamus, cortisol production can go awry.
Ectopic ACTH Syndrome
Adrenocortical carcinomas, or adrenal cancers, are the least common cause of Cushing's syndrome. Cancer cells secrete excess levels of several adrenal cortical hormones, including cortisol and adrenal androgens. Adrenocortical carcinomas usually cause very high hormone levels and rapid development of symptoms.
Familial Cushing's Syndrome
How Is Cushing's Syndrome Diagnosed?Diagnosis is based on a review of the patient's medical history, physical examination and laboratory tests. Often x-ray exams of the adrenal or pituitary glands are useful for locating tumors. These tests help to determine if excess levels of cortisol are present and why.
24-Hour Urinary Free Cortisol Level
Once Cushing's syndrome has been diagnosed, other tests are used to find the exact location of 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.
Dexamethasone Suppression Test
The dexamethasone suppression test can produce false-positive results in patients with depression, alcohol abuse, high estrogen levels, acute illness, and stress. Conversely, drugs such as phenytoin and phenobarbital may cause false-negative results in response to dexamethasone suppression. For this reason, patients are usually advised by their physicians to stop taking these drugs at least one week before the test.
CRH Stimulation Test
Direct Visualization of the Endocrine Glands (Radiologic
Imaging procedures are used to find a tumor after a diagnosis has been established. Imaging is not used to make the diagnosis of Cushing's syndrome because benign tumors, sometimes called "incidentalomas," are commonly found in the pituitary and adrenal glands. These tumors do not produce hormones detrimental to health and are not removed unless blood tests show they are a cause of symptoms or they are unusually large. Conversely, pituitary tumors are not detected by imaging in almost 50 percent of patients who ultimately require pituitary surgery for Cushing's syndrome.
Petrosal Sinus Sampling
The Dexamethasone-CRH Test
Some patients may have sustained high cortisol levels without the effects of Cushing's syndrome. These high cortisol levels may be compensating for the body's resistance to cortisol's effects. This rare syndrome of cortisol resistance is a genetic condition that causes hypertension and chronic androgen excess.
Sometimes other conditions may be associated with many of the symptoms of Cushing's syndrome. These include polycystic ovarian syndrome, which may cause menstrual disturbances, weight gain from adolescence, excess hair growth and sometimes impaired insulin action and diabetes. Commonly, weight gain, high blood pressure and abnormal levels of cholesterol and triglycerides in the blood are associated with resistance to insulin action and diabetes; this has been described as the "Metabolic Syndrome-X." Patients with these disorders do not have abnormally elevated cortisol levels.
How Is Cushing's Syndrome Treated?Treatment depends on the specific reason for cortisol excess and may include surgery, radiation, chemotherapy or the use of cortisol-inhibiting drugs. If the cause is long-term use of glucocorticoid hormones to treat another disorder, the doctor will gradually reduce the dosage to the lowest dose adequate for control of that disorder. Once control is established, the daily dose of glucocorticoid hormones may be doubled and given on alternate days to lessen side effects.
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 6-week period, with improvement occurring in 40 to 50 percent of adults and up to 80 percent of children. It may take several months or years before patients feel better from radiation treatment alone. However, the combination of radiation and the drug mitotane (Lysodren®) 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, trilostane and ketoconazole. Each has its own side effects that doctors consider when prescribing therapy for individual patients.
Ectopic ACTH Syndrome
What Research Is Being Done on Cushing's Syndrome?The National Institutes of Health (NIH) is the biomedical research component of the Federal Government. It is one of the health agencies of the Public Health Service, which is part of the U.S. Department of Health and Human Services. Several components of the NIH conduct and support research on Cushing's syndrome and other disorders of the endocrine system, including 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 (NINDS), and the National Cancer Institute (NCI).
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. Identification of the corticotropin releasing hormone (CRH), which instructs the pituitary gland to release ACTH, enabled researchers to develop the CRH stimulation test, which is increasingly being used to identify the cause of Cushing's syndrome.
Improved techniques for measuring ACTH permit distinction of ACTH-dependent forms of Cushing's syndrome from adrenal tumors. NIH studies have shown that petrosal sinus sampling is a very accurate test to diagnose the cause of Cushing's syndrome in those who have excess ACTH production. The recently described dexamethasone suppression-CRH test is able to differentiate most cases of Cushing's from Pseudo Cushing's.
As a result of this research, doctors are much better able to diagnose Cushing's syndrome and distinguish among the causes of this disorder. Since accurate diagnosis is still a problem for some patients, new tests are under study to further refine the diagnostic process.
Many studies are underway to understand the causes of formation of benign endocrine tumors, such as those which 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. There is increasing evidence that tumor formation is a multi-step process. Understanding the basis of Cushing's syndrome will yield new approaches to therapy.
NIH supports research related to Cushing's syndrome at medical centers throughout the United States. Scientists are also 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 may contact Dr. George P. Chrousos, Developmental Endocrinology Branch, NICHD, Building 10, Room 10N262, Bethesda, Maryland 20892, telephone (301) 496-4686.
Where Can I Find More Information?The following materials can be found in medical libraries, many college and university libraries, and through interlibrary loan in most public libraries.
Cooper, Paul R. "Contemporary Diagnosis and Management of Pituitary Adenomas," Park Ridge, Illinois: American Association of Neurological Surgeons, 1991.
DeGroot, Leslie J., ed., et al. "Cushing's Syndrome," Endocrinology. Vol. 2, Philadelphia: W. B. Saunders Company, 1995. 1741-1769.
Isselbacher, Kurt J., ed., et al. "Cushing's Syndrome Etiology," Harrison's Principles of Internal Medicine. Vol. 2, No. 13, New York: McGraw-Hill Book Company, 1994. 1960-1965.
Wilson, Jean D., ed, et al. "Hyperfunction: Glucocorticoids: Hypercortisolism (Cushing's syndrome)," Williams Textbook of Endocrinology, No. 8, Philadelphia: W.B. Saunders, 1992; 536-562.
Conn, R.B., Gomez, T., Chrousos, G.P., "Current Diagnosis," No. 8, Philadelphia: W.B. Saunders 1991, 868-872.
NCI Research Report: Cancer of the Lung. Prepared by the Office of Cancer Communications, National Cancer Institute, NIH Publication No. 93-526.
What Other Resources Are Available?Cushing's Support and Research Foundation, Inc.
65 East India Row 22B
Boston, Massachusetts 02110
(617) 723-3824 or (617) 723-3674
Louise L. Pace, Founder and President
All information is intended for your general knowledge only and is not a substitute for medical advice or treatment for specific medical conditions. You should seek prompt medical care for any specific health issues and consult your physician or health practitioner before starting a new treatment program. Please see our full disclaimer.