Cushing syndrome

Definition

Cushing syndrome was first described by an American neurosurgeon in the early twentieth century named Harvey Cushing. Cushing recognized a specific set of symptoms that collectively he identified as part of a syndrome. In this disease, prolonged exposure to abnormal levels of the hormone cortisol results in the collection of symptoms that Harvey Cushing described. Cushing Syndrome can also be associated with abnormal levels of another hormone, adrenocorticotropin (ACTH), and both ACTH and cortisol overproduction can often occur as part of other disorders.

Description

Cushing syndrome affects the body in many ways and can lead to severe medical complications if untreated. Effects of the disorder are manifested clinically, physically, and emotionally. Physically, patients develop an abnormal fat distribution that sometimes leads to feelings of insecurity or unattractiveness. Clinically, people with Cushing syndrome are often at risk for a variety of significant medical problems including diabetes, high blood pressure, hair loss (especially in women), and heart disease. Cushing syndrome is relatively rare. Severe fatigue can also develop and this has many ramifications in terms of complications related to daily living. Cushing syndrome is sometimes referred to as hypercortisolism.

Demographics

According to the National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK), an estimated 10 to 15 individuals out of every million people will be affected each year with Cushing syndrome. These individuals are usually adults between the ages of twenty to fifty years old. Pituitary adenomas cause the majority of Cushing syndrome cases, and women that have these types of tumors are at a five-fold higher risk for developing the disease than men.

Causes and symptoms

The function of cortisol is to regulate blood pressure, act as an anti-inflammatory mediator, and to regulate insulin metabolism. Cortisol plays a role during the metabolic activities associated with fat, protein, and carbohydrate metabolism. High levels of cortisol can cause sodium and water retention. Therefore, overproduction of cortisol can have medically important health-related implications that affect muscle contractions, heartbeat, and blood cell function.

The adrenal glands are located on top of each kidney, and are responsible for releasing cortisol. The site of cortisol production is in the outer layer of the adrenal gland called the adrenal cortex. Release of cortisol is stimulated by ACTH, which is produced by another gland. This gland, called the pituitary gland, is juxtaposed to the base of the brain and serves as a type of control center for many other glands in the body. ACTH production occurs only when there is a low concentration of cortisol in the blood. Therefore, cortisol production can be abnormal due to abnormalities in the function of the adrenal gland or the pituitary gland. It can also be overproduced by abnormal regulation of ACTH.

The role of cortisol in tumor formation

Cortisol overproduction can also be caused by many different types of tumors resulting in abnormalities in the function or regulation of the adrenal or pituitary glands. These tumors are usually not malignant and are found in the pituitary and adrenal glands. In the pituitary gland, a specific type of tumor called an adenoma can develop. Pituitary adenomas often can excessively overproduce ACTH in the absence of the normal stimulatory signals. People that develop Cushing syndrome are most likely to develop this disease due to these types of tumors. ACTH overproduction can also occur when the tumor is located outside of the pituitary gland; this condition is known as ectopic ACTH syndrome. These tumors, unlike pituitary adenomas, tend to be cancerous. Tumors can also develop in the adrenal gland and result in excessive cortisol production. Adrenal tumors can often result in malignancy, and patients with these tumors often quickly become symptomatic due to the high levels of cortisol produced.

Familial Cushing syndrome

Cushing syndrome can also develop in multiple individuals from the same family. This familial form is due to a genetically inherited susceptibility to developing specific endocrine tumors. The specific nature of the genetic components have not been clearly elucidated, except in cases of a rare genetic disease called Multiple Endocrine Neoplasia (MEN). MEN is caused by a genetic mutations in a specific gene involved in cell cycle regulation resulting in pituitary tumors that can lead to Cushing syndrome.

The symptoms associated with Cushing syndrome can be easily recognizable by an experienced physician. These clinical manifestations include physical characteristics that involve the face, neck, shoulders, and abdomen. Generally, most affected individuals develop obesity of the upper portion of their bodies. They often have thin arms and legs. The facial feature that characterizes Cushing syndrome is the typically developed round, moon-shaped face. An accumulation of fat pads are often observed on or below the base of the neck, on the patients back, between the patient's shoulders, as well as on the abdomen. Abdominal fat accumulation can be significant and can also be associated with vertical purplish striations (stretch marks). Stretch marks also can be observed on their thighs, arms, breasts, and buttocks. Affected children often suffer from obesity along with growth retardation.

Other clinical manifestations resulting from excessive cortisol production can be quite serious. Myopathy , or wasting away of the muscles often occurs. Due to the abnormal blood cell development that results from cortisol overproduction, the skin bruises more frequently and wounds do not heal as quickly. Skin tends to be fragile and thin. People with Cushing syndrome are susceptible to developing fractures, especially in the pelvic and spinal regions. Women are at a higher risk for developing osteoporosis or brittle bones. Men also frequently develop weak bones. For all affected individuals, difficulty with activities such as lifting objects or getting up from a sitting position can lead to back pain and fractures. Because cortisol is also important for regulating insulin, patients with Cushing syndrome are at risk for developing diabetes.

Diagnosis

The diagnosis of Cushing syndrome is based on the patient's family history and the results from several laboratory tests. The most definitive diagnostic laboratory test is to monitor cortisol production in the person's urine during a 24-hour collection period. A 50–100 microgram result represents the normal cutoff, with any higher value suggestive of Cushing syndrome.

When cortisol is found to be high, x rays are usually requested to identify pituitary or adrenal tumors. A dexamethasone suppression test is often requested with a positive finding on x ray and is used to distinguish between ACTH overproduction due to pituitary adenomas or other tumors. Dexamethasone is a synthetic hormone that, when used to help diagnose Cushing syndrome, is usually orally administered for four days at increasing dosages, during which time the urine is collected. The effect on blood and urine cortisol concentrations can be determined and the different effects can distinguish these two types of ACTH-producing tumors. Radiological imaging such as MRI scans sometimes allow endocrinologists (physicians who specialize in hormone-related health concerns) to directly visualize the glands and determine their size and shape.

Treatment team

Several types of medical doctors are usually required for the diagnosis and treatment of Cushing syndrome. This includes an oncologist, a pathologist, or an endocrinologist. Although it is unlikely that a child would develop this disease, treatment would depend on whether the child has progressed through puberty. As Cushing syndrome in children can result in growth retardation, a pediatric endocrinologist would be the most likely specialist to monitor the child's development.

Treatment

Determining the appropriate treatment for individuals with Cushing syndrome relies on the accurate determination of the cause of excessive cortisol production. As there are a variety of causes, selecting the appropriate treatment depends on characterizing the disease based on the precipitating spectrum of clinical manifestations. For example, abnormal function of the pituitary gland or the adrenal cortex can be important indicators of causation. For this reason, it is important that affected individuals have a comprehensive clinical evaluation by an experienced physician. Tumors of the pituitary gland or the adrenal cortex can stimulate overproduction of ACTH or cortisol. Medical treatments with cortisone for unrelated conditions may also alter the amount of cortisol exposure and concentration circulating within the body.

In cases that involve pituitary tumors as the cause of Cushing syndrome, surgical removal represents a formidable treatment in cases where chemotherapy or radiation is ineffective. Transsphenoidal adenomectomy, a surgical procedure, is the most widely used treatment for pituitary adenomas that cause Cushing syndrome. This usually requires a specialized surgeon or treatment center, as it is a relatively rare and difficult procedure. The success rate is high and synthetic hormone replacement therapy, typically with prednisone, is only necessary for approximately one year. As an alternative, radiation therapy is also a possibility. There are also therapeutic agents that inhibit cortisol production that can be used.

Adrenal gland tumors are usually always surgically removed, whether they are benign or malignant. Adrenal gland removal typically does not affect endocrine function due to compensation from other glands in producing hormones. Hormone therapy is required with removal of both adrenal glands.

If the cause of Cushing syndrome is drug-induced, due to prolonged exposure to steroids called glucocorticoids that are used to treat other ailments, the physician will lower this dose as long as symptoms continue to be manifested.

Recovery and rehabilitation

Transsphenoidal adenomectomy performed by an experienced surgeon has a high success rate, with more than 80% of patients cured. In the event that the surgery is not successful or it provides only a temporary cure, it is often repeated with fairly favorable results. For radiation therapy, adding one of many drugs that suppresses cortisol production such as mitotane can enhance recovery time. These drugs have been considered to be effective when used alone in up to 40% of patients.

As scientists and clinicians better understand how cortisol and ACTH are produced and how disturbances in hormonal regulation affect the body, more treatment modalities will likely become available.

Clinical trials

The National Institutes of Health sponsors several scientists in clinical translational research in Cushing syndrome treatment, as well as the development of drugs leading to clinical trials . As of early 2004, there were at least eight ongoing clinical trials recruiting patients. These include long term post-operative follow ups, the evaluation of novel imaging techniques, understanding the role of stress and depression in Cushing syndrome, and other studies investigating adrenal and pituitary gland tumors. Further information on clinical trials can be found at the National Institutes of Health website on clinical trials, ClinicalTrials.gov, available at: <http://www.clinicaltrials.gov/ct/search?term=cushing+sy ndrome>.

Prognosis

The prognosis for individuals who receive treatment for Cushing syndrome is good with a high likelihood of being cured. However, in affected individuals that are not treated, the prognosis can be poor, with death eventually resulting from complications from hypertension, diabetes, or heart disease.

Resources

BOOKS

Icon Health Publications. The Official Patient's Sourcebook on Cushing's Syndrome: A Revised and Updated Directory for the Internet Age. San Diego: Icon Group, Int., 2002.

DeGroot, Leslie J., ed., et al. "Cushing's Syndrome." In Endocrinology, Vol. 2, pp. 1741–1769. Philadelphia: W. B. Saunders Company, 1995.

Wilson, Jean D., ed, et al. "Hyperfunction: Glucocorticoids: Hypercortisolism (Cushing's syndrome)," pp. 536–562. In Williams Textbook of Endocrinology, No. 8. Philadelphia: W. B. Saunders, 1992.

PERIODICALS

Boscaro, M., L. Barzon, F. Fallo, and N. Sonino. "Cushing Syndrome." Lancet 357, no. 9258 (March 10, 2001): 783–91.

OTHER

NINDS Cushing's Syndrome Information Page. National Institute of Neurological Disorders and Stroke. (January 20, 2004.) <http://www.ninds.nih.gov/health_and_medical/disorders/cushings_doc.htm>.

Cushing's Syndrome. National Institute of Diabetes & Digestive & Kidney Diseases. (January 20, 2004). <http://www.niddk.nih.gov/health/endo/pubs/cushings/cushings.htm>.

ORGANIZATIONS

Cushing's Support and Research Foundation, Inc. 65 East India Row 22B, Boston, MA 02110. (617) 723-3824 or (617) 723-3674. [email protected]. <http://csrf.net/>.

Pituitary Network Association. P.O. Box 1958, Thousand Oaks, CA 91358. (805) 499-9973; Fax: (805) 480-0633. [email protected]. <http://www.pituitary.org>.

Bryan Richard Cobb