Cushing's syndrome is a disorder caused by elevated levels of cortisol in blood and the normal level of cortisol may rise either by the intake of glucocorticoid drugs or by tumors that result in excessive secretion of cortisol or adrenocorticotrophic hormone (ACTH). Truly speaking Cushing's disease is the result of a tumor in the pituitary gland that causes excessive secretion of ACTH which in turn elevates the level of cortisol. About 70% of the patients suffering from this disease get affected due to the tumors and rest 30% suffer from the disease because of the intake of glucocorticod drugs. The pathology of the disease was first studied in detail by Harvey Cushing in 1932. The syndrome is also known as Itsenko-Cushing syndrome or hypercorticism. This syndrome is not only confined to humans only but has also been identified in domestic dogs, horses and rarely in cats. The syndrome should not be confused with a clinical condition identified as Cushing's triad where the intracranial pressure increases enormously. The disease is known to affect the individuals of the age group 20-50. According to a report about 10-15 million individuals suffer from Cushing's syndrome every year.
Individuals suffering from Cushing's syndrome may develop moon-like faces, facial plethora, supraclavicular fat pads, buffalo hump, truncal obesity and purple striae. They often complain of proximal muscle weakness, easy bruising, weight gain, hirsutism and growth retardation in children. Hypertension, osteopenia, diabetes mellitus and impairment of the immune system are other common symptoms. Excessive intake of exogenous glucocorticoids is also responsible for this syndrome. Exogenous steroids results in suppression of the hypothalamic-pituitary-adrenal axis. An individual with suppressed hypothalamic-pituitary-adrenal axis may not be able to increase steroid production appropriately during a medical illness or stress so requires exogenous doses of steroids to avoid adrenal crisis.
The most frequently observed symptoms of Cushing's syndrome include rapid weight gain particularly of the trunk and face with sparing of the limbs. A very common sign is the development of fat pads around the collar bone, on the back of the neck and a round face also known as moon face. Other symptoms include excessive sweating or hyperhidrosis, dilation of capillaries (telangiectasia), thinning of skin and other mucous membranes, purple or red striae on the trunk, buttocks, arms, legs or breasts, proximal muscle weakness, hirsutism, baldness or brittle hairs. The rare symptoms include hypercalcemia that causes skin necrosis. Excessive secretion of cortisol also affects other endocrine systems and causes insomnia, inhibited aromatase, reduced libido, impotence, amenorrhea and infertility due to elevations in androgens. Patients also suffer from psychological disturbances that may range from euphoria to psychosis. Depression and anxiety are other common symptoms. The most striking and remarkable skin changes include facial acne, susceptibility to superficial dermatophyte and malassezia infections and characteristic purplish striae on abdomen.
Other noticeable symptoms include polyuria, persistent hypertension and insulin resistance that cause hyperglycemia and diabetes mellitus. Insulin resistance is accompanied by skin changes like acanthosis nigricans in axilla and around the neck as well as skin tangs in axilla. If left untreated Cushing's syndrome results in the development of heart disease and chances of death increase. Excessive secretion of ACTH causes hyper-pigmentation. Hyper-pigmentation is the due to the activity of Melanocyte Stimulating Hormone (MSH) which is produced as a byproduct from ACTH synthesis. This hormone is formed from Pro-opiomelanocortin (POMC). Cortisol also participates in the exhibition of activity of the mineralocorticoids in high concentrations and causing hypertension and hyperkalemia. Gastrointestinal disturbances, infections and impaired wound healing are the other symptoms of this syndrome. Osteoporosis is also a symptom associated with Cushing's syndrome. Bone loss also occurs and bones of lower back, hip and shoulders also start paining. Cortisol level can also increase due to intake of estrogen in the contraceptive pills that contain a blend of estrogen and progesterone. Estrogen is responsible for the increase of cortisol-binding globulin that is responsible for the elevated level of cortisol.
When body tissues are exposed to elevated levels of cortisol for prolonged period of time then Cushing's syndrome occurs. Many individuals suffer from this syndrome as they consume exogenous glucocorticoid hormones namely prednisone for asthma, rheumatoid arthritis, lupus and other inflammatory diseases. Rest of the individuals develops this syndrome due to overproduction of cortisol by the body. A chain of events generally occur inside the body that finally results in the formation of cortisol. Hypothalamus is a very important part of brain which is about the size of a sugar cube sends corticotrophin releasing hormone (CRH) to the pituitary gland. This CRH stimulates pituitary gland which in turn releases the adrenocorticotrophic hormone (ACTH) that finally acts on the adrenal glands. Adrenal glands are small glands located just above the kidneys and when they are stimulated by the action of ACTH they release cortisol in the bloodstream. Cortisol has a number of important functions to perform inside the body. It maintains blood pressure and cardiovascular function, reduces immune system's inflammatory response and regulates the metabolism of proteins, carbohydrates and fats.
Cortisol also helps the body to respond to stress. For this reason, women in last 3 months of pregnancy and the highly trained athletes normally have high levels of cortisol. People suffering from depression, alcoholism, malnutrition and panic disorders also have elevated levels of this hormone. When the level of this hormone is adequate in blood then, the hypothalamus and pituitary release less CRH and ACTH. This confirms that cortisol released by the adrenal glands is precisely balanced to meet body's requirements. However, if something wrong happens either with adrenal glands, hypothalamus or pituitary glands then this balance may experience fluctuations. Pituitary adenomas are responsible for most of the cases of Cushing's syndrome. These adenomas are benign, non-cancerous, tumors of pituitary glands that result in excessive secretion of ACTH. Most patients have a single adenoma. This type of Cushing's syndrome is five times more frequent in women as compared to that in men. Some benign or malignant tumors that arise outside the pituitary gland can also produce ACTH and this condition is identified as ectopic ACTH syndrome. Lung tumors are associated with 50% of such cases and men are affected three times more than women. The most common forms of ACTH-producing tumors are oat cell, small cell lung cancer or carcinoid tumors and they account for 25% of lung cancer cases. Other types of tumors that also result in the production of ACTH are pancreatic islet cell tumors, medullary carcinomas of thyroid and thymomas.
Sometimes abnormalities may also take place in the adrenal glands and Cushing's syndrome may occur. This condition generally crops up in the individuals of 40 years of age. Most of these cases involve non-cancerous tumors of adrenal tissues known as adrenal adenomas that are responsible for excessive secretion of cortisol in the bloodstream. Adrenal cancers rarely result in the development of Cushing's syndrome. Cancer cells result in excessive secretion of cortisol and adrenal androgens. Most of the cases of this syndrome are not inherited at all. In very rare cases of Cushing's syndrome individuals have inherited tendency of developing tumors of one or more endocrine glands. In Primary Pigmented Micronodular Adrenal Disease children or young individuals develop small cortisol-producing tumors of the adrenal glands. In Multiple Endocrine Neoplasia Type I (MEN I) hormone secreting tumors of parathyroid glands, pancreas and pituitary occur. Cushing's syndrome in MEN I may occur due to pituitary, ectopic or adrenal tumors.
Pituitary gland is located just beneath the hypothalamus and both these essential structures are finally present in the brain. The paraventricular nucleus (PVN) of hypothalamus is responsible for the production of corticotropin-releasing hormone (CRH) which in turn stimulates the pituitary gland to release adrenocorticotropin (ACTH). ACTH travels via blood and reaches the adrenal glands which get activated and release cortisol. The zona fasciculata of the cortex of the adrenal gland respond to ACTH and finally release cortisol. Elevated levels of cortisol exhibit a negative feedback on the pituitary which finally decreases the secretion of ACTH. Adenoma in the cortex of the adrenal glands is also responsible for the excessive secretion of cortisol which is one of the causes responsible for Cushing's syndrome. Adenoma causes the cortisol level to become very high and the levels of ACTH are also very low. This syndrome only refers to hypercortisolism where the ACTH levels become very high along with elevated levels of cortisol in the blood. The levels of ACTH are very high because a tumor in the pituitary gland makes it unresponsive to the negative feedback against the elevated levels of cortisol. This disease was the first autoimmune disease discovered in humans.
Diagnosis of Cushing's syndrome is based on the patient's medical history, physical examination and laboratory tests. Tumors of the adrenal and pituitary gland can be detected by using X-rays. These tests can help a medical expert to identify if the blood cortisol levels are high and why this is so. The 24-hour urinary level free cortisol level test is the most appropriate diagnostic test. In this test as the name indicates urine of the patient is collected after an interval of 24 hours and then levels of cortisol are checked. If the amount of cortisol is higher than 50-100 micrograms within an interval of 24 hour then the individual is at the risk of suffering from this syndrome. The level of cortisol may vary depending upon the techniques utilized. Once Cushing's syndrome is diagnosed other tests are required to locate the exact regions that are associated with the abnormality that results in excessive cortisol production. These tests are based on the choice of the endocrinologist. Dexamethasone suppression test is another test that can be performed. This test helps to distinguish patients with excessive production of ACTH due to pituitary adenomas from those with ectopic-ACTH producing tumors. Here the patients are given a synthetic glucocorticoid known as dexamethasone orally for every 6 hours for 4 days. For the first two days the dose of this compound are kept low while it is increased to higher ones on the last two days. 24-hour urine samples are also collected before the administration of this compound.
Cortisol and other glucocorticoids signal the pituitary gland for lowering the secretion of ACTH in blood so the normal response after taking dexamethasone is a drop in blood and urine of cortisol levels. Different responses of cortisol to dexamethasone are noticed depending upon the cause of Cushing's syndrome either by pituitary adenoma or ectopic ACTH-producing tumor. The dexamethasone suppression test can give false results for the patients suffering from depression, high estrogen levels, alcohol abuse, stress and acute illness. Drugs namely phenytoin and phenobarbital may also give false results in response to this compound. So the physicians advise the patients to stop the usage of these drugs one week before undergoing dexamethasone suppression test. CRH stimulation test helps to distinguish between patients with pituitary adenomas or those with ectopic ACTH-producing tumor and cortisol-secreting adrenal tumors. Patients are given injections of cortiocotropin releasing hormone which in turn is responsible for the secretion of ACTH from the pituitary glands in blood. Patients with pituitary adenomas generally experience very high levels of ACTH and cortisol in blood. This response is generally rarely seen in the patients with ectopic ACTH syndrome and never in patients with cortisol-secreting adrenal tumors.
Direct visualization of endocrine glands or radiologic imaging helps in the identification of shape and size of pituitary and adrenal glands. These techniques help to detect if any tumor is present. The most common techniques used are computerized tomography scan and magnetic resonance imaging. Computerized tomography actually produces a series of X-ray images that imparts a cross-sectional image of any part of body. Magnetic resonance imaging also generates images of body parts but no ionizing radiation is used. The imaging techniques are generally used for the detection of tumor once Cushing's syndrome is finally diagnosed. These techniques are not used for the diagnosis of Cushing's syndrome. Petrosal sinus sampling is another test that is not always used but can be used for the separation of pituitary from the ectopic causes of Cushing's syndrome. Petrosal sinuses are actually the veins that drain blood to the pituitary glands so blood samples are taken from them by the introduction of catheters by using local anesthesia and mild sedation. X-rays are often used for the detection of the correct position of the catheters. To improve the diagnostic accuracy injections of CRH are often given. The levels of ACTH in the petrosal sinuses are measured and then they are compared with the ACTH levels in a forearm vein. Higher levels of ACTH in the petrosal sinuses than in the forearm vein is indicative of the presence of pituitary adenoma and if the levels are similar then ectopic ACTH-syndrome is present.
Some individuals have elevated cortisol levels but do not show progressive effects of Cushing's syndrome like muscle weakness, fractures and thinning of skin. These individuals may be suffering from pseudo-Cushing's syndrome which was originally described in people who were depressed or alcohol addict. These individuals do not show long term effects shown by individuals with Cushing's syndrome so they do not require direct treatment of the endocrine glands. Generally dexamethasone-CRH test is performed to distinguish patients of pseudo-Cushing's syndrome from those with Cushing's syndrome. This test combines dexamethasone suppression and CRH stimulation tests. Elevated levels of cortisol suggest the presence of this disease. Some individuals may have substantially high levels of cortisol but they do not show effects of this syndrome. The high cortisol levels may be compensating for body's resistance for cortisol effects. This rare syndrome of cortisol resistance is a genetic state that results in hypertension and chronic androgen excess. Sometimes other conditions may be associated with this disease like the polycystic ovarian syndrome that causes menstrual disturbances, weight gain from adolescence, excessive hair growth and sometimes diabetes. Generally weight gain, high blood pressure, abnormal levels of cholesterol and triglycerides are associated with resistance to insulin action and diabetes often described as Metabolic Syndrome X. Patients with this disorder generally do not have elevated levels of cortisol.
The common treatments available for Cushing's syndrome include surgery, radiation, chemotherapy or use of cortisol-inhibiting drugs. A number of therapies are available to treat the ACTH-secreting adenomas of Cushing's syndrome. The most commonly used treatment is the surgical removal of the tumor known as transsphenoidal adenomectomy. In this process the surgeon approaches the pituitary gland either through the nostril or through an opening made below the upper lip. Very fine instruments and special kind of microscope required for this purpose. As this surgery is very complicated so the patients are advised to consult the specialized centers only. The success rate of the surgery is 80% if carried out by an experienced surgeon. If surgery fails or only temporary cure is achieved then it can be repeated in order to obtain good results. After the successful pituitary surgery the elevated levels of ACTH drop two times lower as compared to the normal level. This is a natural but temporary drop in the level of ACTH and the patients are given synthetic form of cortisol. This replacement therapy can be stopped in most of the patients within an interval of one year.
Patients who fail to give promising results to transsphenoidal adenomectomy or candidates who are not suitable candidates for surgery, radiotherapy is a promising treatment. Radiation to the pituitary gland is generally given at an interval of 6 weeks. The chances of success range from 50-80% in both adults and children. A combination of radiotherapy and a drug known as mitotane helps in faster recovery. Mitotane suppresses cortisol production and thereby brings a decline in the plasma and urine hormone levels. Mitotane has shown 30-40% better results in the patients with Cushing's syndrome. To cure the overproduction of cortiol due to ectopic ACTH syndrome, it is always beneficial to remove all the cancerous tissue that produces ACTH. Surgery, chemotherapy, radiotherapy, immunotherapy or a combination of these therapies can help in removal of cancerous tissue. The ACTH-secreting tumors may be very small or widespread at the time of diagnosis so mititane is a promising drug that can be administered for better results. In some cases if the pituitary surgery is not successful then surgical removal of the adrenal glands may replace the drug therapy. Surgery is the only treatment available for the benign and cancerous tumors of adrenal glands. Primary Pigmented Micronodular Adrenal Disease and the familial Carney's complex require surgical removal of adrenal glands.
Iatrogenic Cushing's syndrome is the most common form of Cushing's syndrome which is generally caused by treatment with corticosteroids. The incidence of the pituitary tumors may be relatively high but only a minute fraction of them are active and result in excessive hormone secretion. Adults with this disease may show symptoms like extreme weight gain, excessive hair growth in women, high blood pressure and skin problems. Additional symptoms may include muscle and bone weakness, osteoporosis, diabetes mellitus, hypertension, sleep disturbances, moodiness, irritability and depression followed by amenorrhea in women, decreased fertility in men, baldness and hypercholesterolemia. Most of the cases of Cushing's syndrome are due to the action of exogenous glucocorticoids. About 13 cases per million individuals are diagnosed every year that are due to the endogenous reasons. Of these 70% of cases are due to ACTH-producing tumor, 15% due to ectopic-ACTH and 15% due to primary adrenal tumor.
Mortality and morbidity associated with Cushing's syndrome are primarily due to the effects caused by excessive levels of glucocorticoids. A very large pituitary tumor may cause panhypopituitarism and visual loss. Rare adrenocortical adenomas are also associated with a survival rate of only 5 years. Excess glucocorticoids also cause perforated viscera and increased susceptibility to fungal infections. Other additional problems that crop up due to excessive glucocorticoids include hypertension, obesity, osteoporosis, fractures, impaired immune function, impaired woun healing, glucose intolerance and psychosis. The female-to-male ratio of Cushing's syndrome is 5:1 which may be either due to pituitary or adrenal tumor. Ectopic ACTH production is more frequent in men than women due to increased incidence of lung tumors in them. The peak period of occurrence of Cushing's syndrome due to adrenal or pituitary adenoma is 25-40 years. Ectopic production due to lung cancer may occur in later phase of life. For keeping a regular check on Cushing's syndrome patients should be educated about adrenal crisis. Instruction for the intake f specific drug for treatment should be given.
Navodita Maurice
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