Acromegaly

Rondo Hatton, a famous sufferer of acromegaly whose face was distorted by the disorder.

Acromegaly (from Greek akros "high" and megalos "large" - extremities enlargement) is a hormonal disorder that results when the pituitary gland produces excess growth hormone (hGH). Most commonly it is a benign hGH producing tumor derived from a distinct type of cells (somatotrophs) and called pituitary adenoma.

Acromegaly most commonly affects middle-aged adults and can result in serious illness and premature death. Because of its insidious onset and slow progression, the disease is hard to diagnose in the early stages and is frequently missed for many years.

Features that result from high level of hGH or expanding tumor include:

• Soft tissue swelling of the hands and feet (early sign)
• Brow and lower jaw protrusion (enlarging jaw and hat size)
• Enlarging hands (ring size)
• Enlarging feet (shoe size)
• Arthritis and carpal tunnel syndrome
• Teeth spacing increase
• Heart failure (major medical problem)
• Compression of the optic chiasm leading to loss of vision in the outer visual fields
• Diabetes mellitus
• Hypertension

Causes

In over 90 percent of acromegaly patients, 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 breast discharge in women and impotence in men.

There is a marked variation in rates of GH production and the aggressiveness of the tumor. Some adenomas grow slowly and 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 oversecretion currently are the subject of intensive research.

In a few patients, acromegaly is caused not by pituitary tumors but by tumors of the pancreas, lungs, and adrenal glands. These tumors also lead to an excess of GH, either because they produce GH themselves or, more frequently, because they produce GHRH, the hormone that stimulates the pituitary to make GH. In these patients, the excess GHRH can be measured in the blood and establishes that the cause of the acromegaly is not due to a pituitary defect. When these non-pituitary tumors are surgically removed, GH levels fall and the symptoms of acromegaly improve.

In patients with GHRH-producing, non-pituitary tumors, the pituitary still may be enlarged and may be mistaken for a tumor. Therefore, it is important that physicians carefully analyze all "pituitary tumors" removed from patients with acromegaly in order not to overlook the possibility that a tumor elsewhere in the body is causing the disorder.

Treatment

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 normal pituitary function, and to reverse or ameliorate the symptoms of acromegaly. Currently, treatment options include surgical removal of the tumor, drug therapy, and radiation therapy of the pituitary.

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, facial appearance and soft tissue swelling improve within a few days. Surgery is most successful in patients with blood GH levels below 40 ng/ml before the operation and with pituitary tumors no larger than 10 mm in diameter. Success depends on the skill and experience of the surgeon. The success rate also depends on what level of GH is defined as a cure. The best measure of surgical success is normalization of GH and IGF-1 levels. Ideally, GH should be less than 2 ng/ml after an oral glucose load. A review of GH levels in 1,360 patients worldwide immediately after surgery revealed that 60 percent had random GH levels below 5 ng/ml. Complications of surgery 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. More commonly, hormone levels may improve, but not return completely to normal. These patients may then require additional treatment, usually with medications.

Drug therapy

Two medications currently are used to treat acromegaly. These drugs reduce both GH secretion and tumor size. Medical therapy is sometimes used to shrink large tumors before surgery. Bromocriptine (Parlodel) in divided doses of about 20 mg daily reduces GH secretion from some pituitary tumors. Side effects include gastrointestinal upset, nausea, vomiting, light-headedness when standing, and nasal congestion. These side effects can be reduced or eliminated if medication is started at a very low dose at bedtime, taken with food, and gradually increased to the full therapeutic dose.

Because bromocriptine can be taken orally, it is an attractive choice as primary drug or in combination with other treatments. However, bromocriptine lowers GH and IGF-1 levels and reduces tumor size in less than half of patients with acromegaly. Some patients report improvement in their symptoms although their GH and IGF-1 levels still are elevated.

The second medication used to treat acromegaly is octreotide (Sandostatin) and lanreotide (Somatulin). Both are synthetic forms of a brain hormone, somatostatin, that stops GH production. The long-acting forms of these drugs must be injected every 2 to 4 weeks for effective treatment. Most patients with acromegaly respond to this medication. In many patients, GH levels fall within one hour and headaches improve within minutes after the injection. Several studies have shown that octreotide and lanreotide are effective for long-term treatment. Octreotide and lanreotide have also been used successfully to treat patients with acromegaly caused by non-pituitary tumors.

Because octreotide inhibits gastrointestinal and pancreatic function, long-term use causes digestive problems such as loose stools, nausea, and gas in one third of patients. In addition, approximately 25 percent of patients develop gallstones, which are usually asymptomatic. In rare cases, octreotide treatment can cause diabetes. On the other hand, scientists have found that in some acromegaly patients who already have diabetes, octreotide can reduce the need for insulin and improve blood sugar control.

The latest development in the medical treatment of acromegaly is the use of growth hormone receptor antagonists. The only available member of this family is pegvisomant (Somavert). By blocking the action of the endogenous growth hormone molecules, this compound is able to control disease activity of acromegaly in virtually all patients. Pegvisomant has to be administered subcutaneously by daily injections. Combinations of long-acting somatostatin analogues and weekly injections of pegvisomant seem to be equally effective as daily injections of pegvisomant.

Radiation therapy

Radiation therapy has been used both as a primary treatment and combined with surgery or drugs. It is usually reserved for patients who have tumor remaining after surgery. These patients often also receive medication to lower GH levels. Radiation therapy is given in divided doses over four to six weeks. This treatment lowers GH levels by about 50 percent over 2 to 5 years. Patients monitored for more than 5 years show significant further improvement. Radiation therapy causes a gradual loss of production of other pituitary hormones with time. Loss of vision and brain injury, which have been reported, are very rare complications of radiation treatments.

No single treatment is effective for all patients. Treatment should be individualized depending on patient characteristics, such as age and tumor size. If the tumor has not yet invaded surrounding brain tissues, removal of the pituitary adenoma by an experienced neurosurgeon is usually the first choice. After surgery, a patient must be monitored for a long time for increasing GH levels. If surgery does not normalize hormone levels or a relapse occurs, a doctor will usually begin additional drug therapy. The first choice should be bromocriptine because it is easy to administer; octreotide is the second alternative. With both medications, long-term therapy is necessary because their withdrawal can lead to rising GH levels and tumor re-expansion. Radiation therapy is generally used for patients whose tumors are not completely removed by surgery; for patients who are not good candidates for surgery because of other health problems; and for patients who do not respond adequately to surgery and medication.

Pituitary gigantism in children

This condition of growth hormone excess is rare in children and is referred to as pituitary gigantism, because the excessive growth hormone produces excessive growth of bones and the child can achieve excessive height. As an affected child becomes an adult, many of the adult problems can gradually develop. Famous patients were Richard Kiel ('Jaws' in the James Bond movies), and wrestler Andre the Giant, both standing in excess of 2.10 meters. Paul Wight, also a wrestler, had surgery on his pituitary gland in the 1990s to fix the condition, his height peaking at 7' 1" (2.16 m).

External links

This article was largely derived from http://www.niddk.nih.gov/health/endo/pubs/acro/acro.htm

• Endotext.org, an "online Endocrine textbook"
• An article on Acromegaly and gigantism