Cushing's syndrome, or hypercortisolism, is an endocrine disorder caused by the presence of excessive levels of cortisol in the body.
Named after the American surgeon Dr. Harvey Cushing, who first described the condition in 1932, Cushing's syndrome is relatively rare. Only about 1 out of every 100,000 people is diagnosed with Cushing's syndrome every year, and those affected are most commonly adults between the ages of 20 and 50 years.
Known sometimes as the "stress hormone," cortisol is an important component of the body’s response to stress. In Cushing's syndrome, the body's harmonious system of maintaining homeostasis via its endocrine system is disrupted, and too much cortisol is produced (just as in Addison's disease where too little cortisol is produced).
Causes
A disorder in either the regulation of cortisol or ACTH secretion can lead to increased levels of cortisol in the blood.
Normally, the secretion of cortisol follows a specific series of events. Corticotropin releasing hormone, or CRH, is released from the hypothalamus, which is a part of the brain, to the pituitary gland. CRH causes the anterior pituitary to secrete ACTH (adrenocorticotropin), a hormone that then stimulates the adrenal glands, which are located above the kidneys. When ACTH reaches the adrenal glands, cortisol is released into the bloodstream.
Cushing's syndrome has three well-established causes. First, adrenocortical tumors can secrete cortisol autonomously in the absence of ACTH. Such tumors can be either cancerous (malignant) or non-cancerous (benign). This cause of Cushing's syndrome is described as primary hypersecretion.
Second, some benign or malignant tumors that arise outside the anterior pituitary can produce ACTH. This condition is known as ectopic ACTH syndrome. Over 50 percent of such cases are caused by lung tumors. Men are three times more frequently affected than are women.
Third, anterior pituitary malfunctions can cause increased ACTH secretion, which in turn stimulate secretion of cortisol by the adrenal glands. This condition is referred to specifically as Cushing's disease and is called secondary hypersecretion. It affects women five times more frequently than men.
A common iatrogenic cause (brought forth by medical treatment) of Cushing's syndrome is exogenous administration of corticosteroids to treat various other medical conditions, such as inflammation and rheumatoid arthritis. Family heredity can also play a part in the onset of the syndrome, although it is quite rare.
Some individuals have peculiar causes of Cushing's syndrome, due to an inherited disposition to develop tumors of one or more endocrine glands. In primary pigmented micronodular adrenal disease, children or young adults develop small cortisol-producing tumors of the adrenal glands. In multiple endocrine neoplasia type I (MEN I), hormone-secreting tumors of the parathyroid glands, pancreas, and anterior pituitary occur. Cushing's syndrome in MEN I may be due to anterior pituitary, ectopic and/or adrenal tumors (Endocrine and Metabolic Diseases Information Service 2002).
Signs and Symptoms
The majority of signs of Cushing's syndrome can be predicted from the normal range of actions of cortisol. The hormone cortisol is essential for life and serves several purposes in the human body. Its main function is to maintain blood glucose levels, which it does through a variety of mechanisms. Cortisol promotes gluconeogenesis (glucose production) in the liver, balances the breakdown of sugar by insulin, and causes the breakdown of skeletal muscle proteins to provide amino acids for gluconeogenesis. Cortisol also reduces the inflammatory response of the immune system, preventing antibody production by white blood cells, causes a negative calcium balance in the body, and influences brain function by causing mood swings and changes in memory and learning abilities.
Patients with Cushing's syndrome experience symptoms related to increased gluconeogenesis. Tissue wasting occurs as muscle protein is broken down for glucose production, mimicking diabetes. Interestingly, however, weight gain occurs due to increased appetite with extra fat deposited in the trunk and face of patients, causing the appearance of a plump "moon face." Extremities are usually thin, with central obesity and wide purplish striae. Learning and memory become difficult, and an initial mood elevation is followed by depression. Excess sweating, telangiectasia (dilation of the capillaries), and hypertension also are common symptoms of the syndrome. Atrophy of the skin occurs as the skin becomes thin, fragile, and easily bruised. Reaction to infections is attenuated.
Common signs of Cushing's syndrome are growth of fat pads along the collar bone and on the back of the neck (known as a buffalo hump), reduced libido (or sex drive), impotence, amenorrhoea (abnormal suppression or absence of menstruation), and infertility. Patients frequently suffer various psychological disturbances as well.
Other signs include persistent hypertension, or high blood pressure, due to aldosterone-like effects, and insulin resistance, leading to hyperglycemia (high blood sugar levels). Increased hair growth, or hirsutism, on the face, abdomen, chest, and thighs of women may occur because of an excess of androgens (sex hormones). This excess hair growth may go unnoticed in men.
Although uncommon in children and teenagers, those affected with Cushing's syndrome may exhibit excess hair growth, extreme weight gain, retardation of growth, reddish-blue streaks on skin, tiredness and weakness, missed periods in teenage girls, very early or late puberty, and high blood pressure.
Untreated Cushing's syndrome can lead to heart disease and increased mortality, or death.
Diagnosis
Several tests can be employed to diagnose Cushing's syndrome.
The 24-hour urinary free cortisol level test is the most specific diagnostic test available. The patient's urine is collected over a 24-hour period and occasionally tested for the amount of 17-hydroxycorticosteroids (17-OHCS) present. For a normal adult, urinary 17-OHCS of 3 to 7 milligrams per gram of urinary creatinine is usual. Patients with untreated Cushing’s syndrome almost always have 17-OHCS in excess of 10 milligrams per gram of urinary creatinine (Wyngaarden 1982).
The CRH stimulation test can be used to distinguish between patients with anterior pituitary tumors and those with ectopic ACTH syndrome or cortisol-secreting adrenal tumors. In this test, patients are given CRH through an injection. If an anterior pituitary tumor is present, a rise in blood plasma ACTH and cortisol levels is observed. Normal individuals have a plasma cortisol concentration of 8 to 25 micrograms per deciliter in the morning and less than 8 micrograms per deciliter in the later hours of the day. Patients with untreated Cushing’s syndrome and a tumor present in the anterior pituitary have plasma cortisol levels in excess of 15 micrograms per deciliter at all times of the day. On the contrary, a rise in blood plasma ACTH and cortisol levels is rarely seen in patients with ectopic ACTH syndrome and essentially never witnessed in patients with cortisol-secreting adrenal tumors.
A third test, the dexamethasone suppression test, helps to separate patients with excess ACTH production due to pituitary tumors and malfunctions from those with ectopic ACTH-producing tumors. Dexamethasone, a synthetic glucocorticoid, is administered to patients by mouth every 6 hours over a 4-day span, with an increase in dosage during the last two days. Twenty-four hour urine collections are made each day of the test before dexamethasone is given. Since cortisol and other glucocorticoids communicate to the anterior pituitary to lower ACTH secretion through negative feedback mechanisms, the normal response after taking dexamethasone is a drop in blood and urine cortisol levels. Differing responses of cortisol to dexamethasone result depending on whether the cause of Cushing's syndrome is a pituitary tumor or an ectopic ACTH-producing tumor. Various drugs can produce false-positive and false-negative results for this test. Therefore, patients are often advised by their doctor to stop taking these specific drugs at least one week prior to the test.
Once a diagnosis of Cushing’s syndrome has been made, imaging procedures can be used to find the location of the tumor(s). Such procedures are used only after the diagnosis has been made because oftentimes benign tumors are present in the pituitary and adrenal glands. These tumors, being benign, do not produce hormones that are detrimental to the patient's health, and they are not surgically removed unless tests reveal they are the cause of symptoms. Therefore, the detection of irrelevant tumors does not occur by using imaging procedures until after the diagnosis has been made. Radiologic imaging is mostly used to reveal the size and shape of the anterior pituitary and adrenal glands to determine if a malignant tumor is present. A computerized tomography scan, or CT scan, and magnetic resonance imaging scans, also known as MRIs, are the most common imaging tests used.
A petrosal sinus sampling test is another test used during the identification of Cushing's syndrome. Although this test is not always required, it is the best method to differentiate between pituitary and ectopic causes of Cushing's syndrome. Samples of blood are drawn from the petrosal sinuses (veins that drain the pituitary gland) and ACTH levels are compared with ACTH levels in the forearm vein. Similar levels suggest ectopic ACTH syndrome, while higher levels of ACTH in the petrosal sinuses indicate the presence of a pituitary tumor.
Some individuals have high cortisol levels but do not incur the progressive effects of Cushing's syndrome, such as muscle wasting and thinning of the skin. These individuals may have pseudo Cushing's syndrome, which does not have the same long- term effects as Cushing's syndrome. It does not require treatment directed at the endocrine glands. Although observation over months to years is necessary to differentiate between pseudo Cushing's syndrome and Cushing's syndrome, the dexamethasone-CRH test was developed to distinguish between the conditions quickly, so that patients with actual Cushing's syndrome can receive timely treatment. As the name implies, this test combines the dexamethasone suppression and the CRH stimulation tests. An increase in cortisol levels during this test implies Cushing's syndrome (Endocrine and Metabolic Diseases Information Service 2002).
Treatment
Treatment of Cushing's syndrome depends on the specific reason for the cortisol excess present in the body. The main objectives of treatment are to reduce cortisol levels to normal and to destroy any associated tumors. Secondary goals of treatment are to prevent hormonal deficiencies in the body and to keep the patient from becoming dependent upon medications.
If an adrenal tumor is identified, it can be removed through a bilateral adrenalectomy (removal of the adrenal cortex and medulla), which can almost always be depended upon to cure hypercortisolism. However, the surgery does nothing for the pituitary tumors of Cushing's disease. Occasionally, removal of the adrenal glands in the absence of a known tumor is performed in order to eliminate the production of excess cortisol. This oftentimes removes negative feedback from a previously occult pituitary adenoma (benign tumor), which starts growing rapidly and produces extreme levels of ACTH, leading to hyperpigmentation. This clinical situation is known as Nelson's syndrome (Nelson, Meakin, and Thorn 1960).
Pituitary ACTH producing adenomas should be removed only after diagnosis. Ideal treatment for ectopic ACTH syndrome is generally considered to be removal of the tumor producing ectopic ACTH usually by surgery. However, the ectopic tumor has often spread by time of diagnosis. In such cases, further surgeries may be required.
Regardless of the adenoma's location, the majority of patients will require steroid replacement therapy after surgery, at least in the interim, as long-term suppression of pituitary ACTH and normal adrenal tissue does not recover immediately. If both adrenal glands are removed, steroid replacement with hydrocortisone or prednisolone is crucial.
In those patients not capable of undergoing or unwilling to undergo surgery, several drugs, such as mitotane, ketoconazole, and metyrapone, have been found to inhibit cortisol synthesis. However, these drugs have limited capabilities.
In iatrogenic Cushing's, dose adjustment may suffice, or it may be necessary to switch to another kind of immunosuppresive medication.
Regardless of the mode of therapy for Cushing's syndrome and Cushing's disease, the patient should remain under lifelong observation and medical care.
In Animals
Cushing's disease occurs in both dogs and cats, although it is more commonly seen in dogs. The average age of onset is between six and seven years of age with a range of two to sixteen years. The disease afflicts males and females equally and is considered a disease of middle age and older dogs and cats, and it is not particular to a specific breed.
Symptoms of the disease progress slowly and are often mistaken for "old age." For dogs eventually diagnosed with Cushing's disease, hair loss is the most common reason owners first bring their dog in for evaluation. Symptoms of the disease vary in individual pets and include increased water consumption and urination, increased appetite, abdominal enlargement, hair loss and thinning, decline in reproductive ability, increased panting, and recurrent urinary tract infections. Eighty percent of afflicted cats also have diabetes.
Diagnostic tests used with dogs and cats are similar to those used with human patients. About 80 percent of the cases in dogs are due to pituitary tumors oversecreting ACTH.
Non-surgical treatment therapy is most common in canine cases of Cushing's disease. There are several different oral medications being used to treat canine Cushing's disease. Both pituitary and adrenal tumors respond effectively to some oral medicines. Lysodren (also known as mitotane), ketoconazole, L-deprenyl (anipryl), and trilostane are a few of the currently available medications used to treat Cushing's disease in animals (Foster 2006).
Cushing's syndrome is also found in horses, in which treatment is considered to be difficult and lacking any economical or practical cure.
See also
ReferencesISBN links support NWE through referral fees
- Cushing, H. W. 1932. The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). Bulletin of Johns Hopkins Hospital 50:137–195.
- Endocrine and Metabolic Diseases Information Service. 2002. Cushing's Syndrome. NIH Publication No. 02–3007, June 2002. (See external link below).
- Foster and Smith. 2006. Cushing's Disease (Hyperadrenocorticism). Veterinary & Aquatic Services Department, PetEducation.com. http://www.peteducation.com/article.cfm?articleid=416
- Nelson, D. H., J. W. Meakin, and G. W. Thorn. 1960. ACTH-producing tumors following adrenalectomy for Cushing's syndrome. Ann Intern Med 52:560–569. PMID 14426442.
- Raff, H., and J. W. Findling. 2003. A physiologic approach to diagnosis of the Cushing syndrome. Ann Intern Med 138:980–991. PMID 12809455.
- Silverthorn, D. 2004. Human Physiology, An Integrated Approach with Interactive Physiology, 3rd ed. San Francisco: Benjamin Cummings. ISBN 0131020153
- Wyngaarden, J. B., and L. H. Smith. 1982. Cecil Textbook of Medicine, 16th ed. Philadelphia: W. B. Saunders Company. ISBN 072169621X
External links
All links retrieved January 12, 2024.
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