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
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.
What Causes Acromegaly?
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
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
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.
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 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.
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
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
How is Acromegaly Treated?
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
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
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.