Cushing's syndrome

Definition

Cushing's syndrome is a relatively rare endocrine (hormonal) disorder resulting from excessive exposure to the hormone cortisol. The disorder, which leads to a variety of symptoms and physical abnormalities, is most commonly caused by taking medications containing the hormone over a long period of time. A more rare form of the disorder occurs when the body itself produces an excessive amount of cortisol.

Description

The adrenals are two glands, each of which is perched on the upper part of the two kidneys. The outer part of the gland is known as the cortex; the inner part is known as the medulla. Each of these parts of the adrenal gland is responsible for producing different types of hormones. Regulation of hormone production and release from the adrenal cortex involves the pituitary gland, a small gland located at the base of the brain. After the hypothalamus (the part of the brain containing secretions important to metabolic activities) sends "releasing hormones" to the pituitary gland, the pituitary secretes a hormone called adrenocorticotropic hormone (ACTH). The ACTH then travels through the bloodstream to the adrenal cortex, where it encourages the production and release of cortisol (sometimes called the "stress" hormone) and other adrenocortical hormones.

Cortisol, a very potent glucocorticoid—a group of adrenocortical hormones that protects the body from stress and affect protein and carbohydrate metabolism— is involved in regulating the functioning of nearly every type of organ and tissue in the body, and is considered to be one of the few hormones absolutely necessary for life. Cortisol is involved in:

• complex processing and utilization of many nutrients, including sugars (carbohydrates), fats, and proteins
• normal functioning of the circulatory system and the heart
• functioning of muscles
• normal kidney function
• production of blood cells
• normal processes involved in maintaining the skeletal system
• proper functioning of the brain and nerves
• normal responses of the immune system

Cushing's syndrome, also called hypercortisolism, has an adverse effect on all of the processes described above. The syndrome occurs in approximately 10 to 15 out of every one million people per year, usually striking adults between the ages of 20 and 50.

— Rosalyn Carson-DeWitt

A syndrome caused by an increased production of ACTH from a tumor of the adrenal cortex or of the anterior lobe of the pituitary gland, or by excessive intake of glucocorticoids. It is characterized by obesity and weakening of the muscles.

[After Harvey Williams CUSHING.]

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: .

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. cushinfo@csrf.net. http://csrf.net/.

Pituitary Network Association. P.O. Box 1958, Thousand Oaks, CA 91358. (805) 499-9973; Fax: (805) 480-0633. pna@pituitary.org. http://www.pituitary.org.

Bryan Richard Cobb

Key Terms: Adenoma, Adrenocorticotropic hormone, Cortisol, Ectopic, Endocrine, Gland, Glucocorticoids, Hormone, Hypothalamus.

Definition

Cushing's syndrome is a relatively rare endocrine (hormonal) disorder resulting from excessive exposure to the hormone cortisol. The disorder, which leads to a variety of symptoms and physical abnormalities, is most commonly caused by taking medications containing the hormone over a long period of time. A more rare form of the disorder occurs when the body itself produces an excessive amount of cortisol.

Description

The adrenals are two glands, each of which is perched on the upper part of the two kidneys. The outer part of the gland is known as the cortex; the inner part is known as the medulla. Each of these parts of the adrenal gland is responsible for producing different types of hormones. Regulation of hormone production and release from the adrenal cortex involves the pituitary gland, a small gland located at the base of the brain. After the hypothalamus (the part of the brain containing secretions important to metabolic activities) sends "releasing hormones" to the pituitary gland, the pituitary secretes a hormone called adrenocorticotropic hormone (ACTH). The ACTH then travels through the bloodstream to the adrenal cortex, where it encourages the production and release of cortisol (sometimes called the "stress" hormone) and other adrenocortical hormones.

Cortisol, a very potent glucocorticoid—a group of adrenocortical hormones that protects the body from stress and affect protein and carbohydrate metabolism—is involved in regulating the functioning of nearly every type of organ and tissue in the body, and is considered to be one of the few hormones absolutely necessary for life. Cortisol is involved in:

• complex processing and utilization of many nutrients, including sugars (carbohydrates), fats, and proteins
• normal functioning of the circulatory system and the heart
• functioning of muscles
• normal kidney function
• production of blood cells
• normal processes involved in maintaining the skeletal system
• proper functioning of the brain and nerves
• normal responses of the immune system

Cushing's syndrome, also called hypercortisolism, has an adverse effect on all of the processes described above. The syndrome occurs in approximately 10 to 15 out of every one million people per year, usually striking adults between the ages of 20 and 50.

Causes and Symptoms

The most common cause of Cushing's syndrome is the long-term use of glucocorticoid hormones in medications. Medications such as prednisone are used in a number of inflammatory conditions. Such conditions include rheumatoid arthritis, asthma, vasculitis, lupus, and a variety of other autoimmune disorders in which the body's immune cells accidentally attack some part of the body itself. In these disorders, the glucocorticoids are used to dampen the immune response, thereby decreasing damage to the body.

Cushing's syndrome can also be caused by three different categories of disease:

• a pituitary tumor producing abnormally large quantities of ACTH
• the abnormal production of ACTH by some source other than the pituitary
• a tumor within the adrenal gland overproducing cortisol

Although it is rare, about two-thirds of endogenous (occurring within the body rather than from a source outside the body, like a medication) Cushing's syndrome is a result of Cushing's disease. The term "Cushing's disease" refers to Cushing's syndrome, which is caused by excessive secretion of ACTH by a pituitary tumor, usually an adenoma (noncancerous tumor). The pituitary tumor causes increased growth of the adrenal cortex (hyperplasia) and increased cortisol production. Cushing's disease affects women more often than men.

Tumors in locations other than the pituitary can also produce ACTH. This is called ectopic ACTH syndrome ("ectopic" refers to something existing out of its normal place). Tumors in the lung account for more than half of all cases of ectopic ACTH syndrome. Other types of tumors which may produce ACTH include tumors of the thymus, the pancreas, the thyroid, and the adrenal gland. In each case, the secreting part of the tumor may be in the primary tumor, part of the primary tumor, or may be a small, difficult-to-find, metastatic lesion(s). Nearly all adrenal gland tumors are benign (noncancerous), although in rare instances a tumor may actually be cancerous.

Symptoms of cortisol excess (resulting from medication or from the body's excess production of the hormone) include:

• weight gain
• an abnormal accumulation of fatty pads in the face (creating the distinctive "moon face" of Cushing's syndrome); in the trunk (termed "truncal obesity"); and over the upper back and the back of the neck (giving the individual what has been called a "buffalo hump")
• purple and pink stretch marks across the abdomen and flanks
• high blood pressure
• weak, thinning bones (osteoporosis)
• weak muscles
• low energy
• thin, fragile skin, with a tendency toward both bruising and slow healing
• abnormalities in the processing of sugars (glucose), with occasional development of actual diabetes
• kidney stones
• increased risk of infections
• emotional disturbances, including mood swings, depression, irritability, confusion, or even a complete break with reality (psychosis)
• irregular menstrual periods in women
• decreased sex drive in men and difficulty maintaining an erection
• abormal hair growth in women (in a male pattern, such as in the beard and mustache area), as well as loss of hair from the head (receding hair line).

Diagnosis

Diagnosing Cushing's syndrome can be complex. Diagnosis must not only identify the cortisol excess but also locate its source. Many of the symptoms listed above can be attributed to numerous other diseases. Although a number of these symptoms seen together would certainly suggest Cushing's syndrome, the symptoms are still not specific to Cushing's syndrome. Following a review of the patient's medical history, physical examination, and routine blood tests, a series of more sophisticated tests is available to achieve a diagnosis.

24-Hour Free Cortisol Test

This is the most specific diagnostic test for identifying Cushing's syndrome. It involves measuring the amount of cortisol present in the urine over a 24-hour period. When excess cortisol is present in the bloodstream, it is processed by the kidneys and removed as waste in the urine. This 24-hour free cortisol test requires that an individual collect exactly 24-hours' worth of urine in a single container. The urine is then analyzed in a laboratory to determine the quantity of cortisol present. This technique can also be paired with the administration of dexamethasone, which in a normal individual would cause urine cortisol to be very low. Once a diagnosis has been made using the 24-hour free cortisol test, other tests are used to find the exact location of the abnormality causing excess cortisol production.

Dexamethasone Suppression Test

This test is useful in distinguishing individuals with excess ACTH production due to a pituitary adenoma from those with ectopic ACTH-producing tumors. Patients are given dexamethasone (a synthetic glucocorticoid) orally every six hours for four days. Low doses of dexamethasone are given during the first two days; for the last two days, higher doses are administered. Before dexamethasone is administered, as well as on each day of the test, 24-hour urine collections are obtained.

Because cortisol and other glucocorticoids signal the pituitary to decrease ACTH, the normal response after taking dexamethasone is a drop in blood and urine cortisol levels. Thus, the cortisol response to dexamethasone differs depending on whether the cause of Cushing's syndrome is a pituitary adenoma or an ectopic ACTH-producing tumor.

However, the dexamethasone suppression test may produce false-positive results in patients with conditions such as depression, alcohol abuse, high estrogen levels, acute illness, and stress. On the other hand, drugs such as phenytoin and phenobarbital may produce false-negative results. Thus, patients are usually advised to stop taking these drugs at least one week prior to the test.

Corticotropin-Releasing Hormone (CRH) Stimulation Test

The CRH stimulation test is given to help distinguish between patients with pituitary adenomas and those with either ectopic ACTH syndrome or cortisolsecreting adrenal tumors. In this test, patients are given an injection of CRH, the corticotropin-releasing hormone that causes the pituitary to secrete ACTH. In patients with pituitary adenomas, blood levels of ACTH and cortisol usually rise. However, in patients with ectopic ACTH syndrome, this rise is rarely seen. In patients with cortisol-secreting adrenal tumors, this rise almost never occurs.

Petrosal Sinus Sampling

Although this test is not always necessary, it may be used to distinguish between a pituitary adenoma and an ectopic source of ACTH. Petrosal sinus sampling involves drawing blood directly from veins that drain the pituitary. This test, which is usually performed with local anesthesia and mild sedation, requires inserting tiny, flexible tubes (catheters) through a vein in the upper thigh or groin area. The catheters are then threaded up slowly until they reach veins in an area of the skull known as the petrosal sinuses. X rays are typically used to confirm the correct position of the catheters. Often CRH is also given during the test to increase the accuracy of results.

When blood tested from the petrosal sinuses reveals a higher ACTH level than blood drawn from a vein in the forearm, the likely diagnosis is a pituitary adenoma. When the two samples show similar levels of ACTH, the diagnosis indicates ectopic ACTH syndrome.

Radiologic Imaging Tests

Imaging tests such as computed tomography scans (CT) and magnetic resonance imaging (MRI) are only used to look at the pituitary and adrenal glands after a firm diagnosis has already been made. The presence of a pituitary or adrenal tumor does not necessarily guarantee that it is the source of increased ACTH production. Many healthy people with no symptoms or disease whatsoever have noncancerous tumors in the pituitary and adrenal glands. Thus, CT and MRI is often used to image the pituitary and adrenal glands in preparation for surgery.

Treatment

The choice of a specific treatment depends on the type of problem causing the cortisol excess. Pituitary and adrenal adenomas are usually removed surgically. Malignant adrenal tumors always require surgical removal.

Treatment of ectopic ACTH syndrome also involves removing all of the cancerous cells which are producing ACTH. This may be done through surgery, chemotherapy (using combinations of cancer-killing drugs), or radiation therapy (using x rays to kill cancer cells), depending on the type of cancer and how far it has spread. Radiation therapy may also be used on the pituitary (with or without surgery), for patients who cannot undergo surgery, or for patients whose surgery did not successfully decrease pituitary release of ACTH.

There are a number of drugs that are effective in decreasing adrenal production of cortisol. These medications include mitotane, ketoconazole, metyrapone, trilostane, aminoglutethimide, and mifepristone. These drugs are sometimes given prior to surgery in an effort to reverse the problems brought on by cortisol excess. However, the drugs may also need to be administered after surgery (sometimes along with radiation treatments) in patients who continue to have excess pituitary production of ACTH.

Because pituitary surgery can cause ACTH levels to drop too low, some patients require short-term treatment with a cortisol-like medication after surgery. Patients who need adrenal surgery may also require glucocorticoid replacement. If the entire adrenal gland has been removed, the patient must take oral glucocorticoids for the rest of his or her life.

Prognosis

Prognosis depends on the source of the problem. When pituitary adenomas are identified as the source of increased ACTH leading to cortisol excess, about 80% of patients are cured by surgery. When cortisol excess is due to some other form of cancer, the prognosis depends on the type of cancer and the extent of its spread.

Resources

Periodicals

Boscaro, Marco, Luisa Barzon, and Nicoletta Sonino. "The Diagnosis of Cushing's Syndrome: Atypical Presentations and Laboratory Shortcomings." Archives of Internal Medicine 160 (2000): 3045-53.

Boscaro, Marco, Luisa Barzon, Francesco Fallo, and Nicoletta Sonino. "Cushing's Syndrome." Lancet 357 (2001): 783-91.

Kirk, Lawrence F., Robert B. Hash, Harold P. Katner, and Tom Jones. "Cushing's Disease: Clinical Manifestations and Diagnostic Evaluation." American Family Physician 62, no.5 (September 1, 2001): 1119-27.

Newell-Price J., and A. Grossman. "Diagnosis and Management of Cushing's Syndrome." Lancet 353 (1999): 2087-88.

—Rosalyn Carson-DeWitt, M.D.

A symptom complex associated with an excess of adrenal steroids of all types resulting from hyperplasia of the adrenal cortex, malignant neoplasms, pituitary basophilia, or prolonged administration of adrenocorticotropic hormone (ACTH). Manifestations include hypertension, obesity, diabetes mellitus, osteoporosis, purple striae of the skin in areas of tension, and disorders of glucose tolerance.

For more information on Cushing syndrome, visit Britannica.com.

A group of signs produced by an excess of free circulating cortisol from the adrenal cortex. Causes are: (1) excessive secretion of adrenocorticotropic hormone (ACTH) from the pituitary gland, which may actually result from faulty release of corticotropin-releasing factor (CRF) from the hypothalamus or a functional tumor, usually corticotroph adenoma; (2) tumor of the adrenal cortex, causing hypersecretion of the glucocorticoids; (3) iatrogenic Cushing's syndrome resulting from excessive or prolonged administration of exogenous glucocorticoids; and in humans (4) ectopic production of ACTH by extrapituitary tumors. Most commonly seen in dogs (canine Cushing's syndrome; CCS), infrequently in aged horses and rarely in other species. See also hyperadrenocorticism.
Affected dogs show polyuria, polydipsia, polyphagia, muscle weakness and atrophy, pendulous abdomen, hair loss and an increased susceptibility to infection, particularly of the skin and urinary tract.

Canine Cushing’s syndrome.

• pseudo C. s. — see growth hormone-responsive dermatosis.

"Cushing's" redirects here. For the circulatory reflex, see Cushing reflex. For the related three-part condition, see Cushing's triad.

Cushing's syndrome
Classification and external resources
Cortisol
ICD-10	E24.
ICD-9	255.0
DiseasesDB	3242
MedlinePlus	000410
eMedicine	med/485
MeSH	D003480

Cushing's syndrome (also called hyperadrenocorticism or hypercorticism) is a hormone (endocrine) disorder caused by high levels of cortisol (hypercortisolism) in the blood. This can be caused by taking glucocorticoid drugs, or by tumors that produce cortisol or adrenocorticotropic hormone (ACTH).^[1] Cushing's disease refers to one specific cause, a non-cancerous tumor (adenoma) in the pituitary gland that produces large amounts of ACTH, which in turn elevates cortisol. It can usually be cured by surgery.

Cushing's syndrome is not confined to humans and is also a relatively common condition in domestic dogs and horses. It was described by American Dr. Harvey Cushing in 1932.^[2]

Contents 1 Classification and etiology 1.1 Exogenous vs. endogenous 1.2 ACTH-dependent vs. ACTH-independent 2 Signs and symptoms 2.1 In humans 2.2 In dogs 3 Diagnosis 4 Pathophysiology 5 Treatment 6 Epidemiology 7 References 8 See also 9 External links

Classification and etiology

There are several possible causes of Cushing's syndrome.

Exogenous vs. endogenous

Hormones that come from outside the body are called exogenous; hormones that come from within the body are called endogenous.

The most common is exogenous administration of glucocorticoids prescribed by physicians to treat other diseases (called iatrogenic Cushing's syndrome). This can be an effect of steroid treatment of a variety of disorders such as asthma and rheumatoid arthritis, or in immunosuppression after an organ transplant. Administration of synthetic ACTH is also possible, but ACTH is less often prescribed due to cost and lesser utility.

Endogenous Cushing's syndrome results from some derangement of the body's own system of secreting cortisol. Normally, ACTH is released from the pituitary gland when necessary to stimulate the release of cortisol from the adrenal glands.

• In pituitary Cushing's, a benign pituitary adenoma secretes ACTH. This is also known as Cushing's disease and is responsible for 65% of endogenous Cushing's syndrome.

• In adrenal Cushing's, excess cortisol is produced by adrenal gland tumors, hyperplastic adrenal glands, or adrenal glands with nodular adrenal hyperplasia.

• Finally, tumors outside the normal pituitary-adrenal system can produce ACTH that affects the adrenal glands. This final etiology is called ectopic or paraneoplastic Cushing's syndrome and is seen in diseases like small cell lung cancer.

ACTH-dependent vs. ACTH-independent

Cushing's syndrome can also be sub-classified according to whether or not the excess cortisol is dependent on increased ACTH.

• ACTH-dependent Cushing's syndrome is driven by increased ACTH and includes exogenous ACTH administration as well as pituitary and ectopic Cushing's.

• ACTH-independent Cushing's syndrome shows increased cortisol, but the ACTH is not elevated but rather decreased due to negative feedback. It can be caused by exogenous administration of glucocorticoids or by adrenal adenoma, carcinoma, or nodular hyperplasia.

Signs and symptoms

In humans

Symptoms include rapid weight gain, particularly of the trunk and face with sparing of the limbs (central obesity). A common sign is the growth of fat pads along the collar bone and on the back of the neck (buffalo hump) (known as a lipodystrophy) and a round face often referred to as a "moon face". Other symptoms include excess sweating, telangiectasia (dilation of capillaries), thinning of the skin (which causes easy bruising and dryness, particularly the hands) and other mucous membranes, purple or red striae (the weight gain in Cushing's syndrome stretches the skin, which is thin and weakened, causing it to hemorrhage) on the trunk, buttocks, arms, legs or breasts, proximal muscle weakness (hips, shoulders), and hirsutism (facial male-pattern hair growth). The excess cortisol may also affect other endocrine systems and cause, for example, insomnia, reduced libido, impotence, amenorrhoea and infertility. Patients frequently suffer various psychological disturbances, ranging from euphoria to psychosis. Depression and anxiety are also common.^[3]

Cushing's syndrome may present with striking and distressing skin changes including hyperhidrosis, dryness, fragility of the skin, facial acne, susceptibility to superficial dermatophyte and malassezia infections, a plethora over the cheeks, anterior neck, and V of the chest, and the characteristic purplish, atrophic striae on the abdomen.^[4]:500

Other signs include polyuria (and accompanying polydipsia), persistent hypertension (due to cortisol's enhancement of epinephrine's vasoconstrictive effect) and insulin resistance (especially common in ectopic ACTH production), leading to hyperglycemia (high blood sugar) which can lead to diabetes mellitus. Untreated Cushing's syndrome can lead to heart disease and increased mortality. Cushing's syndrome due to excess ACTH may also result in hyperpigmentation. This is due to Melanocyte-Stimulating Hormone production as a byproduct of ACTH synthesis from Pro-opiomelanocortin (POMC). Cortisol can also exhibit mineralcorticoid activity in high concentrations, worsening the hypertension and leading to hypokalemia (common in ectopic ACTH secretion). Furthermore, gastrointestinal disturbances, opportunistic infections and impaired wound healing (cortisol is a stress hormone, so it depresses the immune and inflammatory responses). Osteoporosis is also an issue in Cushing's syndrome since, as mentioned before, cortisol evokes a stress-like response. Consequently, the body's maintenance of bone (and other tissues) becomes secondary to maintenance of the false stress response. Cushing's syndrome may also elicit hirsutism (male-pattern hair growth in a female, and/or cause hair to become extremely dry and brittle) and oligomenorrhea (decreased frequency of menstruation) due to elevations in androgens (male sex hormones), normally at low levels in women. Additionally, Cushing's may cause sore and aching joints, particularly in the hip, shoulders, and lower back.

In dogs

Cushings anecdotally presents itself mainly in smaller dogs. Generally more common in the cross bred "fluffies". Common symptoms include polyuria (increased urination), polydipsia (increased water intake), polyphagia (increased appetite), bald patches - or general hair loss, usually accompanied by a "pot" belly (though the dog appears normal weight elsewhere). Bloodwork will show liver enzyme elevations. If left untreated, the dog can develop hepatopathy, weak abdominal muscles, fragile skin and calcinosis cutis (calcified patches of skin).

Diagnosis

When Cushing's syndrome is suspected, either a dexamethasone suppression test (administration of dexamethasone and frequent determination of cortisol and ACTH level), or a 24-hour urinary measurement for cortisol offer equal detection rates.^[5] Dexamethasone is a glucocorticoid and simulates the effects of cortisol, including negative feedback on the pituitary gland. When dexamethasone is administered and a blood sample is tested, high cortisol would be indicative of Cushing's syndrome because there is an ectopic source of cortisol or ACTH (eg: adrenal adenoma) that is not inhibited by the dexamethasone. A novel approach, recently cleared by the US FDA, is sampling cortisol in saliva over 24 hours, which may be equally sensitive, as late night levels of salivary cortisol are high in Cushingoid patients. Other pituitary hormone levels may need to be ascertained. Performing a physical examination to determine any visual field defect may be necessary if a pituitary lesion is suspected, which may compress the optic chiasm causing typical bitemporal hemianopia.

When any of these tests are positive, CT scanning of the adrenal gland and MRI of the pituitary gland are performed to detect the presence of any adrenal or pituitary adenomas or incidentalomas (the incidental discovery of harmless lesions). Scintigraphy of the adrenal gland with iodocholesterol scan is occasionally necessary. Very rarely, determining the cortisol levels in various veins in the body by venous catheterization, working towards the pituitary (petrosal sinus sampling) is necessary.

Pathophysiology

Both the hypothalamus and the pituitary gland are in the brain. The paraventricular nucleus (PVN) of the hypothalamus releases corticotropin-releasing hormone (CRH), which stimulates the pituitary gland to release adrenocorticotropin (ACTH). ACTH travels via the blood to the adrenal gland, where it stimulates the release of cortisol. Cortisol is secreted by the cortex of the adrenal gland from a region called the zona fasciculata in response to ACTH. Elevated levels of cortisol exert negative feedback on the pituitary, which decreases the amount of ACTH released from the pituitary gland. Strictly, Cushing's syndrome refers to excess cortisol of any etiology. One of the causes of Cushing's syndrome is a cortisol secreting adenoma in the cortex of the adrenal gland. The adenoma causes cortisol levels in the blood to be very high, and negative feedback on the pituitary from the high cortisol levels causes ACTH levels to be very low. Cushing's disease refers only to hypercortisolism secondary to excess production of ACTH from a corticotrophic pituitary adenoma. This causes the blood ACTH levels to be elevated along with cortisol from the adrenal gland. The ACTH levels remain high because a tumor causes the pituitary to be unresponsive to negative feedback from high cortisol levels.

Treatment

Most Cushing's syndrome cases are caused by steroid medications (iatrogenic). Consequently, most patients are effectively treated by carefully tapering off (and eventually stopping) the medication that causes the symptoms.

If an adrenal adenoma is identified it may be removed by surgery. An ACTH-secreting corticotrophic pituitary adenoma should be removed after diagnosis. Regardless of the adenoma's location, most patients will require steroid replacement postoperatively at least in the interim as long-term suppression of pituitary ACTH and normal adrenal tissue does not recover immediately. Clearly, if both adrenals are removed, replacement with hydrocortisone or prednisolone is imperative.

In those patients not suitable for or unwilling to undergo surgery, several drugs have been found to inhibit cortisol synthesis (e.g. ketoconazole, metyrapone) but they are of limited efficacy.

Removal of the adrenals in the absence of a known tumor is occasionally performed to eliminate the production of excess cortisol. In some occasions, this removes negative feedback from a previously occult pituitary adenoma, which starts growing rapidly and produces extreme levels of ACTH, leading to hyperpigmentation. This clinical situation is known as Nelson's syndrome.^[6]

Epidemiology

Iatrogenic Cushing's syndrome (caused by treatment with corticosteroids) is the most common form of Cushing's syndrome. The incidence of pituitary tumors may be relatively high, as much as one in five people, ^[7] but only a minute fraction are active and produce excessive hormones.

References

1. ^ Kumar, Abbas, Fausto. Robbins and Cotran Pathologic Basis of Disease, 7th ed. Elsevier-Saunders; New York, 2005.
2. ^ Cushing HW. (1932). "The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism).". Bull Johns Hopkins Hosp 50: 137–95. 
3. ^ Yudofsky, Stuart C.; Robert E. Hales (2007). The American Psychiatric Publishing Textbook of Neuropsychiatry and Behavioral Neurosciences (5th ed.). American Psychiatric Pub, Inc.. ISBN 1585622397. 
4. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0.
5. ^ Raff H, Findling JW (2003). "A physiologic approach to diagnosis of the Cushing syndrome". Ann. Intern. Med. 138 (12): 980–91. PMID 12809455. http://www.annals.org/cgi/pmidlookup?view=long&pmid=12809455. 
6. ^ Nelson DH, Meakin JW, Thorn GW (1960). "ACTH-producing pituitary tumors following adrenalectomy for Cushing syndrome". Ann. Intern. Med. 52: 560–9. PMID 14426442. 
7. ^ Ezzat S, Asa SL, Couldwell WT, et al. (2004). "The prevalence of pituitary adenomas: a systematic review". Cancer 101 (3): 613–9. doi:10.1002/cncr.20412. PMID 15274075. 

See also

• Addison's disease
• Pseudo-Cushing's syndrome

External links

Wikimedia Commons has media related to: Cushing's syndrome

• Cushing's syndrome
• Cushing's Fact Sheets from The Hormone Foundation
• Cushing's syndrome
• Endocrine and Metabolic Diseases Information Service
• European Register on Cushing's syndrome
• Patient information Booklet from The Pituitary Society

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