Cushing’s syndrome occurs when the body’s tissues are exposed to excessive levels of cortisol for long periods of time. Many people suffer the symptoms of Cushing’s syndrome because they take glucocorticoid hormones such as prednisone for asthma, rheumatoid arthritis, lupus and other inflammatory diseases, or for immunosuppression after transplantation.
Symptoms vary, but most people have upper body obesity, rounded face, increased fat around the neck, and thinning arms and legs. Children tend to be obese with slowed growth rates. Other symptoms appear in the skin, which becomes fragile and thin. It bruises easily and heals poorly. Purplish pink stretch marks may appear on the abdomen, thighs, buttocks, arms and breasts. The bones are weakened, and routine activities such as bending, lifting or rising from a chair may lead to backaches, rib and spinal column fractures. Most people have severe fatigue, weak muscles, high blood pressure and high blood sugar. Irritability, anxiety and depression are common. Women usually have excess hair growth on their faces, necks, chests, abdomens, and thighs. Their menstrual periods may become irregular or stop. Men have decreased fertility with diminished or absent desire for sex.
Others develop Cushing’s syndrome because of overproduction of cortisol by the body. Normally, the production of cortisol follows a precise chain of events. First, the hypothalamus, a part of the brain which is about the size of a small sugar cube, sends corticotropin releasing hormone (CRH) to the pituitary gland. CRH causes the pituitary to secrete ACTH (adrenocorticotropin), a hormone that stimulates the adrenal glands. When the adrenals, which are located just above the kidneys, receive the ACTH, they respond by releasing cortisol into the bloodstream. Cortisol performs vital tasks in the body. It helps maintain blood pressure and cardiovascular function, reduces the immune system’s inflammatory response, balances the effects of insulin in breaking down sugar for energy, and regulates the metabolism of proteins, carbohydrates, and fats. One of cortisol’s most important jobs is to help the body respond to stress. For this reason, women in their last 3 months of pregnancy and highly trained athletes normally have high levels of the hormone. People suffering from depression, alcoholism, malnutrition and panic disorders also have increased cortisol levels. When the amount of cortisol in the blood is adequate, the hypothalamus and pituitary release less CRH and ACTH. This ensures that the amount of cortisol released by the adrenal glands is precisely balanced to meet the body’s daily needs. However, if something goes wrong with the adrenals or their regulating switches in the pituitary gland or the hypothalamus, cortisol production can go awry.
Pituitary adenomas cause most cases of Cushing’s syndrome. They are benign, or non-cancerous, tumors of the pituitary gland which secrete increased amounts of ACTH. Most patients have a single adenoma. This form of the syndrome, known as “Cushing’s disease,” affects women five times more frequently than men.
1. Ectopic ACTH Syndrome
Some benign or malignant (cancerous) tumors that arise outside the pituitary can produce ACTH. This condition is known as ectopic ACTH syndrome. Lung tumors cause over 50 percent of these cases. Men are affected 3 times more frequently than women. The most common forms of ACTH-producing tumors are oat cell, or small cell lung cancer, which accounts for about 25 percent of all lung cancer cases, and carcinoid tumors. Other less common types of tumors that can produce ACTH are thymomas, pancreatic islet cell tumors, and medullary carcinomas of the thyroid.
2. Adrenal Tumors
Sometimes, an abnormality of the adrenal glands, most often an adrenal tumor, causes Cushing’s syndrome. The average age of onset is about 40 years. Most of these cases involve non-cancerous tumors of adrenal tissue, called adrenal adenomas, which release excess cortisol into the blood.
Adrenocortical carcinomas, or adrenal cancers, are the least common cause of Cushing’s syndrome. Cancer cells secrete excess levels of several adrenal cortical hormones, including cortisol and adrenal androgens. Adrenocortical carcinomas usually cause very high hormone levels and rapid development of symptoms.
3. Familial Cushing’s Syndrome
Most cases of Cushing’s syndrome are not inherited. Rarely, 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 pituitary occur. Cushing’s syndrome in MEN I may be due to pituitary, ectopic or adrenal tumors.
Cushing’s syndrome is a hormonal disorder caused by prolonged exposure of the body’s tissues to high levels of the hormone cortisol. Sometimes called “hypercortisolism,” it 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.
Treatment depends on the specific reason for cortisol excess and may include surgery, radiation, chemotherapy or the use of cortisol-inhibiting drugs. If the cause is long-term use of glucocorticoid hormones to treat another disorder, the doctor will gradually reduce the dosage to the lowest dose adequate for control of that disorder. Once control is established, the daily dose of glucocorticoid hormones may be doubled and given on alternate days to lessen side effects.
Several therapies are available to treat the ACTH-secreting pituitary adenomas of Cushing’s disease. The most widely used treatment is surgical removal of the tumor, known as transsphenoidal adenomectomy. Using a special microscope and very fine instruments, the surgeon approaches the pituitary gland through a nostril or an opening made below the upper lip. Because this is an extremely delicate procedure, patients are often referred to centers specializing in this type of surgery. The success, or cure, rate of this procedure is over 80 percent when performed by a surgeon with extensive experience. If surgery fails, or only produces a temporary cure, surgery can be repeated, often with good results. After curative pituitary surgery, the production of ACTH drops two levels below normal. This is a natural, but temporary, drop in ACTH production, and patients are given a synthetic form of cortisol (such as hydrocortisone or prednisone). Most patients can stop this replacement therapy in less than a year.
For patients in whom transsphenoidal surgery has failed or who are not suitable candidates for surgery, radiotherapy is another possible treatment. Radiation to the pituitary gland is given over a 6-week period, with improvement occurring in 40 to 50 percent of adults and up to 80 percent of children. It may take several months or years before patients feel better from radiation treatment alone. However, the combination of radiation and the drug mitotane (Lysodren®) can help speed recovery. Mitotane suppresses cortisol production and lowers plasma and urine hormone levels. Treatment with mitotane alone can be successful in 30 to 40 percent of patients. Other drugs used alone or in combination to control the production of excess cortisol are aminoglutethimide, metyrapone, trilostane and ketoconazole. Each has its own side effects that doctors consider when prescribing therapy for individual patients.
Ectopic ACTH Syndrome
To cure the overproduction of cortisol caused by ectopic ACTH syndrome, it is necessary to eliminate all of the cancerous tissue that is secreting ACTH. The choice of cancer treatment—surgery, radiotherapy, chemotherapy, immunotherapy, or a combination of these treatments—depends on the type of cancer and how far it has spread. Since ACTH-secreting tumors (for example, small cell lung cancer) may be very small or widespread at the time of diagnosis, cortisol-inhibiting drugs, like mitotane, are an important part of treatment. In some cases, if pituitary surgery is not successful, surgical removal of the adrenal glands (bilateral adrenalectomy) may take the place of drug therapy.
Surgery is the mainstay of treatment for benign as well as cancerous tumors of the adrenal glands. In Primary Pigmented Micronodular Adrenal Disease and the familial Carney’s complex, surgical removal of the adrenal glands is required.