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Cushing's Fact Sheet
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- 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 also can 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 carious 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.
- Dexamethasone 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. 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 ACTH.
- 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 1 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 fell 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
amioglutethimide, 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 still 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
altogether, 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 10N262, 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. Harrison'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
- Cushing Support & Research Foundation, Inc.
65 East India Row, Ste. 22-B
Boston, MA 02110
Email: csrf@world.std.com
WWW: http://world.std.com/~csrf/
This fact sheet was written by Eileen K. Corrigan of
NIDDK's Office of Health Research Reprots. 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.
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