cushing syndroma

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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," it isrelatively rare and most commonly affects adults aged 20 to 50. An estimated 10 to 15 of

every million people are affected each year.

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, liftingor 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 bloodsugar. 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 decreasedfertility with diminished or absent desire for sex.

Causes

Cushing's syndrome occurs when the body's tissues are exposed to excessive levels ofcortisol for long periods of time. Many people suffer the symptoms of Cushing'ssyndrome because they take glucocorticoid hormones such as prednisone for asthma,

rheumatoid arthritis, lupus and other inflammatory diseases, or for immunosuppression

after transplantation.

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, thehypothalamus, 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, theyrespond by releasing cortisol into the bloodstream.

Cortisol performs vital tasks in the body. It helps maintain blood pressure andcardiovascular 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 bodyrespond to stress. For this reason, women in their last 3 months of pregnancy and highly

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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 theadrenal 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. Mostpatients 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 produceACTH. This condition is known as ectopic ACTH syndrome. Lung tumors cause over 50percent 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 lesscommon 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 releaseexcess cortisol into the blood.

Adrenocortical carcinomas, or adrenal cancers, are the least common cause of Cushing'ssyndrome. 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 developtumors of one or more endocrine glands. In Primary Pigmented Micronodular Adrenal

Disease, children or young adults develop small cortisol-producing tumors of the adrenalglands. In Multiple Endocrine Neoplasia Type I (MEN I), hormone secreting tumors ofthe parathyroid glands, pancreas and pituitary occur. Cushing's syndrome in MEN I may

be due to pituitary, ectopic or adrenal tumors.

Diagnosis

Diagnosis is based on a review of the patient's medical history, physical examination and

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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

This is the most specific diagnostic test. The patient's urine is collected over a 24-hourperiod 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 isperformed.

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 givendexamethasone, a synthetic glucocorticoid, by mouth every 6 hours for 4 days. For thefirst 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 signalthe 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 aninjection 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 ACTHsyndrome 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 seriesof 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.

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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 adrenalglands. 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 patientswho 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 usedto 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 ina 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 ofCushing'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 asCushing'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 theconditions 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 thatcauses hypertension and chronic androgen excess.

Sometimes other conditions may be associated with many of the symptoms of Cushing'ssyndrome. 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 abnormallevels 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.

Treatment for Cushing's Syndrome depends on thespecific cause for cortisol excess and

may include surgery, radiation, chemotherapy or the use of cortisol-inhibiting drugs. If

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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 bedoubled and given on alternate days to lessen side effects.

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 ofthis 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 dropstwo 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 thepituitary 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 suppressescortisol 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 cancertreatmentsurgery, radiotherapy, chemotherapy, immunotherapy, or a combination of

these treatmentsdepends 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 widespreadat 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 theadrenal 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.

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