Drug-induced (exogenous): The most common cause of Cushing's syndrome is the long-term use of high doses of oral corticosteroids. These drugs have the same effects on the body as cortisol, which regulates proper glucose metabolism, blood pressure and insulin release for blood sugar maintenance and inflammation. Since this form of Cushing's syndrome is caused by factors outside of the body, it is also called exogenous Cushing's syndrome. Corticosteroids that commonly cause this condition include prednisone, dexamethasone (Decadron®) and methylprednisolone (Medrol®).
Corticosteroids are often prescribed to treat inflammatory diseases such as rheumatoid arthritis, lupus (autoimmune disorder that causes chronic swelling) and asthma, or to prevent the body from rejecting a transplanted organ. Since the doses necessary to treat these conditions are usually higher than the amount of cortisol produced in the body of a healthy person, some individuals develop Cushing's syndrome.
Individuals may also develop Cushing's syndrome after they receive high-doses of intravenous corticosteroids, which are often used to treat joint pain, bursitis (inflammation of a fluid-filled sac between the joint and tendon) and back pain.
Although certain inhaled steroids (used to treat asthma) and steroid skin creams (used to treat skin conditions like eczema) are in the same category of drugs, they generally do not cause Cushing's syndrome unless they are taken in extremely high doses.
Pituitary: The pituitary gland, located at the base of the brain, secretes a hormone called adrenocorticotropic hormone (ACTH). This hormone stimulates the adrenal glands to produce cortisol. If the pituitary gland produces too much ACTH, Cushing's syndrome may result. A non-cancerous (benign) tumor in the pituitary gland causes excessive ACTH to be secreted, which subsequently stimulates the adrenal glands to produce more cortisol. When this form of the syndrome develops, it is called Cushing's disease. This form of Cushing's syndrome occurs five times more often in women than men, and it is the most common form of endogenous (caused by factors inside the body) Cushing's syndrome.
In rare cases, a tumor that grows in an organ that does not normally produce ACTH will begin to secrete high levels of this hormone, resulting in Cushing's syndrome. These tumors, which can be benign or malignant (cancerous), are most often found in the lung, thyroid, pancreas or thymus gland. This condition is called ectopic ACTH syndrome. Lung tumors cause more than 50% of these cases.
Adrenal: If the adrenal glands are not functioning properly and they secrete too much cortisol, Cushing's syndrome may result. The most common adrenal disorder that has been associated with Cushing's syndrome is a non-cancerous tumor of the adrenal cortex, called adrenal adenoma.
Cancerous tumors of the adrenal cortex are rare, but they can also cause Cushing's syndrome. Sometimes, benign tumors on one or both adrenal glands can result in Cushing's syndrome.
Common symptoms of Cushing's syndrome include weight gain (especially around the midsection and upper back), buffalo hump (fatty hump between the shoulders), fatigue, muscle weakness, rounded face (often called moon face), facial flushing, thin and fragile skin that bruises easily, depression, anxiety, irritability, hirsutism (thicker or more visible body and facial hair), irregular or absent menstrual periods in females, erectile dysfunction in males, high blood pressure, acne and pink or purple stretch marks on the skin of the abdomen, thighs, breasts and arms.
General: Cushing's syndrome can be difficult to diagnose because many other conditions, such as polycystic ovary syndrome (hormone disorder in women that causes enlarged ovaries), depression, eating disorders and alcoholism, share some of the same signs and symptoms. Urine, blood and saliva tests are conducted to determine if the patient has elevated levels of cortisol in the body. Patients who have excessive cortisol levels will then undergo imaging studies (body scans that produce pictures of the internal organs) to determine whether a tumor inside the body is causing the condition. If the patient is taking corticosteroids, it is suspected that the medication is causing the condition. These tests may also help the healthcare provider rule out other medical conditions with similar symptoms.
Urine and blood tests: Urine and blood tests are conducted to measure the patient's hormone levels. Cortisol is present in both the urine and blood. High levels may indicate Cushing's syndrome. For the urine test, the patient may be asked to collect a sample of urine over 24 hours. Levels higher than 50-100 micrograms a day for an adult indicate Cushing's syndrome.
Dexamethasone suppression test: The dexamethasone suppression test helps determine whether the patient has a pituitary tumor. Patients are given dexamethasone, which is a synthetic glucocorticoid (type of corticosteroid) every six hours for four days. Patients receive low doses for the first two days followed by higher doses for the last two days. Twenty-four hour urine collections are made before the drug is given and on each day of the test. Since glucocorticoids signal the pituitary gland to produce lower amounts of ACTH, the normal response after taking dexamethasone is a decline in blood and urine cortisol levels. Patients who experience no change in cortisol levels at both the low and high doses of dexamethasone may have either an adrenal tumor or ectopic ACTH-producing tumor. Patients who experience no change in cortisol levels at low doses, but normal suppression at high doses of dexamethasone, have a pituitary tumor.
The test can produce false-positive results in patients who suffer from depression, alcoholism, high estrogen levels, acute illness or stress. Also, drugs like phenytoin and phenobarbital may cause false negative results.
Corticotropin-releasing hormone (CRH) stimulation test: The corticotropin-releasing hormone (CRH) stimulation test helps distinguish between patients who have pituitary adenomas and those who have ectopic ACTH syndrome or cortisol-secreting adrenal tumors. Patients receive an injection of CRH, which causes the pituitary gland to secrete ACTH. Patients who have pituitary adenomas usually experience an increase in ACTH and cortisol levels in the blood. This response is rarely seen in patients who have ectopic ACTH syndrome and almost never observed in patients who have cortisol-secreting adrenal tumors.
Saliva test: Cortisol levels normally rise and fall throughout the day. Healthy patients experience a significant drop in cortisol levels overnight. If Cushing's syndrome is suspected, a healthcare provider may take samples of the patient's saliva from 11:00 p.m. to midnight. If cortisol levels are abnormally high, Cushing's syndrome is indicated.
Imaging studies: Imaging studies, including computerized tomography (CT) and magnetic resonance imaging (MRI) scans, are conducted at the hospital after a patient shows elevated levels of cortisol in the urine, blood or saliva. During these procedures, which are noninvasive and painless, pictures of the internal organs are taken with machines that use X-rays and magnetic waves. These tests are used to determine the cause of the syndrome if the patient is not taking corticosteroids. The imaging studies provide detailed images of the pituitary and adrenal glands. The radiologist (specialized doctor who analyzes the images) will look for abnormalities, such as tumors, which may be causing the condition.
If left untreated, Cushing's syndrome can be fatal. Without treatment, patients may experience bone loss, high blood pressure, kidney stones, infections and/or diabetes. This is because cortisol regulates proper glucose metabolism, blood pressure and insulin release for blood sugar maintenance, and it is involved in the inflammatory response.