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Acromegaly

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Causes of Acromegaly

Acromegaly is caused by prolonged overproduction of growth hormone (GH) by the pituitary gland. The pituitary produces several important hormones that control body functions such as growth and development, reproduction, and metabolism. But hormones never seem to act simply and directly. They usually "cascade" or flow in a series, affecting each other's production or release into the bloodstream.

Growth hormone (GH) is part of a cascade of hormones that, as the name implies, regulates the physical growth of the body. This cascade begins in a part of the brain called the hypothalamus. The hypothalamus makes hormones that regulate the pituitary. One of the hormones in the growth hormone (GH) series, or "axis," is growth hormone-releasing hormone (GHRH), which stimulates the pituitary gland to produce growth hormone (GH).

Secretion of growth hormone (GH) by the pituitary into the bloodstream stimulates the liver to produce another hormone called insulin-like growth factor I (IGF-I). Insulin-like growth factor I (IGF-I) is what actually causes tissue growth in the body. High levels of insulin-like growth factor I (IGF-I), in turn, signal the pituitary to reduce growth hormone (GH) production.

The hypothalamus makes another hormone called somatostatin, which inhibits growth hormone (GH) production and release. Normally, growth hormone-releasing hormone (GHRH), somatostatin, growth hormone (GH), and insulin-like growth factor I (IGF-I) levels in the body are tightly regulated by each other and by sleep, exercise, stress, food intake, and blood sugar levels. If the pituitary continues to make growth hormone (GH) independent of the normal regulatory mechanisms, the level of insulin-like growth factor I (IGF-I) continues to rise, leading to bone overgrowth and organ enlargement. High levels of insulin-like growth factor I (IGF-I) also cause changes in glucose (sugar) and lipid (fat) metabolism and can lead to diabetes, high blood pressure, and heart disease.

Pituitary Tumors
In more than 95 percent of people with acromegaly, a benign tumor of the pituitary gland, called an adenoma, produces excess growth hormone (GH). Pituitary tumors are labeled either micro- or macro-adenomas, depending on their size. Most GH-secreting tumors are macro-adenomas, meaning they are larger than 1 centimeter. Depending on their location, these larger tumors may compress surrounding brain structures. For example, a tumor growing upward may affect the optic chiasm - where the optic nerves cross - leading to visual problems and vision loss. If the tumor grows to the side, it may enter an area of the brain called the cavernous sinus where there are many nerves, potentially damaging them.

Compression of the surrounding normal pituitary tissue can alter production of other hormones. These hormonal shifts can lead to changes in menstruation and breast discharge in women and erectile dysfunction in men. If the tumor affects the part of the pituitary that controls the thyroid - another hormone-producing gland - then thyroid hormones may decrease. Too little thyroid hormone can cause weight gain, fatigue, and hair and skin changes. If the tumor affects the part of the pituitary that controls the adrenal gland, the hormone cortisol may decrease. Too little cortisol can cause weight loss, dizziness, fatigue, low blood pressure, and nausea.

Some GH-secreting tumors may also secrete too much of other pituitary hormones. For example, they may produce prolactin, the hormone that stimulates the mammary glands to produce milk. Rarely, adenomas may produce thyroid-stimulating hormone. Doctors should assess all pituitary hormones in people with acromegaly.

Rates of growth hormone (GH) production and the aggressiveness of the tumor vary greatly among people with adenomas. Some adenomas grow slowly and symptoms of growth hormone (GH) excess are often not noticed for many years. Other adenomas grow more rapidly and invade surrounding brain areas or the venous sinuses, which are located near the pituitary gland. Younger patients tend to have more aggressive tumors. Regardless of size, these tumors are always benign.

Most pituitary tumors develop spontaneously and are not genetically inherited. They are the result of a genetic alteration in a single pituitary cell, which leads to increased cell division and tumor formation. This genetic change, or mutation, is not present at birth, but happens later in life. The mutation occurs in a gene that regulates the transmission of chemical signals within pituitary cells. It permanently switches on the signal that tells the cell to divide and secrete growth hormone (GH). The events within the cell that cause disordered pituitary cell growth and growth hormone (GH) oversecretion currently are the subject of intensive research.

Nonpituitary Tumors
Rarely, acromegaly is caused not by pituitary tumors but by tumors of the pancreas, lungs, and other parts of the brain. These tumors also lead to excess growth hormone (GH), either because they produce growth hormone (GH) themselves or, more frequently, because they produce growth hormone-releasing hormone (GHRH), the hormone that stimulates the pituitary to make growth hormone (GH). When these nonpituitary tumors are surgically removed, growth hormone (GH) levels fall and the symptoms of acromegaly improve.

In patients with GHRH-producing, nonpituitary tumors, the pituitary still may be enlarged and may be mistaken for a tumor. Physicians should carefully analyze all "pituitary tumors" removed from patients with acromegaly so they do not overlook the rare possibility that a tumor elsewhere in the body is causing the disorder.

References:
National Endocrine and Metabolic Diseases Information Service
NIH Publication No. 07-3924
April 2007
www.endocrine.niddk.nih.gov/pubs/acro/acro.htm

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