Acromegaly is a hormonal disorder that results when a pituitary adenoma produces excess growth hormone (GH). It most commonly affects middle-aged adults and can result in serious illness and premature death.

Overgrowth of bone and cartilage often leads to arthritis. When tissue thickens, it may trap nerves, causing carpal tunnel syndrome, characterized by numbness and tingling of the hands. Other symptoms of acromegaly include thick, coarse, oily skin; skin tags; enlarged lips, nose and tongue; deepening of the voice due to enlarged sinuses and vocal cords; snoring due to upper airway obstruction; excessive sweating and skin odor; fatigue and weakness; headaches; and impaired vision. There may also be abnormalities of the menstrual cycle in women and erectile dysfunction in men. There may be enlargement of body organs, including the liver, spleen, kidneys and heart.

Acromegaly is caused by prolonged overproduction of GH by a pituitary adenoma, a benign tumor of the pituitary gland. The pituitary is a small gland at the base of the brain that produces several important hormones which control body functions including growth and development, reproduction, and metabolism. 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, which makes hormones that regulate the pituitary. One of these, growth hormone-releasing hormone (GHRH), stimulates the pituitary gland to produce GH. Another hypothalamic hormone, somatostatin, inhibits GH production and release.

Secretion of GH by the pituitary into the bloodstream causes the production of another hormone, called insulin-like growth factor 1 (IGF-1), in the liver. IGF-1 is the factor that actually causes the growth of bones and other tissues of the body. GHRH, somatostatin, GH, and IGF-1 levels in the body are tightly regulated by each other and by sleep, exercise, stress, food intake and blood sugar levels. If a pituitary tumor continues to make GH independent of the normal regulatory mechanisms, the level of IGF-1 continues to rise, leading to bone growth and organ enlargement. The excess GH also causes changes in sugar and lipid metabolism and can cause diabetes.

In almost all patients with acromegaly, the overproduction of GH is caused by a benign tumor of the pituitary gland, called an adenoma. These tumors produce excess GH and, as they expand, compress surrounding brain tissues, such as the optic nerves. This expansion causes the headaches and visual disturbances that are often symptoms of acromegaly. In addition, compression of the surrounding normal pituitary tissue can alter production of other hormones, leading to changes in menstruation and erectile dysfunction.

There is a marked variation in rates of GH production and the aggressiveness of the tumor. Some adenomas grow slowly, and the symptoms of GH excess are often not noticed for many years. Other adenomas grow rapidly and invade surrounding brain areas or the sinuses, which are located near the pituitary.

In general, younger patients tend to have more aggressive tumors.

Most pituitary tumors arise spontaneously and are not genetically inherited. Many pituitary tumors arise from 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 is acquired during 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 GH. The events within the cell that cause disordered pituitary cell growth and GH over secretion currently are the subject of intensive research. There are rare genetic syndromes in which the predisposition to acromegaly is inherited. There are also extraordinarily rare tumors occurring elsewhere in the body which can also lead to acromegaly.

The most serious health consequences of acromegaly are diabetes mellitus, hypertension, and increased risk of cardiovascular disease. Patients with acromegaly are also at increased risk for polyps of the colon that can develop into cancer. Other serious complications can include arthritis and sleep apnea. Patients with untreated acromegaly have an increased mortality rate of about 2-3 times that of the general population. With successful treatment, many of these complications improve or resolve, and life expectancy normalizes.

If a doctor suspects acromegaly, he or she may measure the GH level in the blood after a patient has fasted overnight to determine if it is elevated. However, a single measurement of an elevated blood GH level is not enough to diagnose acromegaly, because GH is secreted by the pituitary in pulses, and its concentration in the blood can vary widely from minute to minute. At a given moment, a patient with acromegaly may have a normal GH level, whereas a GH level in a healthy person may be high.

Because of these challenges, more accurate information can be obtained when GH is measured under conditions in which GH secretion is normally suppressed. Physicians often use the oral glucose tolerance test to diagnose acromegaly, because ingestion of sugar should lower blood GH levels in healthy people. In patients with acromegaly, this reduction does not occur. The glucose tolerance test is a reliable method of confirming a diagnosis of acromegaly.

Another excellent way to determine whether a patient has acromegaly is to measure an IGF-1 level. Elevated GH levels increase IGF-1 blood levels. Because IGF-1 levels are much more stable over the course of the day, they are often a more practical and reliable measure than GH levels. Elevated IGF-1 levels almost always indicate acromegaly, with some exceptions such as pregnancy.

After acromegaly has been diagnosed, magnetic resonance imaging (MRI) scans of the pituitary are used to locate the pituitary adenoma that causes the GH overproduction.

The goals of treatment are to reduce GH production to normal levels, to relieve the pressure that the growing pituitary tumor exerts on the surrounding brain areas, to preserve or restore normal pituitary function, and to reverse or improve the symptoms of acromegaly. Currently, treatment options include surgical removal of the tumor, drug therapy, and radiation therapy of the pituitary tumor.

No single treatment is effective for all patients. Treatment should be individualized depending on patient characteristics, such as age and tumor size. Removal of the pituitary adenoma by an experienced neurosurgeon is usually first-line therapy. If surgery does not normalize hormone levels or a relapse occurs, treatment with medications is usually an option. Medications that are used to treat acromegaly include cabergoline (a dopamine agonist), octreotide and lanreotide (somatostatin agonists) and pegvisomant (a GH receptor antagonist). Although these medications help to control the disease, none of these medications are curative, and long-term therapy is necessary. In some patients who are not surgical candidates, medication can be used as first-line treatment. Radiation therapy is another option for patients who do not respond adequately to surgery and medication or who cannot safely undergo surgery.

• SURGERY -- Surgery is a rapid and effective treatment. The surgeon reaches the pituitary through an incision in the nose and, with special tools, removes the tumor tissue in a procedure called transsphenoidal surgery. This procedure promptly relieves the pressure on the surrounding brain regions and leads to a lowering of GH levels. If the surgery is successful, soft tissue swelling improves within a few days. Success depends on the skill and experience of the surgeon and size and location of the tumor. Complications of surgery are rare but may include cerebrospinal fluid leaks, meningitis, or damage to the surrounding normal pituitary tissue, requiring lifelong pituitary hormone replacement.

  Even when surgery is successful and hormone levels return to normal, patients must be carefully monitored for years for possible recurrence. If surgery is not successful at completely normalizing IGF-1 levels, additional treatment is required.

• MEDICATION TREATMENT -- There are a number of medications that are effective treatments in acromegaly. These include:

  • Cabergoline: This is a dopamine agonist which is effective in about 10% of patients. It is an oral medication, usually well tolerated, relatively inexpensive, and most effective in patients with a minimal elevation in IGF-1 levels.

  • Somatostatin analogs, including octreotide, lanreotide, and pasireotide: These are injectable medications that are usually administered monthly at a doctor's office, though lanreotide can be self-injected or injected by a partner in some cases. An oral version of octreotide is also available and is usually considered for patients who have responded well to injectable octreotide or lanreotide.These drugs are effective in up to 50% of patients. They can lower GH and IGF-1 level and also lead to tumor shrinkage.

  • The GH receptor antagonist, pegvisomant: This is also an injectable medication. It is self-injected subcutaneously (just under the skin with a small needle) daily. This medication normalizes the IGF-1 level in approximately 90% of patients. Because it acts on the GH receptor, it does not shrink the tumor, and therefore it is used with caution in large or aggressive tumors. Additional treatment directed at controlling the tumor itself is sometimes required.

    Medical therapy is sometimes used to shrink large tumors before surgery.

• RADIATION TREATMENT -- Radiation can used both as a primary treatment and combined with surgery and/or medications. It is usually reserved for patients who have tumor remaining after surgery who do not respond to medication or who do not wish to take medications lifelong. Radiation treatment does not immediately lower GH or IGF-1 levels, and adjunctive medical therapy is required until hormone levels normalize. Radiation treatment can be given as one dose ("stereotactic radiosurgery") or in multiple small doses over 4-6 weeks ("fractionated treatment"). This treatment normalizes GH and IGF-1 levels in about 50% of patients over 4-5 years. Radiation treatment can cause a gradual loss of production of other pituitary hormones over time, and therefore hormone levels need to be monitored annually by an endocrinologist in all patients who receive radiation. Loss of vision, brain injury, and secondary cancers, which have been reported, are very rare complications of radiation treatments.