Cushing’s syndrome

Synonyms

3

Overview

Cushing's syndrome is an endocrine disorder caused by prolonged exposure of the body's tissues to high levels of cortisol (a hormone produced by the adrenal gland). It most commonly affects adults between age 20 and 50 years. Signs and symptoms of Cushing's syndrome include upper body obesity, fatigue, muscle weakness, high blood pressure, backache, high blood sugar, easy bruising and bluish-red stretch marks on the skin. Affected women may also experience irregular menstrual periods and increased growth of body and facial hair. This condition may be caused by a variety of factors including long-term use of corticosteroid medications, tumors in the pituitary gland or adrenal adenomas. Treatment depends on the underlying cause, but may include decreasing the dosage of corticosteroids or surgery to remove tumors.

Symptoms

The signs and symptoms of Cushing's syndrome may include:

  • Upper body obesity
  • Severe fatigue
  • Muscle weakness
  • High blood pressure
  • Backache
  • Elevated blood sugar
  • Easy bruising
  • Bluish-red stretch marks on the skin
  • Neurological issues

Women with Cushing's syndrome may also experience increased growth of facial and body hair, and menstrual periods may become irregular or cease. Men may have decreased fertility, diminished sexual desire, and/or erectile dysfunction.

Causes

Cushing's syndrome is caused by long-term exposure of the body's tissues to cortisol, a hormone that is naturally produced by the adrenal gland. Exposure to too much cortisol can result from long-term use of corticosteriod medications used to treat inflammatory illnesses. Pituitary adenomas (benign tumors of the pituitary gland) or tumors of the adrenal gland may also cause cortisol imbalances.

Prevention

Most cases of Cushing's syndrome are not inherited. However, Cushing's syndrome rarely occurs in inherited conditions characterized by the development of tumors of one or more endocrine gland. These conditions may include:

  • Primary pigmented micronodular adrenal disease, in which children or young adults develop small cortisol-producing tumors of the adrenal glands,
  • Multiple endocrine neoplasia type 1 (MEN1), in which hormone-secreting tumors of the parathyroid glands, pancreas, and pituitary develop. Cushing's syndrome in MEN1 may be due to pituitary or adrenal tumors.

Diagnosis

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 and why.

24-Hour Urinary 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 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 is performed.

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 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 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 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.

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 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.

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 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.

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 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.

The Dexamethasone-CRH Test

Some individuals 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 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 that causes hypertension and chronic androgen excess.

Sometimes other 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 levels.

Prognosis

Without treatment, complications of Cushing syndrome may include:

  • Bone loss (osteoporosis), which can result in unusual bone fractures, such as rib fractures and fractures of the bones in the feet
  • High blood pressure (hypertension)
  • Type 2 diabetes
  • Frequent or unusual infections
  • Loss of muscle mass and strength

Treatment

Treatments for Cushing syndrome are designed to lower the high level of cortisol in your body. The best treatment for you depends on the cause of the syndrome. Treatment options include:

  • Reducing corticosteroid use. If the cause of Cushing syndrome is long-term use of corticosteroid medications, your doctor may be able to keep your Cushing signs and symptoms under control by reducing the dosage of the drug over a period of time, while still adequately managing your asthma, arthritis or other condition. For many of these medical problems, your doctor can prescribe noncorticosteroid drugs, which will allow him or her to reduce the dosage or eliminate the use of corticosteroids altogether.

    Don't reduce the dose of corticosteroid drugs or stop taking them on your own. Do so only under your doctor's supervision.

    Abruptly discontinuing these medications could lead to deficient cortisol levels. Slowly tapering off corticosteroid drugs allows your body to resume normal cortisol production.

  • Surgery. If the cause of Cushing syndrome is a tumor, your doctor may recommend complete surgical removal. Pituitary tumors are typically removed by a neurosurgeon, who may perform the procedure through your nose. If a tumor is present in the adrenal glands, lungs or pancreas, the surgeon can remove it through a standard operation or in some cases by using minimally invasive surgical techniques, with smaller incisions.

    After the operation, you'll need to take cortisol replacement medications to provide your body with the correct amount of cortisol. In most cases, you'll eventually experience a return of normal adrenal hormone production, and your doctor can taper off the replacement drugs.

    However, this process can take up to a year or longer. In some instances, people with Cushing syndrome never experience a resumption of normal adrenal function; they then need lifelong replacement therapy.

  • Radiation therapy. If the surgeon can't totally remove a pituitary tumor, he or she will usually prescribe radiation therapy to be used in conjunction with the operation. Additionally, radiation may be used for people who aren't suitable candidates for surgery.

    Radiation can be given in small doses over a six-week period, or with a technique called stereotactic radiosurgery (Gamma Knife surgery). In the latter procedure, administered as a single treatment, a large dose of radiation is delivered to the tumor, and the radiation exposure to surrounding tissues is minimized.

  • Medications. Medications can be used to control cortisol production when surgery and radiation don't work. Medications may also be used before surgery in people who have become very sick with Cushing syndrome. Doctors may recommend drug therapy before surgery to improve signs and symptoms and minimize surgical risk. Medications to control excessive production of cortisol at the adrenal gland include ketoconazole (Nizoral), mitotane (Lysodren) and metyrapone (Metopirone).

    Approved therapies:

    • Mifepristone (Korlym) -  FDA-approved indication: Korlym is approved for use in patients with endogenous Cushing's syndrome who have type 2 diabetes or glucose intolerance and are not candidates for surgery or have not responded to prior surgery. 
    • Pasireotide (Signifor) -  FDA-approved indication: Treatment of adult patients with Cushing's disease for whom pituitary surgery is not an option or has not been curative. Treatment of patients with acromegaly who have had an inadequate response to surgery and/or for whom surgery is not an option. 

 If none of these treatment options are appropriate or effective, your doctor may recommend surgical removal of your adrenal glands (bilateral adrenalectomy). This procedure will cure excess production of cortisol, but will require lifelong replacement medications.