Patient education: Cushing syndrome (Beyond the Basics)

CUSHING SYNDROME OVERVIEW — Cushing syndrome occurs when there is an excess of cortisol, a hormone produced by the adrenal glands (figure 1). Cortisol is a type of hormone called a "glucocorticoid." It has many important functions and is necessary for the body to work properly; however, too much cortisol can cause problems.

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

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

CUSHING SYNDROME CAUSES — The cause of Cushing syndrome is usually divided into several broad categories, based upon whether the problem is due to:

●The pituitary gland (a small structure at the base of the brain) releasing too much of the hormone corticotropin (ACTH) (figure 1).

●A nonpituitary tumor releasing too much of the hormone ACTH.

●The adrenal glands, which lie above the kidneys, releasing too much cortisol (figure 1).

●Cushing syndrome can also occur in individuals who take large doses of glucocorticoids (eg, prednisone) for diseases such as asthma and rheumatoid arthritis.

The most common cause of Cushing syndrome is the use of medications called glucocorticoids. These medications mimic the effects of cortisol. Glucocorticoids have powerful anti-inflammatory actions and are used to treat autoimmune conditions, such as rheumatoid arthritis, and to prevent organ transplant rejection. Most forms of glucocorticoids, including inhaled and topical forms (ie, creams or ointments that go on the skin), can cause Cushing syndrome.

Among people with Cushing syndrome that is not due to the use of glucocorticoids, up to 70 percent 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 disease, which is one specific cause of Cushing syndrome. Most of these tumors are very small, and they may be difficult to identify.

CUSHING SYNDROME SYMPTOMS — The symptoms of Cushing syndrome result from an excess of cortisol. Most people 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 syndrome

●In people with adrenal adenomas (benign tumors), the symptoms may be very subtle

Weight gain — Progressive weight gain is the most common symptom of Cushing syndrome. This weight gain may affect the face, neck, trunk, and abdomen more than the limbs, which may be thin. People with Cushing syndrome often develop a rounded face and increased amounts of fat on the upper back and at the base of the neck.

Skin changes — In Cushing syndrome, the skin tends to become thin, fragile, and more susceptible to bruises and infections. Wounds heal poorly. Wide, reddish-purple stretch marks, called striae (picture 1), can develop in areas of weight gain.

Irregular menstrual periods — Females with Cushing syndrome may have a variety of menstrual problems, most typically infrequent or absent menstrual periods. They often have difficulty becoming pregnant.

Excess body hair and acne — Females with Cushing syndrome may have signs of male hormone (androgen) excess, such as hirsutism (growth of coarse body or facial hair in a male pattern), oily skin, and acne. Males with Cushing syndrome do not develop excess body hair, but they may have acne. (See "Patient education: Hirsutism (excess hair growth in females) (Beyond the Basics)" and "Patient education: Acne (Beyond the Basics)".)

Muscle loss and weakness — Prolonged Cushing syndrome causes the muscles of the shoulder and thighs/hips to become 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 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 education: Bone density testing (Beyond the Basics)" and "Patient education: Osteoporosis prevention and treatment (Beyond the Basics)".)

Prediabetes — Excess cortisol can cause an elevation of blood glucose levels (often called "prediabetes"). People with Cushing syndrome may develop glucose intolerance, a condition that can progress to diabetes, or diabetes itself. (See "Patient education: Type 2 diabetes: Overview (Beyond the Basics)".)

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

Psychologic symptoms and "brain fog" — Over one-half of people with Cushing 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 education: Depression in adults (Beyond the Basics)" and "Patient education: Insomnia (Beyond the Basics)".)

Many people with Cushing syndrome have difficulties with memory, processing written information, and mathematical calculations.

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

Blood clots — People with Cushing syndrome tend to form blood clots more easily. A blood clot in a leg vein is called a deep vein thrombosis (DVT). If a 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. People with Cushing syndrome also are more likely to develop stroke from a blood clot. (See "Patient education: Deep vein thrombosis (DVT) (Beyond the Basics)" and "Patient education: Pulmonary embolism (Beyond the Basics)".)

CUSHING SYNDROME DIAGNOSIS — People with symptoms of Cushing syndrome will undergo a medical history, physical examination, and laboratory testing.

Laboratory testing is needed to measure cortisol levels. People with Cushing 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 at bedtime).

●A low-dose dexamethasone test with measurement of blood cortisol levels the next morning. Low doses of the glucocorticoid dexamethasone suppress cortisol production in healthy people but not in those with Cushing syndrome.

DETERMINING THE CAUSE OF CUSHING SYNDROME — Once Cushing 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.

Initial blood tests — Blood tests can determine levels of cortisol and corticotropin (ACTH). These measurements may be repeated on two or three separate days. The relative levels of cortisol and ACTH can help differentiate between the various causes of Cushing syndrome.

Normal or high blood ACTH levels — Most people with Cushing syndrome who have high blood ACTH levels have a pituitary tumor that produces too much ACTH. This form of Cushing syndrome is called Cushing disease. (See 'Cushing syndrome causes' above.)

Other causes of high blood ACTH levels include nonpituitary tumors that produce ACTH. This form of Cushing syndrome is called the ectopic (occurring in an abnormal place) ACTH syndrome. Many of these tumors occur in the lungs or elsewhere in the chest.

Low blood ACTH levels — Most people with Cushing syndrome who have low blood ACTH levels take medications that contain glucocorticoids such as prednisone. (See 'Cushing syndrome causes' above.)

Less common causes of Cushing syndrome that occur with low ACTH levels include benign or malignant (cancerous) tumors of the adrenal gland, which produce excess cortisol. Nodular hyperplasia (overgrowth) of both adrenal glands is a rare cause of cortisol excess.

Additional tests — If ACTH levels are low, imaging tests (computed tomography [CT] or magnetic resonance imaging [MRI]) of the adrenal glands are done to look for adrenal tumor(s).

If ACTH levels are normal or high, the following tests may be done:

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

Blood tests

Desmopressin stimulation test — During this test, a person is given a dose of desmopressin into a vein. In a person with a pituitary tumor, this usually stimulates the tumor to secrete ACTH so that both blood ACTH and cortisol levels increase. In contrast, in a person with ectopic ACTH syndrome, there usually is no ACTH response to the desmopressin.

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 nonpituitary tumor, cortisol production is less likely to be suppressed.

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 sampling is accomplished by inserting a catheter into a vein in the groin and threading the catheter up and into the blood vessels that lead to the pituitary. The procedure is done under light anesthesia.

Levels of ACTH in blood from the petrosal sinuses are measured and compared with ACTH levels in a vein far from the pituitary gland. If ACTH levels are higher in the petrosal sinuses than in the other vein, a pituitary adenoma is likely; similar levels at both locations suggest ACTH secretion by a nonpituitary tumor. This test is usually done with administration of desmopressin to stimulate ACTH secretion.

Scintigraphy — Scintigraphy involves injection of a radioactive substance followed by an imaging scan. This test is helpful for locating elusive tumors that cause ectopic ACTH syndrome. (See "Patient education: Cushing syndrome treatment (Beyond the Basics)", section on 'Ectopic ACTH syndrome'.)

CUSHING SYNDROME TREATMENT — The treatment of Cushing syndrome is discussed separately. (See "Patient education: Cushing syndrome treatment (Beyond the Basics)".)

WHERE TO GET MORE INFORMATION — Your health care provider is the best source of information for questions and concerns related to your medical problem.

This article will be updated as needed on our website (www.uptodate.com/patients). Related topics for patients, as well as selected articles written for health care professionals, are also available. Some of the most relevant are listed below.

Patient level information — UpToDate offers two types of patient education materials.

The Basics — The Basics patient education pieces answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials.

Patient education: Cushing syndrome (The Basics)
Patient education: Pituitary adenoma (The Basics)
Patient education: Adrenal cancer (The Basics)

Beyond the Basics — Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are best for patients who want in-depth information and are comfortable with some medical jargon.

Patient education: Cushing syndrome treatment (Beyond the Basics)
Patient education: Hirsutism (excess hair growth in females) (Beyond the Basics)
Patient education: Acne (Beyond the Basics)
Patient education: Bone density testing (Beyond the Basics)
Patient education: Osteoporosis prevention and treatment (Beyond the Basics)
Patient education: Type 2 diabetes: Overview (Beyond the Basics)
Patient education: Depression in adults (Beyond the Basics)
Patient education: Insomnia (Beyond the Basics)
Patient education: Deep vein thrombosis (DVT) (Beyond the Basics)
Patient education: Pulmonary embolism (Beyond the Basics)

Professional level information — Professional level articles are designed to keep doctors and other health professionals up-to-date on the latest medical findings. These articles are thorough, long, and complex, and they contain multiple references to the research on which they are based. Professional level articles are best for people who are comfortable with a lot of medical terminology and who want to read the same materials their doctors are reading.

Causes and pathophysiology of Cushing syndrome
Epidemiology and clinical manifestations of Cushing syndrome
Cushing's syndrome due to primary bilateral macronodular adrenal hyperplasia
Diagnosis and management of Cushing syndrome during pregnancy
Dexamethasone suppression tests
Establishing the cause of Cushing syndrome
Establishing the diagnosis of Cushing syndrome
Overview of the treatment of Cushing syndrome
Primary therapy of Cushing disease: Transsphenoidal surgery and pituitary irradiation
Medical therapy of hypercortisolism (Cushing's syndrome)

The following organizations also provide reliable health information.

●National Library of Medicine

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

●Hormone Health Network

(www.hormone.org/diseases-and-conditions/adrenal/cushing-syndrome)

●National Institute of Diabetes and Digestive and Kidney Diseases

(https://www.niddk.nih.gov/health-information/endocrine-diseases/cushings-syndrome)

●Cushing Support & Research Foundation

(617) 723-3675

(http://csrf.net)

●National Adrenal Diseases Foundation

(516) 487-4992

(www.nadf.us)

●Pituitary Tumor Network Association

(www.pituitary.org)

ACKNOWLEDGMENT — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States Government or its components.