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| Acromegaly |
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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 recognized, 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, characterized
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 tumors 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.
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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 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.
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Small pituitary adenomas are common. During
autopsies, they are found in up to 25 percent of the U.S. population.
However, these tumors 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.
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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 tumor that
causes the GH overproduction. Both techniques are excellent tools to
visualize a tumor without surgery. If scans fail to detect a pituitary
tumor, the physician should look for non-pituitary tumors in the chest,
abdomen, or pelvis as the cause for excess GH. The presence of such
tumors usually can be diagnosed by measuring GHRH in the blood and by
a CT scan of possible tumor sites.
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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 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.
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®).
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 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.
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.
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