What is Acromegaly?
Acromegaly is a hormonal disorder that results when the pituitary gland produces excess growth hormone (GH). It most commonly affects middle-aged adults and can result in serious illness and premature death. Once recognised, acromegaly is treatable in most patients, but because of its slow and often insidious onset, it frequently is not diagnosed correctly.
The name acromegaly comes from the Greek words for "extremities" and "enlargement" and reflects one of its most common symptoms, the abnormal growth of the hands and feet. Soft tissue swelling of the hands and feet is often an early feature, with patients noticing a change in ring or shoe size. Gradually, bony changes alter the patient's facial features: the brow and lower jaw protrude, the nasal bone enlarges, and spacing of the teeth increases.
Overgrowth of bone and cartilage often leads to arthritis. When tissue thickens, it may trap nerves, causing carpal tunnel syndrome, characterised by numbness and weakness 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; impaired vision; abnormalities of the menstrual cycle and sometimes breast discharge in women; and impotence in men. There may be enlargement of body organs, including the liver, spleen, kidneys and heart.
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.
When GH-producing tumours occur in childhood, the disease that results is called gigantism rather than acromegaly. Fusion of the growth plates of the long bones occurs after puberty so that development of excessive GH production in adults does not result in increased height. Prolonged exposure to excess GH before fusion of the growth plates causes increased growth of the long bones and increased height.
What causes acromegaly?
Acromegaly is caused by prolonged overproduction of GH by the pituitary gland. The pituitary is a small gland at the base of the brain that produces several important hormones to control body functions such as 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. IGF-1, in turn, signals the pituitary to reduce GH production. 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 the pituitary 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 over 90 percent of acromegaly patients, the overproduction of GH is caused by a benign tumour of the pituitary gland, called an adenoma. These tumours 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 tumour. 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 tumours.
Most pituitary tumours arise spontaneously and are not genetically inherited. Many pituitary tumours arise from a genetic alteration in a single pituitary cell which leads to increased cell division and tumour 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 tumours but by tumours of the pancreas, lungs, and adrenal glands. These tumours 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 tumours are surgically removed, GH levels fall and the symptoms of acromegaly improve.
In patients with GHRH-producing, non-pituitary tumours, the pituitary still may be enlarged and may be mistaken for a tumour. Therefore, it is important that physicians carefully analyze all "pituitary tumours" removed from patients with acromegaly in order not to overlook the possibility that a tumour elsewhere in the body is causing the disorder
How common is acromegaly?
Small pituitary adenomas are common. During autopsies, they are found in up to 25 percent of the U.S. population. However, these tumours rarely cause symptoms or produce excessive GH or other pituitary hormones. Scientists estimate that about 3 out of every million people develop acromegaly each year and that 40 to 60 out of every million people suffer from the disease at any time. However, because the clinical diagnosis of acromegaly often is missed, these numbers probably underestimate the frequency of the disease.
How is acromegaly diagnosed?
If a doctor suspects acromegaly, he or she can 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 spurts 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 five times higher.
Because of these problems, 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 75 g of the sugar glucose lowers blood GH levels less than 2 ng/ml in healthy people. In patients with GH overproduction, this reduction does not occur. The glucose tolerance test is the most reliable method of confirming a diagnosis of acromegaly.
Physicians also can measure IGF-1 levels in patients with suspected acromegaly. As mentioned earlier, 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. However, a pregnant woman's IGF-1 levels are two to three times higher than normal. In addition, physicians must be aware that IGF-1 levels decline in aging people and may be abnormally low in patients with poorly controlled diabetes mellitus.
After acromegaly has been diagnosed by measuring GH or IGF-1, imaging techniques, such as computed tomography (CT) scans or magnetic resonance imaging (MRI) scans of the pituitary are used to locate the tumour that causes the GH overproduction. Both techniques are excellent tools to visualize a tumour without surgery. If scans fail to detect a pituitary tumour, the physician should look for non-pituitary tumours in the chest, abdomen, or pelvis as the cause for excess GH. The presence of such tumours usually can be diagnosed by measuring GHRH in the blood and by a CT scan of possible tumour sites.
How is acromegaly treated?
The goals of treatment are to reduce GH production to normal levels, to relieve the pressure that the growing pituitary tumour 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 tumour, drug therapy, and radiation therapy of the pituitary.
Surgery is a rapid and effective treatment. The surgeon reaches the pituitary through an incision in the nose and, with special tools, removes the tumour 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 tumours 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.
Two medications currently are used to treat acromegaly. These drugs reduce both GH secretion and tumour size. Medical therapy is sometimes used to shrink large tumours before surgery. Bromocriptine (Parlodel®) in divided doses of about 20 mg daily reduces GH secretion from some pituitary tumours. 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 tumour 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®). Octreotide is a synthetic form of a brain hormone, somatostatin, that stops GH production. This drug must be injected under the skin every 8 hours 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 is effective for long-term treatment. Octreotide also has been used successfully to treat patients with acromegaly caused by non-pituitary tumours.
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.
Radiation therapy has been used both as a primary treatment and combined with surgery or drugs. It is usually reserved for patients who have tumour 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 tumour size. If the tumour 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 tumour re-expansion. Radiation therapy is generally used for patients whose tumours 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.