NORD gratefully acknowledges Cushing's Support and Research Foundation, Inc., Edward R. Laws, MD, FACS, Professor of Neurosurgery, Harvard Medical School, Director, Pituitary/Neuroendocrine Center, Brigham and Women’s Hospital, Boston, MA and Lynnette Nieman, MD, FACP, Senior Investigator, Intramural Research Program on Reproductive and Adult Endocrinology, The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Chief, Endocrinology Consultation Service, National Institutes of Health and Constantine A. Stratakis, MD, D(med)Sci, Scientific Director, The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, for assistance in the preparation of this report.
Cushing syndrome is a rare endocrine disorder characterized by a variety of symptoms and physical abnormalities that occur due to excessive amounts of the hormone cortisol, a vital glucocorticoid. Glucocorticoids are a class of steroid hormones that are important in the regulation of the metabolism of glucose, and also modulate the response to stress. Although it may occur in children, Cushing syndrome most commonly affects adults between the ages of 25 to 40. It can be caused by prolonged exposure to elevated levels of glucocorticoids produced within the body (endogenous) or introduced from outside the body (exogenous). Symptoms can include weight gain, obesity, a rounded face, thin purple streaks (purple striae) which occur on the skin, increased fat around the neck, and slender arms and legs. Children with Cushing syndrome are typically obese and have delay in growth.
In 1912, Harvey Cushing described a patient who had typical features of hypercortisolemia, but assumed it to be a “polyglandular” disorder. The cause was disputed for almost 40 years. Cushing disease, which is pituitary adrenocorticotropin hormone (ACTH) dependent Cushing syndrome produced by a benign pituitary tumor, was first definitively described by Dr. Cushing in 1932. Although pituitary surgery was introduced in the early 20th century, it was not until 1933 that pituitary neurosurgery was performed on patients with Cushing disease.
People with Cushing syndrome gain an excessive amount of weight. Obesity extends to include fat deposits around the face causing a “moon-shaped” or rounded appearance. Fat also accumulates around the neck (supraclavicular) and upper back (dorsal cervical) areas. Obesity also occurs in the trunk of the body (“centripetal obesity”), but the arms and legs remain slender. People with Cushing syndrome may have skin that is reddened, thin, fragile, and slow to heal. The connective tissue may also become weak, resulting in the appearance of reddish-blue stretch marks on the arms, breasts, underarms (axillae), abdomen, buttocks, and/or thighs.
Women with Cushing syndrome may have excessive body hair (hirsutism) on the face, neck, chest, abdomen, and/or thighs. Acne affecting the face, chest and back may also develop. Some people have thinning of the hair on the head, and some women may develop menstrual irregularity (oligoamenorrhea, amenorrhea). Men (and women) with this disorder may experience a decrease in fertility and a diminished or absent sex drive (loss of libido).
Children and adolescents with Cushing syndrome may experience delayed growth with or without weight gain, and/or hypertension. Growth does not always stop entirely; it may be slower than before or only partially affected; however, Cushing syndrome in growing children always affects growth in one way or another.
Co-morbidities in this condition include abnormally high blood pressure (hypertension), which occurs in approximately 85 percent of people with Cushing syndrome. Bones may become brittle and break easily. This occurs as a result of progressive bone thinning (osteoporosis). Other features often include abnormally high blood sugar (hyperglycemia), increased thirst and urination, impaired immune function leading to frequent infections, severe weakness, fatigue, easy bruising, and muscle wasting (lower limbs muscle atrophy). Mild to severe psychic disturbances, including anxiety, depression and irritability, occur in many patients. Headache may also be present. Sleep disorders and sleep apnea are frequent in advanced cases. Some patients note cognitive difficulties and troubles with work performance.
Cushing syndrome is a rare endocrine disorder caused by abnormally excessive amounts of the hormone cortisol.
Many people develop Cushing syndrome as a result of exogenous, long-term administration of a cortisol-like drug therapy to treat another medical condition such as arthritis, lupus, and other inflammatory diseases (oral medication or injection into a joint or muscle), asthma, chronic obstructive lung disease, malignant tumors, or leukemia. Steroid treatment is effective for these conditions, but can cause symptoms and signs of Cushing syndrome as a side effect of such treatment.
Cushing syndrome can also be due to endogenous causes; approximately 70% of Cushing syndrome is the result of Cushing disease. Cushing disease occurs when excess adrenocorticotropin hormone (ACTH) production from a benign pituitary tumor (adenoma) causes the adrenal glands to produce excessive amounts of cortisol. Approximately 10 to 15 percent of cases of endogenous Cushing syndrome are caused by non-pituitary tumors that secrete excessive ACTH. The causes of this “ectopic ACTH syndrome” include benign or malignant tumors, most commonly in the chest cavity or abdomen. Other types of ACTH-producing tumors include medullary carcinomas of the thyroid, pheochromocytomas, and pancreatic islet cell tumors. Another 10 – 15% of patients have benign or malignant tumors of the adrenal glands (adenomas) that secrete excessive cortisol.
Although most cases of Cushing syndrome are not inherited, in rare instances it results from an inherited tendency to develop tumors in one or more hormone-secreting glands. Children or young adults with primary pigmented nodular adrenocortical disease (PPNAD) develop small cortisol-producing tumors in the adrenal glands. Cushing syndrome may develop with multiple endocrine neoplasia type 1 (MEN1), associated with hormone-secreting tumors of the lung, pancreas, parathyroids or pituitary gland.
Most cases of Cushing syndrome are due to exogenous corticosteroid medication. It is reported that the incidence of endogenous Cushing syndrome is approximately 13 per million people annually.
Cushing syndrome caused by either an adrenal or pituitary tumor affects females five times more frequently than males. Symptoms commonly begin between 25 to 40 years of age. Men are affected 3 times more than women by ectopic ACTH production that is caused by lung cancer, which occurs later in life.
Diagnosis is based upon a detailed medical history to assess for any use of exogenous glucocorticoids (oral, topical, injection, inhaled), a physical examination, and laboratory tests.
Usually several laboratory tests are used to confirm the diagnosis of Cushing syndrome. Tests used include: 24-hour urine test for cortisol; measurement of late-night cortisol levels in the blood and saliva; low dose dexamethasone suppression test (LDDST) which evaluates the cortisol response to a low dose of a synthetic glucocorticoid (dexamethasone).
The dexamethasone-corticotropin-releasing hormone (CRH) test helps to distinguish Cushing syndrome from other causes of excess cortisol, such as pseudo-Cushing syndrome. This test combines the LDDST and a CRH stimulation test. In the CRH stimulation test, an injection of CRH causes the pituitary to secrete ACTH. People with pseudo-Cushing respond to the pretreatment with dexamethasone, which prevents CRH from causing an increase in ACTH and hence cortisol. Elevated cortisol levels from this test generally indicate Cushing syndrome.
Clinical Testing and Work-up
Once Cushing syndrome has been diagnosed, the cause of excess cortisol production needs to be determined.
The first test is measurement of blood (plasma) ACTH levels. A low or undetectable level of ACTH in the blood combined with simultaneously elevated blood (serum) cortisol levels indicates the cause of Cushing syndrome is due to a primary cortisol-producing adrenal adenoma or carcinoma, assuming that use of corticosteroid medication as the cause has been ruled out.
Patients with ACTH-producing tumors have measurable (normal) or high ACTH levels, and a tumor that is in the pituitary gland (termed Cushing disease) or elsewhere (ectopic ACTH syndrome). Radiologic imaging helps to identify these tumors. Because pituitary disease is most common, and identification of such a tumor influences the need for other testing, magnetic resonance imaging (MRI) of the pituitary is usually the next test. However, pituitary tumors are often very small (microadenomas) and may not be detected with radiologic imaging in almost half of people who ultimately require surgery.
A CRH stimulation test conducted without pretreatment with dexamethasone helps to distinguish between pituitary and non-pituitary tumors. The high-dose dexamethasone suppression test (HDDST) may also be helpful. HDDST testing follows the same format as LDDST, but uses higher doses of dexamethasone.
Petrosal sinus sampling is an effective way to identify a pituitary etiology for Cushing syndrome, in which levels of ACTH are measured in the blood from veins that drain the pituitary (petrosal sinuses). If this study indicates ectopic ACTH secretion, other imaging tests are done to find the tumor, possibly including computerized tomography (CT) and MRI scans, and other nuclear medicine studies such as Octreoscan or PET scans.
The treatment of Cushing syndrome is directly related to the cause of the cortisol overproduction.
If the cause of the elevated level of cortisol is the result of the long-term use of hormones such as prednisone for the treatment of another disorder, the dosage should gradually be reduced under medical supervision until symptoms are under control.
Pituitary tumors may be surgically removed during an operation known as a trans-nasal or sub-labial transsphenoidal adenomectomy. Specific surgical procedures and long-term results can vary greatly depending on the type and location of the tumor and the expertise of the surgeon. The success rate of this surgery is approximately 80 percent. The complication rate is generally low, and similar to that for gall bladder surgery. If surgery only produces a temporary cure, or if it fails, surgery can be repeated. After successful surgery, there is an expected drop in the production of adrenocorticotrophic hormone and cortisol. Therefore, patients may require temporary administration of synthetic replacement hormone (hydrocortisone or prednisone). This drug therapy typically lasts for less than one year, while the normal glands are recovering.
Some people with Cushing disease are not good candidates for surgery and some others may have had surgery that was unsuccessful. For these affected individuals, conventional radiation therapy directed at the pituitary gland may be administered for a minimum of six weeks. Alternatively, at certain centers, a one-time, focused radiation treatment can be used (stereotactic radiosurgery, gamma knife, and Cyber knife or proton beam radiation). Improvement of symptoms over time occurs in up to 85 percent patients.
The drug ketoconazole may be given alone or in combination with radiation therapy to help inhibit cortisol production and to speed recovery. Other drugs used to reduce adrenal gland production of cortisol include metyrapone and mitotane. Another drug, cabergoline, was shown to reduce cortisol production in about 20% of patients by acting on the pituitary tumor.
The removal or destruction of ACTH-secreting tumors is essential to reverse ectopic ACTH syndrome. Surgical removal is effective treatment of benign and some malignant tumors. Other treatments of cancers producing Cushing syndrome depend on the type of cancer and the extent to which it has spread. Such treatments may include surgery, radiation, chemotherapy, and/or immunotherapy. In addition, the administration of a cortisol-inhibiting drug such as ketoconazole or mitotane can be an important part of this treatment.
Korlym (also known as mifepristone) by Corcept Therapeutics was approved by the FDA in 2012 as a treatment to control hyperglycemia in adults with endogenous Cushing syndrome who have type 2 diabetes or glucose intolerance and are not candidates for surgery, or who have not successfully responded to surgery. Korlym works by blocking the binding of cortisol to its receptor, thus reducing the effects of excess cortisol. Another form of suppressive medical therapy is the drug pasireotide which may be effective but has elevated glucose levels as a side effect.
Because cortisol hypersecretion comes from the adrenal glands, in selected cases (usually in very ill patients who have not responded to other therapies), surgical removal of the adrenal glands can be considered. This surgery risks the development of another problem called Nelson syndrome, which can result in the activation of the underlying pituitary tumor due to a loss of inhibition from adrenal secretions.
Active investigation of novel diagnostic and therapeutic strategies for the management of Cushing syndrome and its causes are under continuing investigation in the United States and abroad.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials conducted in Europe, contact:
Contacts for additional information about Cushing syndrome:
Constantine A. Stratakis, MD, D(med)Sci
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Institutes of Health
31 Center Dr, Room 2A46, MSC 2425
Bethesda, MD 20892-2425
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