& Pituitary Center
Neuroendocrine Bulletin Archive
Guestbook | Neurosurgery
Home | Links
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 to15 of every million people are affected each year.
What are the symptoms?
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.
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
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?
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.
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.
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.
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.
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.
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.
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.
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.
How is Cushing's
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
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
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.
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
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.
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.
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.
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.
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.
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
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.
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
How is Cushing's
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
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
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.
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.
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.
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).
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.
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
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
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
J., ed., et al. "Cushing's Syndrome," Endocrinology.
Vol. 2, Philadelphia: W. B. Saunders Company, 1995. 1741-1769.
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
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
Pituitary Tumor Network Association
16350 Ventura Blvd. #231
Encino, CA 91436
Fax: (805) 499-1523
This epub is not
copyrighted. Readers are encouraged to duplicate and distribute
as many copies as needed.
NIH Publication No. 96-3007