The adrenals are two glands, each 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. The pituitary gland releases a hormone called Adrenocorticotropic Hormone (ACTH) which travels through the bloodstream to the adrenal cortex, where it encourages the production and release of cortisol and other steroid hormones.

Cortisol is a very potent hormone belonging to a class of hormones called steroids. It is involved in regulating the functioning of nearly every type of organ and tissue throughout the body, and is considered to be one of the few hormones absolutely necessary for life. Cortisol is involved in:

The very complex processing and utilization of many nutrients, including sugars (carbohydrates), fats, and proteins
The normal functioning of the circulatory system and the heart
The functioning of muscles
Normal kidney function
Production of blood cells
The normal processes involved in maintaining the skeletal system
Proper functioning of the brain and nerves
The normal responses of the immune system.

Cushing's syndrome results in too much cortisol production, which has an adverse effect on all of the processes described above. Cushing's syndrome occurs in about 10-15 of every one million people per year, usually striking adults between the ages of 20-50.

Causes & symptoms

Cushing's syndrome can be caused by four 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 over-producing cortisol
The use of steroid-containing medications.

The most common cause of Cushing's syndrome is the development of a non-cancerous tumor in the pituitary (called a pituitary adenoma). This adenoma produces overly-large quantities of ACTH, which causes increased growth of the adrenal cortex (hyperplasia) and increased cortisol production. This situation is referred to as Cushing's disease.

Some tumors in locations other than the pituitary can also produce ACTH. This is called Ectopic ACTH syndrome ("ectopic" is a word that describes something being 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, and the thyroid.

Tumors within the adrenal gland are also a cause of Cushing's syndrome. Nearly all of these are non-cancerous adrenal adenomas, although very rarely a tumor may actually be cancerous.

Steroid medications, such as prednisone, are used in a number of conditions which have inflammation as a central process. Such conditions include rheumatoid arthritis, asthma, vasculitis, lupus, and a variety of other autoimmune disorders in which the body's immune cells are accidentally attacking some part of the body itself; in this situation, steroid medications are used to dampen the immune response, thereby decreasing damage. When steroid medications must be given in large doses, over a long period of time, Cushing's syndrome may develop.

Symptoms of cortisol excess include:

Weight gain, and an abnormal accumulation of fatty pads in the face (creating the distinctive "moon face" of Cushing's); 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 chance of infections
Emotional disturbances, including mood swings, depression, irritability, confusion, or even a complete break with reality (psychosis)
Irregular menstrual periods in women
In men, decreased sex drive and difficulty maintaining an erection
In women, abnormal hair growth (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 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.

Demonstrating cortisol excess is somewhat complicated because cortisol production in a normal individual varies quite widely according to a number of factors (general health status, exposure to infection, activity level, time of day or night). Therefore, simply measuring the quantity of circulating cortisol in a patient's bloodstream is not enough information to warrant a diagnosis of Cushing's syndrome. Instead, efforts are made to suppress the adrenal production of cortisol, by giving the patient a steroid preparation by mouth (called dexamethasone). In a healthy patient, the adrenal glands will recognize that plenty of steroid hormone is present in the blood, and will turn off cortisol production. In a patient with Cushing's syndrome, no such decrease in cortisol production will occur. This is called a dexamethasone suppression test.

Another method of screening for Cushing's syndrome involves measuring the amount of cortisol present in the urine over a 24 hour period. When excess cortisol is present in the bloodstream, excess cortisol is processed by the kidneys and removed as waste in the urine. This 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. 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 excess cortisol has been confirmed, diagnostic efforts shift to determining the source of the increased levels of cortisol. Simply determining the level of ACTH in the bloodstream is not sufficient, because this does not identify the source of the ACTH. Furthermore, tumors have an idiosyncratic pattern of ACTH production, so demonstrating a low or normal level of ACTH does not actually mean that no ACTH-producing tumor exists. A hormone called corticotropin-releasing hormone (CRH) is given to the patient, and blood is drawn to measure the levels of ACTH and cortisol. High levels of ACTH and cortisol usually indicate the presence of a pituitary adenoma.

Another test to distinguish between a pituitary adenoma and an ectopic source of ACTH involves drawing blood directly from veins which drain the pituitary. This requires inserting a tiny, flexible tube through a vein in the upper thigh, and threading it up slowly until it reaches veins in an area of the skull known as the petrosal sinuses. When blood tested from the petrosal sinuses reveals higher ACTH level than does blood drawn from a vein in the arm, the likely diagnosis is a pituitary adenoma. When the two samples show approximately equal levels of ACTH, the diagnosis leans towards ectopic ACTH production.

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. This is because 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. Instead, CT and MRI should be 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. Cancerous adrenal tumors are also removed surgically. 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). 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.

A number of drugs are available which can decrease adrenal production of cortisol. These include mitotane, ketoconazole, metyrapone, trilostane, and aminoglutethimide. These drugs are sometimes given prior to surgery, to begin the efforts to reverse the problems brought on by cortisol excess. These drugs may also need to be given 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 will require short-term treatment with a cortisol-like medication after surgery. Patients who need adrenal surgery may also require steroid replacement. If the entire adrenal gland has been removed, the patient will need to take steroids by mouth 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 will depend on the type of cancer and the extent of its spread.

Key Terms

Adenoma: A type of noncancerous (benign) tumor which often involves the overgrowth of certain cells of the type normally found within glands.
Gland: A collection of cells whose function is to release certain chemicals, or hormones, which are important to the functioning of other, sometimes distantly located, organs or body systems.
Hormone: A chemical produced in one part of the body, which travels to another part of the body in order to exert its effect.
Pituitary: A gland located at the base of the brain, the pituitary produces a number of hormones, including hormones which regulate growth and reproductive function.

For Your Information

Books

DeGroot, Leslie J., ed., et al. "Cushing's syndrome." Endocrinology. Philadelphia: W.B. Saunders Co., 1995.
Williams, Gordon H., and Robert G. Dluhy. "Hyperfunction of the Adrenal Cortex." In Harrison's Principles of Internal Medicine, edited by Anthony S. Fauci, et al. New York: McGraw-Hill, 1998.
Periodicals
Orth, David N. "Cushing's syndrome." The New England Journal of Medicine, 332 (no. 12) (March 23, 1995): 791+.
Sanghani, Prashant. "Pituitary Problems." Chemist and Druggist, 245 (no. 6022) (February 17, 1996): I+.
Utiger, Robert D. "Treatment, and Retreament, of Cushing's Disease." The New England Journal of Medicine, 336 (no. 3) (January 16, 1997): 215+.
Organizations
National Adrenal Disease Foundation. 505 Northern Boulevard, Suite 200, Great Neck, NY 11021. (516)487-4992.

Gale Encyclopedia of Medicine. Gale Research, 1999.

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