What is Cushing's syndrome?
Cushing'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, Cushing's syndrome
is relatively rare and most commonly affects adults aged 20 to
50. People who are obese and have type 2 diabetes, along with
poorly controlled blood glucose-also called blood sugar-and high
blood pressure, have an increased risk of developing the
What are the signs and symptoms of Cushing's syndrome?
Signs and symptoms of Cushing's syndrome vary, but most
people with the disorder have upper body obesity, a rounded
face, increased fat around the neck, and relatively slender arms
and legs. Children tend to be obese with slowed growth rates.
Other signs appear in the skin, which becomes fragile and
thin, bruises easily, and heals poorly. Purple or 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
and rib or spinal column fractures.
Women with Cushing's syndrome usually have excess hair growth
on their face, neck, chest, abdomen, and thighs. Their menstrual
periods may become irregular or stop. Men may have decreased
fertility with diminished or absent desire for sex and,
sometimes, erectile dysfunction.
Other common signs and symptoms include
- severe fatigue
- weak muscles
- high blood pressure
- high blood glucose
- increased thirst and urination
- irritability, anxiety, or depression
- a fatty hump between the shoulders
Sometimes other conditions have many of the same signs as
Cushing's syndrome, even though people with these disorders do
not have abnormally elevated cortisol levels. For example,
polycystic ovary syndrome can cause menstrual disturbances,
weight gain beginning in adolescence, excess hair growth, and
impaired insulin action and diabetes. Metabolic syndrome-a
combination of problems that includes excess weight around the
waist, high blood pressure, abnormal levels of cholesterol and
triglycerides in the blood, and insulin resistance-also mimics
the symptoms of Cushing's syndrome.
What causes Cushing's syndrome?
Cushing's syndrome occurs when the body's tissues are exposed
to high levels of cortisol for too long. Many people develop
Cushing's syndrome because they take glucocorticoids-steroid
hormones that are chemically similar to naturally produced
cortisol—such as prednisone for asthma, rheumatoid arthritis,
lupus, and other inflammatory diseases. Glucocorticoids are also
used to suppress the immune system after transplantation to keep
the body from rejecting the new organ or tissue.
Other people develop Cushing's syndrome because their bodies
produce too much cortisol. Normally, the production of cortisol
follows a precise chain of events. First, the hypothalamus, a
part of the brain about the size of a small sugar cube, sends
corticotropin-releasing hormone (CRH) to the pituitary gland.
CRH causes the pituitary to secrete adrenocorticotropin hormone
(ACTH), which 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 including
- helping maintain blood pressure and cardiovascular
- reducing the immune system's inflammatory response
- balancing the effects of insulin, which breaks down
glucose for energy
- regulating the metabolism of proteins, carbohydrates, and
The hypothalamus sends CRH to the
pituitary, which responds by secreting ACTH. ACTH then causes
the adrenals to release cortisol into the bloodstream.
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, or panic disorders also have increased
When the amount of cortisol in the blood is adequate, the
hypothalamus and pituitary release less CRH and ACTH. This
process ensures 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 the
regulating switches in the pituitary gland or hypothalamus,
cortisol production can go awry.
Pituitary adenomas cause 70 percent of Cushing's syndrome
excluding those caused by glucocorticoid use. These benign, or
noncancerous, tumors of the pituitary gland secrete extra ACTH.
Most people with the disorder have a single adenoma. This form
of the syndrome, known as Cushing's disease, affects women five
times more often than men.
Ectopic ACTH Syndrome
Some benign or, more often, cancerous tumors that arise
outside the pituitary can produce ACTH. This condition is known
as ectopic ACTH syndrome. Lung tumors cause more than half of
these cases, and men are affected three times more often than
women. The most common forms of ACTH-producing tumors are small
cell lung cancer, which accounts for about 13 percent of all
lung cancer cases,2
and carcinoid tumors-small, slow-growing tumors that arise from
hormone-producing cells in various parts of the body. Other less
common types of tumors that can produce ACTH are thymomas,
pancreatic islet cell tumors, and medullary carcinomas of the
In rare cases, an abnormality of the adrenal glands, most
often an adrenal tumor, causes Cushing's syndrome. Adrenal
tumors are four to five times more common in women than men, and
the average age of onset is about 40. Most of these cases
involve noncancerous tumors of adrenal tissue called adrenal
adenomas, which release excess cortisol into the blood.
Adrenocortical carcinomas-adrenal cancers-are the least
common cause of Cushing's syndrome. With adrenocortical
carcinomas, cancer cells secrete excess levels of several
adrenocortical hormones, including cortisol and adrenal
androgens, a type of male hormone. Adrenocortical carcinomas
usually cause very high hormone levels and rapid development of
Familial Cushing's Syndrome
Most cases of Cushing's syndrome are not inherited. Rarely,
however, Cushing's syndrome results from an inherited tendency
to develop tumors of one or more endocrine glands. Endocrine
glands release hormones into the bloodstream. With primary
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 Medicine. 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 Oncology. 2006;24:4539-4544.
How is Cushing's syndrome diagnosed?
Diagnosis is based on a review of a person's medical history,
a physical examination, and laboratory tests. X rays of the
adrenal or pituitary glands can be useful in locating tumors.
Tests to Diagnose Cushing's Syndrome
No single lab test is perfect and usually several are needed.
The three most common tests used to diagnose Cushing's syndrome
are the 24-hour urinary free cortisol test, measurement of
midnight plasma cortisol or late-night salivary cortisol, and
the low-dose dexamethasone suppression test. Another test, the
dexamethasone-corticotropin-releasing hormone test, may be
needed to distinguish Cushing's syndrome from other causes of
24-hour urinary free cortisol level. In
this test, a person's urine is collected several times over
a 24-hour period and tested for cortisol. Levels higher than
50 to 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
Midnight plasma cortisol and late-night salivary
cortisol measurements. The midnight plasma cortisol
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.
However, a late-night or bedtime saliva sample can be
obtained at home, then tested to determine the cortisol
level. Diagnostic ranges vary, depending on the measurement
Low-dose dexamethasone suppression test (LDDST).
In the LDDST, a person is given a low dose of dexamethasone,
a synthetic glucocorticoid, by mouth every 6 hours for 2
days. Urine is collected before dexamethasone is
administered and several times on each day of the test. A
modified LDDST uses a onetime overnight dose.
Cortisol and other glucocorticoids signal the pituitary
to release less ACTH, so the normal response after taking
dexamethasone is a drop in blood and urine cortisol levels.
If cortisol levels do not drop, Cushing's syndrome is
The LDDST may not show a drop in cortisol levels in
people with depression, alcoholism, high estrogen levels,
acute illness, or stress, falsely indicating Cushing's
syndrome. On the other hand, drugs such as phenytoin and
phenobarbital may cause cortisol levels to drop, falsely
indicating that Cushing’s is not present in people who
actually have the syndrome. For this reason, physicians
usually advise their patients to stop taking these drugs at
least 1 week before the test.
Dexamethasone-corticotropin-releasing hormone (CRH)
test. Some people 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 people may have pseudo-Cushing's syndrome, a
condition sometimes found in people who have depression or
anxiety disorders, drink excess alcohol, have poorly
controlled diabetes, or are severely obese.
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.
The dexamethasone-CRH test rapidly distinguishes
pseudo-Cushing's from mild cases of Cushing's. This test
combines the LDDST and a CRH stimulation test. In the CRH
stimulation test, an injection of CRH causes the pituitary
to secrete ACTH. Pretreatment with dexamethasone prevents
CRH from causing an increase in cortisol in people with
pseudo-Cushing's. Elevations of cortisol during this test
suggest Cushing's syndrome.
Tests to Find the Cause of Cushing's Syndrome
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.
CRH stimulation test. The CRH test,
without pretreatment with dexamethasone, helps separate
people with pituitary adenomas from those with ectopic ACTH
syndrome or adrenal tumors. As a result of the CRH
injection, people with pituitary adenomas usually experience
a rise in blood levels of ACTH and cortisol because CRH acts
directly on the pituitary. This response is rarely seen in
people with ectopic ACTH syndrome and practically never in
those with adrenal tumors.
high-dose dexamethasone suppression test (HDDST).
The HDDST is the same as the LDDST, except it uses higher
doses of dexamethasone. This 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
Radiologic imaging: direct visualization of the
endocrine glands. Imaging tests reveal the size and
shape of the pituitary and adrenal glands and help determine
if a tumor is present. The most common imaging tests are the
computerized tomography (CT) scan and magnetic resonance
imaging (MRI). A CT scan produces a series of x-ray pictures
giving a cross-sectional image of a body part. MRI also
produces images of internal organs but without exposing
patients to ionizing radiation.
Imaging procedures are used to find a tumor after a
diagnosis has been made. Imaging is not used to make the
diagnosis of Cushing's syndrome because benign tumors are
commonly found in the pituitary and adrenal glands. These
tumors, sometimes called incidentalomas, do not produce
hormones in quantities that are harmful. They are not
removed unless blood tests show they are a cause of symptoms
or they are unusually large. Conversely, pituitary tumors
may not be detectable by imaging in almost half of people
who ultimately need pituitary surgery for Cushing's
Petrosal sinus sampling. This test is
not always required, but in many cases, it is the best way
to distinguish pituitary from ectopic causes of Cushing's
syndrome. Samples of blood are drawn from the petrosal
sinuses-veins that drain the pituitary-by inserting tiny
tubes through a vein in the upper thigh or groin region. A
local anesthetic and mild sedation are given, and x rays are
taken to confirm the correct position of the tubes. Often
CRH, the hormone that causes the pituitary to release 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. Higher levels
of ACTH in the sinuses than in the forearm vein indicate a
pituitary adenoma. Similar levels of ACTH in the petrosal
sinuses and the forearm suggest ectopic ACTH syndrome.
How is Cushing's syndrome treated?
Treatment depends on the specific reason for excess cortisol
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. In some cases,
noncorticosteroid drugs can be prescribed.
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
fine instruments, the surgeon approaches the pituitary gland
through a nostril or an opening made below the upper lip.
Because this procedure is extremely delicate, patients are often
referred to centers specializing in this type of surgery. The
success, or cure, rate of this procedure is more than 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 drop is natural and
temporary, and patients are given a synthetic form of cortisol
such as hydrocortisone or prednisone to compensate. Most people
can stop this replacement therapy in less than 1 or 2 years, but
some must be on it for life.
If transsphenoidal surgery fails or a patient is not a
suitable candidate for surgery, radiation therapy 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 85 percent of children. Another
technique, called stereotactic radiosurgery or gamma knife
radiation, can be given in a single high-dose treatment. It may
take several months or years before people feel better from
radiation treatment alone. Combining radiation with cortisol-inhibiting
drugs can help speed recovery.
Drugs used alone or in combination to control the production
of excess cortisol are ketoconazole, mitotane, aminoglutethimide,
and metyrapone. Each drug has its own side effects that doctors
consider when prescribing medical therapy for individual
Ectopic ACTH Syndrome
To cure the overproduction of cortisol caused by ectopic ACTH
syndrome, all of the cancerous tissue that is secreting ACTH
must be eliminated. The choice of cancer treatment-surgery,
radiation, chemotherapy, immunotherapy, or a combination of
these treatments—depends on the type of cancer and how far it
has spread. Because ACTH-secreting tumors may be small or
widespread at the time of diagnosis, making them difficult to
locate and treat directly, cortisol-inhibiting drugs are an
important part of treatment. In some cases, if other treatments
fail, surgical removal of the adrenal glands, called bilateral
adrenalectomy, may replace drug therapy.
Surgery is the mainstay of treatment for benign and cancerous
tumors of the adrenal glands. Primary pigmented micronodular
adrenal disease and the inherited Carney complex-primary tumors
of the heart that can lead to endocrine overactivity and
Cushing's syndrome-require surgical removal of the adrenal
Points to Remember
Cushing's syndrome is a disorder caused by prolonged
exposure of the body's tissues to high levels of the hormone
Typical signs and symptoms of Cushing's syndrome include
upper body obesity, a rounded face, skin that bruises easily
and heals poorly, weakened bones, excess body hair growth
and menstrual irregularities in women, and decreased
fertility in men.
Cushing's syndrome is caused by exposure to
glucocorticoids, which are used to treat inflammatory
diseases, or by the body's overproduction of cortisol, most
often due to tumors of the pituitary gland or lung.
Several tests are usually needed to diagnosis Cushing's
syndrome, including urine, blood, and saliva tests. Other
tests help find the cause of the syndrome.
Treatment depends on the specific reason for excess
cortisol and may include surgery, radiation, chemotherapy,
or the use of cortisol-inhibiting drugs.
Hope through Research
Several components of the National Institutes of Health (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, the
National Institute of Child Health and Human Development (NICHD),
the National Institute of Neurological Disorders and Stroke, the
National Cancer Institute, and the National Center for Research
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.
Researchers continue to study the effects of excess cortisol,
including its effect on brain structure and function. To refine
the diagnostic process, studies are under way to assess the
accuracy of existing screening tests and the effectiveness of
new imaging techniques to evaluate patients with ectopic ACTH
syndrome. Researchers are also investigating jugular vein
sampling as a less invasive alternative to petrosal sinus
sampling. Research into treatment options includes study of a
new drug to treat the symptoms of Cushing's syndrome caused by
ectopic ACTH secretion.
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.
The 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
Clinical Center in Bethesda, MD. Physicians who are interested
in referring an adult patient may contact Lynnette Nieman, M.D.,
at NICHD, 10 Center Drive, Room 1-3140, Bethesda, MD 20892-1109,
or by phone at 301-496-8935. Physicians interested in referring
a child or adolescent may contact Constantine Stratakis, M.D.,
D.Sc., at NICHD, 10 Center Drive, Room 1-3330, Bethesda, MD
20892-1103, or by phone at 301-402-1998.
For More Information
The following articles about Cushing's syndrome can be found
in medical libraries, some college and university libraries, and
through interlibrary loan in most public libraries.
Labeur M, Arzt E, Stalla GK, Páez-Pereda M. New perspectives
in the treatment of Cushing's syndrome. Current Drug
Targets-Immune, Endocrine & Metabolic Disorders.
Lin D, Loughlin K. Diagnosis and management of surgical
adrenal diseases. Urology. 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.
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.
NIH Publication No. 08-3007
information should not be used for diagnosis or treatment. A
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