Patient information: Cushing's syndrome

CUSHING'S SYNDROME OVERVIEW

Cushing's syndrome occurs when there is an excess of cortisol, a hormone produced by the adrenal glands (figure 1). Cortisol has many important functions and is necessary for life; however, an excess of this hormone has negative effects on the body. Cortisol, which is also called hydrocortisone, is classified as a glucocorticoid.

Normally, the adrenal glands' production of cortisol is carefully controlled by the hypothalamus and pituitary gland (figure 1). Cushing's syndrome can result from several different conditions that affect this control system. Cushing's syndrome affects about three times more women than men.

Today, virtually all people with Cushing's syndrome can be treated effectively, and most can be cured. Because Cushing's syndrome is potentially fatal if untreated, people with this condition should have regular medical care and follow their treatment plan closely.

CUSHING'S SYNDROME CAUSES

The cause of Cushing's syndrome is usually divided into two broad categories, based upon whether the problem lies in the pituitary gland (a small structure at the base of the brain, (figure 1) or in the adrenal glands, which lie above the kidneys. Cushing's syndrome can also occur in individuals who take large doses of glucocorticoids (eg, prednisone) for diseases such as asthma and rheumatoid arthritis.

High blood corticotropin (ACTH) levels — Up to 70 percent of people with Cushing's syndrome have benign pituitary tumors (called adenomas) that produce excess amounts of ACTH, the hormone that stimulates the adrenal gland to produce cortisol. This condition is called Cushing's disease, which shouldn't be confused with Cushing's syndrome. Most of these tumors are very small, and they may be difficult to identify.

Other causes of high blood ACTH levels include non-pituitary tumors that produce ACTH. This form of Cushing's syndrome is called the ectopic ACTH syndrome. Many of these tumors occur in the lungs or elsewhere in the chest.

Normal or low blood ACTH levels — Most people with Cushing's syndrome who have normal or low blood ACTH levels use medications that contain glucocorticoids such as prednisone, which mimics the effects of cortisol. Glucocorticoids have powerful anti-inflammatory actions and are used to treat autoimmune conditions, such as rheumatoid arthritis, and to prevent transplant rejection. Most forms of glucocorticoids, including inhaled and topical forms, can cause Cushing's syndrome.

Less common causes of Cushing's syndrome occur with normal or low ACTH levels, include benign or malignant (cancerous) tumors of the adrenal gland, which produce excess cortisol. Nodular hyperplasia (overgrowth) of the adrenal gland is an even less common cause of cortisol excess.

CUSHING'S SYNDROME SYMPTOMS

The symptoms of Cushing's syndrome result from an excess of cortisol (table 1). Most patients develop at least a few of these symptoms, and the symptoms typically worsen over time. However, each person's symptoms depend upon several factors, including:

• The degree and duration of cortisol excess
• The levels of other adrenal hormones
• The underlying cause of Cushing's syndrome
• Age; the symptoms may be very subtle in people over the age of 50 years

Weight gain — Progressive weight gain is the most common symptom of Cushing's syndrome (picture 1). This weight gain usually affects the face, neck, trunk, and abdomen more than the limbs, which may be thin. People with Cushing's syndrome often develop a rounded face (picture 2) and collections of fat on the upper back and at the base of the neck.

Skin changes — In Cushing's syndrome, the skin tends to become thin, fragile, and more susceptible to bruises and infections (picture 3). Wounds heal poorly, and wide, reddish-purple streaks, called striae (stretch marks, (picture 4), may occur in areas of weight gain.

Menstrual irregularities — Women with Cushing's syndrome may have a variety of menstrual problems, most typically infrequent or absent menstrual periods. They often have difficulty becoming pregnant.

Symptoms of androgen excess — Women with Cushing's syndrome may have signs of male hormone (androgen) excess, such as hirsutism (growth of coarse body hair in a male pattern), oily skin, and acne. (See "Patient information: Hirsutism (excess hair growth)" and "Patient information: Acne".)

Muscle loss and weakness — Prolonged Cushing's syndrome causes the muscles of the upper arms and legs to become thin and weaker. Some individuals notice that it becomes more difficult to get out of a chair or climb stairs because of the upper leg weakness.

Bone loss — Cushing's syndrome can lead to thinning of the bones (osteoporosis), which can eventually result in fractures of the ribs, long bones, and spinal vertebrae. (See "Patient information: Bone density testing" and "Patient information: Osteoporosis prevention and treatment".)

Glucose intolerance — Excess cortisol can cause an elevation of blood glucose levels. People with Cushing's syndrome may develop glucose intolerance, a prediabetic condition that can progress to diabetes mellitus. (See "Patient information: Diabetes mellitus type 2: Overview".)

High blood pressure and cardiovascular disease — Excess cortisol raises blood pressure and puts stress on the heart and vascular system.

Psychologic symptoms — Over half of all patients with Cushing's syndrome have psychologic symptoms that range from loss of emotional control, irritability, and depression to panic attacks and paranoia. Insomnia is also common. (See "Patient information: Depression in adults" and "Patient information: Insomnia".)

Infections — Cortisol suppresses the immune system, and people with Cushing's syndrome may develop infections more frequently.

Blood clots — People with Cushing's syndrome tend to form blood clots more easily. A blood clot in a leg vein is called a deep vein thrombosis (DVT). If the DVT breaks off and travels to the lungs, this is called a pulmonary embolism (PE). A pulmonary embolism is a serious and life-threatening condition. (See "Patient information: Deep vein thrombosis (DVT)" and "Patient information: Pulmonary embolism".)

CUSHING'S SYNDROME DIAGNOSIS

People with symptoms of Cushing's syndrome will undergo a medical history, physical examination, and laboratory testing.

Laboratory testing is needed to measure cortisol levels. People with Cushing's syndrome typically have high cortisol levels.

Tests may include one or more of the following:

• Measurements of cortisol in a 24-hour urine specimen
• A blood or saliva test to check for the normal daily rise and fall of cortisol levels (this test may require collection of blood or saliva late at night)
• A low-dose dexamethasone test. Low doses of dexamethasone suppress cortisol production in healthy people but not in those with Cushing's syndrome.

DETERMINING THE CAUSE OF CUSHING'S SYNDROME

Once Cushing's syndrome has been diagnosed, other tests are used to determine the cause of the excess cortisol production. The type and number of tests recommended will depend upon the results of preliminary tests.

Blood tests — Blood tests can determine relative levels of cortisol and ACTH. Because these hormones are secreted episodically, measurements may be done on two or three separate days. The relative levels of cortisol and ACTH can help differentiate between the various causes of Cushing's syndrome.

Petrosal sinus sampling — Blood from the pituitary gland collects in vascular spaces in the head called sinuses. Taking a sample of blood from these sinuses may reveal high levels of ACTH. This is accomplished by inserting a catheter into a vein in the groin and threading the catheter through the blood vessels that lead to the pituitary. The procedure is done while the patient is under anesthesia.

Levels of ACTH in blood from the petrosal sinuses are measured and compared with ACTH levels in a vein in the forearm. If ACTH levels are higher in the petrosal sinuses than in the forearm vein, a pituitary adenoma is likely; similar levels at both locations suggest ACTH secretion by a non-pituitary tumor.

High-dose dexamethasone suppression test — High doses of dexamethasone usually suppress production of ACTH by pituitary adenomas (benign tumors). As a result, blood and urine levels of cortisol should fall. If the excess ACTH is being produced by a non-pituitary tumor, cortisol production is less likely to be suppressed.

Corticotropin-releasing hormone test — During this test, a person is given a dose of corticotropin-releasing hormone into a vein. In a person with a pituitary tumor, this should stimulate the tumor to secrete ACTH so that both blood ACTH and cortisol levels increase. In contract, in a person with ectopic ACTH syndrome, there is no response to the CRH.

Imaging tests — CT or MRI scans of the adrenal glands, pituitary gland, lungs, and abdomen can identify hormone-producing tumors.

Scintigraphy — Scintigraphy involves injection of a radioactive substance followed by a imaging scan. This test is helpful for locating elusive tumors that cause ectopic ACTH syndrome (see "Patient information: Cushing's syndrome treatment", section on 'Ectopic ACTH syndrome'.

CUSHING'S SYNDROME TREATMENT

The treatment of Cushing's syndrome is discussed separately. (See "Patient information: Cushing's syndrome treatment".)

WHERE TO GET MORE INFORMATION

Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two people are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.

This discussion will be updated as needed every four months on our web site (www.uptodate.com/patients). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

Some of the most pertinent include:

Patient Level Information:
Patient information: Hirsutism (excess hair growth)
Patient information: Acne
Patient information: Bone density testing
Patient information: Osteoporosis prevention and treatment
Patient information: Diabetes mellitus type 2: Overview
Patient information: Depression in adults
Patient information: Insomnia
Patient information: Deep vein thrombosis (DVT)
Patient information: Pulmonary embolism
Patient information: Cushing's syndrome treatment

Professional Level Information:
Causes and pathophysiology of Cushing's syndrome
Clinical manifestations of Cushing's syndrome
Cushing's syndrome due to ACTH-independent macronodular adrenal hyperplasia
Cushing's syndrome in pregnancy
Dexamethasone suppression tests
Establishing the cause of Cushing's syndrome
Establishing the diagnosis of Cushing's syndrome
Overview of the treatment of Cushing's syndrome
Primary therapy of Cushing's disease: Transsphenoidal surgery and pituitary irradiation
Treatment of Cushing's syndrome: Diminishing adrenal cortisol synthesis

A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable.

• National Library of Medicine

      (www.nlm.nih.gov/medlineplus/healthtopics.html)

• The Hormone Foundation

      (www.hormone.org/public/other.cfm, available in English, Spanish, and Portuguese)

• National Institute of Diabetes and Digestive and Kidney Diseases

      (http://endocrine.niddk.nih.gov/index.htm)

• National Adrenal Diseases Foundation

      (516) 487-4992
      (www.nadf.us)

• Pituitary Tumor Network Association

      (www.pituitary.org)

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