Article title: Cushing's Syndrome: NIDDK
Main condition: Cushing's syndrome
Conditions: Cushing's syndrome
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.
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.
Pituitary Adenomas
Pituitary adenomas cause most cases of
Cushing's syndrome. They are benign, or non-cancerous, tumors of the
pituitary gland which secrete increased amounts of ACTH. Most patients
have a single adenoma. This form of the syndrome, known as "Cushing's
disease," affects women five times more frequently than men.
Ectopic ACTH Syndrome
Some benign or malignant (cancerous)
tumors that arise outside the pituitary can produce ACTH. This condition
is known as ectopic ACTH syndrome. Lung tumors cause over 50 percent of
these cases. Men are affected 3 times more frequently than women. The most
common forms of ACTH-producing tumors are oat cell, or small cell lung
cancer, which accounts for about 25 percent of all lung cancer cases, and
carcinoid tumors. Other less common types of tumors that can produce ACTH
are thymomas, pancreatic islet cell tumors, and medullary carcinomas of
the thyroid.
Adrenal Tumors
Sometimes, an abnormality of the adrenal
glands, most often an adrenal tumor, causes Cushing's syndrome. The
average age of onset is about 40 years. Most of these cases involve
non-cancerous tumors 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. 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
Most cases of Cushing's syndrome
are not inherited. Rarely, however, some individuals have special causes
of Cushing's syndrome due to an inherited tendency to develop tumors of
one or more endocrine glands. In Primary Pigmented Micronodular Adrenal
Disease, children or young adults develop small cortisol-producing tumors
of the adrenal glands. In Multiple Endocrine Neoplasia Type I (MEN I),
hormone secreting tumors of the parathyroid glands, pancreas and pituitary
occur. Cushing's syndrome in MEN I may be due to pituitary, ectopic or
adrenal tumors.
24-Hour Urinary Free Cortisol Level
This is the most specific
diagnostic test. The patient's urine is collected over a 24-hour period
and tested for the amount of cortisol. Levels higher than 50-100
micrograms a day for an adult suggest Cushing's syndrome. The normal upper
limit varies in different laboratories, depending on which measurement
technique is used.
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
This test helps to distinguish
patients with excess production of ACTH due to pituitary adenomas from
those with ectopic ACTH-producing tumors. Patients are given
dexamethasone, a synthetic glucocorticoid, by mouth every 6 hours for 4
days. For the first 2 days, low doses of dexamethasone are given, and for
the last 2 days, higher doses are given. Twenty-four hour urine
collections are made before dexamethasone is administered and on each day
of the test. Since cortisol and other glucocorticoids signal the pituitary
to lower secretion of ACTH, the normal response after taking dexamethasone
is a drop in blood and urine cortisol levels. Different responses of
cortisol to dexamethasone are obtained depending on whether the cause of
Cushing's syndrome is a pituitary adenoma or an ectopic ACTH-producing
tumor.
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
This test helps to distinguish between
patients with pituitary adenomas and those with ectopic ACTH syndrome or
cortisol-secreting adrenal tumors. Patients are given an injection of CRH,
the corticotropin-releasing hormone which causes the pituitary to secrete
ACTH. Patients with pituitary adenomas usually experience 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 the Endocrine Glands (Radiologic
Imaging)
Imaging tests reveal the size and shape of the pituitary
and adrenal glands and help determine if a tumor is present. 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.
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
This test is not always required, but
in many cases, it is the best way to separate pituitary from ectopic
causes of Cushing's syndrome. Samples of blood are drawn from the petrosal
sinuses, veins which drain the pituitary, by introducing catheters through
a vein in the upper thigh/groin region, with local anesthesia and mild
sedation. X-rays are used to confirm the correct position of the
catheters. Often CRH, the hormone which causes the pituitary to secrete
ACTH, is given during this test to improve diagnostic accuracy. Levels of
ACTH in the petrosal sinuses are measured and compared with ACTH levels in
a forearm vein. ACTH levels higher in the petrosal sinuses than in the
forearm vein indicate the presence of a pituitary adenoma; similar levels
suggest ectopic ACTH syndrome.
The Dexamethasone-CRH Test
Some individuals have high
cortisol levels, but do not develop the progressive effects of Cushing's
syndrome, such as muscle weakness, fractures and thinning of the skin.
These individuals may have Pseudo Cushing's syndrome, which was originally
described in people who were depressed or drank excess alcohol, but is now
known to be more common. Pseudo Cushing's does not have the same long-term
effects on health as Cushing's syndrome and does not require treatment
directed at the endocrine glands. Although observation over months to
years will distinguish Pseudo Cushing's from Cushing's, the
dexamethasone-CRH test was developed to distinguish between the conditions
rapidly, so that Cushing's patients can receive prompt treatment. This
test combines the dexamethasone suppression and the CRH stimulation tests.
Elevations of cortisol during this test suggest Cushing's syndrome.
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.
Pituitary Adenomas
Several therapies are available to treat
the ACTH-secreting pituitary adenomas of Cushing's disease. The most
widely used treatment is surgical removal of the tumor, 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 below the upper lip. 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 performed by a surgeon with extensive experience. If
surgery fails, or only produces a temporary cure, surgery can be repeated,
often with good results. After curative pituitary surgery, the production
of ACTH drops two levels below normal. This is a natural, but temporary,
drop in ACTH production, and patients are given a synthetic form of
cortisol (such as hydrocortisone or prednisone). Most patients can stop
this replacement therapy in less than a 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 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
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, are 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.
Adrenal Tumors
Surgery is the mainstay of treatment for
benign as well as cancerous tumors of the adrenal glands. In Primary
Pigmented Micronodular Adrenal Disease and the familial Carney's complex,
surgical removal of the adrenal glands is required.
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.
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.
Pituitary Tumor Network Association
16350 Ventura Blvd.
#231
Encino, CA 91436
(805) 499-9973
Fax: (805) 499-1523
This e-text is not copyrighted. NIDDK encourages users to duplicate and distribute as many copies as needed. Printed single copies may be obtained from the Office of Communications and Public Liaison, NIDDK, 31 CENTER DRIVE, MSC 2560, Bethesda, Maryland 20892-2560.
NIH Publication No. 96-3007
June 1996
e-text posted: 20 February 1998
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