Cushing's syndrome
Cushing's syndrome, or hypercortisolism, is an endocrine disorder caused by the presence of excessive levels of cortisol in the body. It is named after the American surgeon Dr. Harvey Cushing, who first described the condition in 1932. Cushing's syndrome is relatively rare and most commonly affects adults aged 20 to 50. An estimated 10 to 15 of every million people are affected each year.
Cushing's syndrome implies a disorder in the regulation of cortisol or ACTH secretion, which can both 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, 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. When the adrenal glands, which are located above the kidneys, receive the ACTH, they respond by releasing cortisol 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 or non- cancerous (benign). These tumors are described as primary hypersecretions. Second, some benign or malignant (cancerous) tumors that arise outside the anterior pituitary can produce ACTH. This condition is known as ectopic ACTH syndrome. Lung tumors cause over 50 percent of these cases. Men are affected three times more frequently than women. Third, anterior pituitary malfunctions can cause increased ACTH secretion which in turn stimulates the secretion of cortisol by the adrenal glands. This condition is referred to specifically as Cushing's disease and is referred to as a secondary hypersecretion. It affects women five times more frequently than men.
Although family hereditary can play a part in the onset of the syndrome, it is very rare. However, some individuals have special causes of Cushing's syndrome due to an inherited tendency 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 or adrenal tumors.
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 throuh a variety of mechanisms. Cortisol promotes gluconeogenesis (glucose production) in the liver, causes the breakdown of skeletal muscle proteins to provide amino acids for gluconeogenesis, suppresses the immune system by 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.
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).
In patients with Cushing's syndrome, symptoms include mimicked diabetes due to excess gluconeogenesis, and tissue wasting occurs as muscle protein is broken down for glucose production. 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." Extremeties are usually thin, 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. Atropy of the skin occurs as the skin becoming thin, fragile, and easily bruised.
Untreated Cushing's syndrome can lead to heart disease and increased mortality, or death.
Diagnosis
When Cushing's is suspected, a dexamethasone suppression test (administration of dexamethasone and frequent determination of cortisol and ACTH levels) and 24-hour urinary measurement for cortisol have equal detection rates (Raff & Findling 2003). A novel approach is sampling cortisol in saliva over 24 hours, which may be equally sensitive. Other pituitary hormones may need to be determined, and performing physical examination directed for any visual field defect may be necessary if a pituitary lesion is suspected (which may compress the optic chiasm causing typical bitemporal hemianopia).
When these tests are positive, CT scanning of the adrenal gland and MRI of the pituitary gland are performed. These should be performed when other tests are positive, to decrease likelihood of incidentalomas (incidental discovery of harmless lesions in both organs). 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 catheterisation working towards the pituitary (petrosal sinus sampling) is necessary.
Pathophysiology
Cortisol is secreted by the adrenal glands under regulation by the pituitary gland and hypothalamus. Strictly, Cushing's syndrome refers to excess cortisol of any etiology. Cushing's disease refers only to hypercortisolism secondary to excess production of adrenocorticotropin (ACTH) from a pituitary gland adenoma. More recently the US FDA has cleared a new enzyme-linked immunosorbent assay testing levels of salivary cortisol. Late night salivary levels of cortisol are elevated in patients with Cushing's syndrome.
Therapy
If an adrenal adenoma is identified it may be removed by surgery. Pituitary ACTH producing 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 (Nelson et al 1960).
In iatrogenic Cushing's, dose adjustment may be sufficient or it may be necessary to change to another type of immunosuppresive medication.
Epidemiology
Iatrogenic Cushing's syndrome (caused by treatment with corticosteroids) is the most common form of Cushing's syndrome. Endogenous (i.e. non-iatrogenic) Cushing's syndrome is relatively rare.
Incidence of causes of Cushing's syndrome per million person-years:
- Cushing's disease: 10
- Primary adrenal: 3
- Ectopic ACTH: 1.4
See also
ReferencesISBN links support NWE through referral fees
- Cushing HW. The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). Bull Johns Hopkins Hosp 1932;50:137-195.
- Nelson DH, Meakin JW, Thorn GW. ACTH-producing tumors following adrenalectomy for Cushing's syndrome. Ann Intern Med 1960;52:560–569. PMID 14426442.
- Raff H, Findling JW. A physiologic approach to diagnosis of the Cushing syndrome. Ann Intern Med 2003;138:980-91. PMID 12809455.
External links
- Cushing's Syndrome
- Cushing's information at Oregon Health Sciences University
- Cushing's doctors
- Cushing's syndrome
- Cushing's Syndrome and Cushing's Disease
- Cushing's Syndrome mailing list
- Cushing's Disease (from Pituitary Foundation UK)
- Cushing's Syndrome/Disease in dogs
- Cushing Syndrome information at Merck.com
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