Acromegaly

• Problems with bones and joints, including osteoarthritis, nerve compression syndrome due to bony overgrowth, and carpal tunnel syndrome[10]
• Hypertension[10][11]
• Diabetes mellitus[12]
• Cardiomyopathy, potentially leading to heart failure[10]
• Colorectal cancer[13]
• Sleep Apnea[10]
• Thyroid nodules and thyroid cancer[14]
• Hypogonadism[10]
• Compression of the optic chiasm by the growth of pituitary adenoma leading to visual problems[15]

About 98% of cases of acromegaly are due to the overproduction of growth hormone by a benign tumor of the pituitary gland called an adenoma.[16] These tumors produce excessive growth hormone and compress surrounding brain tissues as they grow larger. In some cases, they may compress the optic nerves. Expansion of the tumor may cause headaches and visual disturbances. 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 because of reduced testosterone production.

A marked variation in rates of GH production and the aggressiveness of the tumor occurs. 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 people 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 that 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 growth hormones. The events within the cell that cause disordered pituitary cell growth and GH oversecretion currently are the subject of intensive research.

Pituitary adenomas and diffuse somatomammotroph hyperplasia may result from somatic activating mutations GNAS, which may be acquired or associated with McCune-Albright syndrome.[17][18]

In a few people, 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 (growth hormone releasing hormone), the hormone that stimulates the pituitary to make GH. In these people, 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 nonpituitary tumors are surgically removed, GH levels fall and the symptoms of acromegaly improve.

In people 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 people with acromegaly so as to not overlook the possibility that a tumor elsewhere in the body is causing the disorder.

Pseudoacromegaly is a condition with the usual acromegaloid features, but without an increase in growth hormone and IGF-1. It is frequently associated with insulin resistance.[19] Cases have been reported due to minoxidil at an unusually high dose.[20] It can also be caused by a selective post receptor defect of insulin signalling, leading to the impairment of metabolic, but preservation of mitogenic, signalling.[21]

The primary current medical treatment of acromegaly is to use somatostatin analogues – octreotide (Sandostatin) or lanreotide (Somatuline). These somatostatin analogues are synthetic forms of a brain hormone, somatostatin, which stops GH production. The long-acting forms of these drugs must be injected every 2 to 4 weeks for effective treatment. Most people with acromegaly respond to this medication. In many people with acromegaly, GH levels fall within one hour and headaches improve within minutes after the injection. Octreotide and lanreotide are effective for long-term treatment. Octreotide and lanreotide have also been used successfully to treat people with acromegaly caused by non-pituitary tumors.

Somatostatin analogues are also sometimes used to shrink large tumors before surgery.

Because octreotide inhibits gastrointestinal and pancreatic function, long-term use causes digestive problems such as loose stools, nausea, and gas in one third of people. In addition, approximately 25 percent of people with acromegaly develop gallstones, which are usually asymptomatic.[22] In some cases, octreotide treatment can cause diabetes due to the fact that somatostatin and its analogues can inhibit the release of insulin.

For those who are unresponsive to somatostatin analogues, or for whom they are otherwise contraindicated, it is possible to treat using one of the dopamine agonists, bromocriptine or cabergoline. As tablets rather than injections, they cost considerably less. These drugs can also be used as an adjunct to somatostatin analogue therapy. They are most effective in those whose pituitary tumours cosecrete prolactin. Side effects of these dopamine agonists 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. Bromocriptine lowers GH and IGF-1 levels and reduces tumor size in fewer than half of people with acromegaly. Some people report improvement in their symptoms although their GH and IGF-1 levels still are elevated.

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 everyone with acromegaly. 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.

Surgical removal of the pituitary tumor is usually effective in lowering growth hormone levels. Two surgical procedures are available for use. The first is endonasal transsphenoidal surgery, which involves the surgeon reaching the pituitary through an incision in the nasal cavity wall. The wall is reached by passing through the nostrils with microsurgical instruments. The second method is transsphenoidal surgery during which an incision is made into the gum beneath the upper lip. Further incisions are made to cut through the septum to reach the nasal cavity, where the pituitary is located. Endonasal transsphenoidal surgery is a less invasive procedure with a shorter recovery time than the older method of transsphenoidal surgery, and the likelihood of removing the entire tumor is greater with reduced side effects. Consequently, endonasal transsphenoidal surgery is the more common surgical choice.

These procedures normally relieve the pressure on the surrounding brain regions and lead to a lowering of GH levels. Surgery is most successful in people 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 people worldwide immediately after surgery revealed that 60% 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, people must be carefully monitored for years for possible recurrence. More commonly, hormone levels may improve, but not return completely to normal. These people may then require additional treatment, usually with medications.

Radiation therapy has been used both as a primary treatment and combined with surgery or drugs. It is usually reserved for people who have tumor remaining after surgery. These people 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. People 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.

The initial treatment chosen should be individualized depending on the person's 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 person must be monitored long-term for increasing GH levels.

If surgery does not normalize hormone levels or a relapse occurs, a doctor will usually begin additional drug therapy. The current first choice is generally octreotide or lanreotide; however, bromocriptine and cabergoline are both cheaper and easier to administer. With all of these 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 people whose tumors are not completely removed by surgery, for people who are not good candidates for surgery because of other health problems, and for people who do not respond adequately to surgery and medication.