Acromegaly
What is acromegaly?
Acromegaly is a hormonal disorder that results from too much
growth hormone (GH) in the body. The pituitary, a small gland in the
brain, makes GH. In acromegaly, the pituitary produces excessive
amounts of GH. Usually the excess GH comes from benign, or
noncancerous, tumors on the pituitary. These benign tumors are
called adenomas.
Acromegaly is most often diagnosed in middle-aged adults,
although symptoms can appear at any age. If not treated, acromegaly
can result in serious illness and premature death. Acromegaly is
treatable in most patients, but because of its slow and often
“sneaky” onset, it often is not diagnosed early or correctly. The
most serious health consequences of acromegaly are type 2 diabetes,
high blood pressure, increased risk of cardiovascular disease, and
arthritis. Patients with acromegaly are also at increased risk for
colon polyps, which may develop into colon cancer if not removed.
When GH-producing tumors occur in childhood, the disease that
results is called gigantism rather than acromegaly. A child’s height
is determined by the length of the so-called long bones in the legs.
In response to GH, these bones grow in length at the growth
plates—areas near either end of the bone. Growth plates fuse after
puberty, so the excessive GH production in adults does not result in
increased height. However, prolonged exposure to excess GH before
the growth plates fuse causes increased growth of the long bones and
thus increased height. Pediatricians may become concerned about this
possibility if a child’s growth rate suddenly and markedly increases
beyond what would be predicted by previous growth and how tall the
child’s parents are.
[top]
What are the symptoms of acromegaly?
The name acromegaly comes from the Greek words for “extremities”
and “enlargement,” reflecting one of its most common symptoms—the
abnormal growth of the hands and feet. Swelling of the hands and
feet is often an early feature, with patients noticing a change in
ring or shoe size, particularly shoe width. Gradually, bone changes
alter the patient’s facial features: The brow and lower jaw
protrude, the nasal bone enlarges, and the teeth space out.
Overgrowth of bone and cartilage often leads to arthritis. When
tissue thickens, it may trap nerves, causing carpal tunnel syndrome,
which results in numbness and weakness of the hands. Body organs,
including the heart, may enlarge.
Other symptoms of acromegaly include
- joint aches
- thick, coarse, oily skin
- skin tags
- enlarged lips, nose, and tongue
- deepening of the voice due to enlarged sinuses and vocal
cords
- sleep apnea—breaks in breathing during sleep due to
obstruction of the airway
- excessive sweating and skin odor
- fatigue and weakness
- headaches
- impaired vision
- abnormalities of the menstrual cycle and sometimes breast
discharge in women
- erectile dysfunction in men
- decreased libido
[top]
What causes acromegaly?
Acromegaly is caused by prolonged overproduction of GH by the
pituitary gland. The pituitary produces several important hormones
that control body functions such as growth and development,
reproduction, and metabolism. But hormones never seem to act simply
and directly. They usually “cascade” or flow in a series, affecting
each other’s production or release into the bloodstream.
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. The hypothalamus makes
hormones that regulate the pituitary. One of the hormones in the GH
series, or “axis,” is growth hormone-releasing hormone (GHRH), which
stimulates the pituitary gland to produce GH.
Secretion of GH by the pituitary into the bloodstream stimulates
the liver to produce another hormone called insulin-like growth
factor I (IGF-I). IGF-I is what actually causes tissue growth in the
body. High levels of IGF-I, in turn, signal the pituitary to reduce
GH production.
The hypothalamus makes another hormone called somatostatin, which
inhibits GH production and release. Normally, GHRH, somatostatin,
GH, and IGF-I 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-I continues to rise, leading
to bone overgrowth and organ enlargement. High levels of IGF-I also
cause changes in glucose (sugar) and lipid (fat) metabolism and can
lead to diabetes, high blood pressure, and heart disease.
Pituitary Tumors
In more than 95 percent of people with acromegaly, a benign tumor
of the pituitary gland, called an adenoma, produces excess GH.
Pituitary tumors are labeled either micro- or macro-adenomas,
depending on their size. Most GH-secreting tumors are
macro-adenomas, meaning they are larger than 1 centimeter. Depending
on their location, these larger tumors may compress surrounding
brain structures. For example, a tumor growing upward may affect the
optic chiasm—where the optic nerves cross—leading to visual problems
and vision loss. If the tumor grows to the side, it may enter an
area of the brain called the cavernous sinus where there are many
nerves, potentially damaging them.
Compression of the surrounding normal pituitary tissue can alter
production of other hormones. These hormonal shifts can lead to
changes in menstruation and breast discharge in women and erectile
dysfunction in men. If the tumor affects the part of the pituitary
that controls the thyroid—another hormone-producing gland—then
thyroid hormones may decrease. Too little thyroid hormone can cause
weight gain, fatigue, and hair and skin changes. If the tumor
affects the part of the pituitary that controls the adrenal gland,
the hormone cortisol may decrease. Too little cortisol can cause
weight loss, dizziness, fatigue, low blood pressure, and nausea.
Some GH-secreting tumors may also secrete too much of other
pituitary hormones. For example, they may produce prolactin, the
hormone that stimulates the mammary glands to produce milk. Rarely,
adenomas may produce thyroid-stimulating hormone. Doctors should
assess all pituitary hormones in people with acromegaly.
Rates of GH production and the aggressiveness of the tumor vary
greatly among people with adenomas. Some adenomas grow slowly and
symptoms of GH excess are often not noticed for many years. Other
adenomas grow more rapidly and invade surrounding brain areas or the
venous sinuses, which are located near the pituitary gland. Younger
patients tend to have more aggressive tumors. Regardless of size,
these tumors are always benign.
Most pituitary tumors develop spontaneously and are not
genetically inherited. They are the result of 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 happens later in 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.
Nonpituitary Tumors
Rarely, acromegaly is caused not by pituitary tumors but by
tumors of the pancreas, lungs, and other parts of the brain. These
tumors also lead to excess GH, either because they produce GH
themselves or, more frequently, because they produce GHRH, the
hormone that stimulates the pituitary to make GH. 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.
Physicians should carefully analyze all “pituitary tumors” removed
from patients with acromegaly so they do not overlook the rare
possibility that a tumor elsewhere in the body is causing the
disorder.
[Top]
How common is acromegaly?
Small pituitary adenomas are common, affecting about 17 percent
of the population. 1
However, research suggests most of these tumors do not cause
symptoms and rarely produce excess GH.
2 Scientists estimate
that three to four out of every million people develop acromegaly
each year and about 60 out of every million people suffer from the
disease at any time.3
Because the clinical diagnosis of acromegaly is often missed, these
numbers probably underestimate the frequency of the disease.
1Ezzat
S, Asa SL, Couldwell WT, Barr CE, Dodge WE, Vance ML, McCutcheon IE.
The prevalence of pituitary adenomas: a systematic review. Cancer.
2004;101(3):613–619.
2Rumboldt Z.
Pituitary adenomas. Topics in Magnetic Resonance Imaging: TMRI.
2005;16(4):277–288.
3Ayuk J,
Sheppard MC. Growth hormone and its disorders. Postgraduate
Medical Journal. 2006;82:24–30.
[Top]
How is acromegaly diagnosed?
Blood tests
If acromegaly is suspected, a doctor must measure the GH level in
a person’s blood 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 impulses, or
spurts, its concentration in the blood can vary widely from minute
to minute. At a given moment, a person with acromegaly may have a
normal GH level, whereas a GH level in a healthy person may even be
five times higher.
More accurate information is obtained when GH is measured under
conditions that normally suppress GH secretion. Health care
professionals often use the oral glucose tolerance test to diagnose
acromegaly because drinking 75 to 100 grams of glucose solution
lowers blood GH levels to less than 1 nanogram per milliliter
(ng/ml) in healthy people. In people with GH overproduction, this
suppression does not occur. The oral glucose tolerance test is a
highly reliable method for confirming a diagnosis of acromegaly.
Physicians also can measure IGF-I levels, which increase as GH
levels go up, in people with suspected acromegaly. Because IGF-I
levels are much more stable than GH levels over the course of the
day, they are often a more practical and reliable screening measure.
Elevated IGF-I levels almost always indicate acromegaly. However, a
pregnant woman’s IGF-I levels are two to three times higher than
normal. In addition, physicians must be aware that IGF-I levels
decline with age and may also be abnormally low in people with
poorly controlled diabetes or liver or kidney disease.
Imaging
After acromegaly has been diagnosed by measuring GH or IGF-I
levels, a magnetic resonance imaging (MRI) scan of the pituitary is
used to locate and detect the size of the tumor causing GH
overproduction. MRI is the most sensitive imaging technique, but
computerized tomography (CT) scans can be used if the patient should
not have MRI. For example, people who have pacemakers or other types
of implants containing metal should not have an MRI scan because MRI
machines contain powerful magnets.
If a head scan fails to detect a pituitary tumor, the physician
should look for non-pituitary “ectopic” tumors in the chest,
abdomen, or pelvis as the cause of 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.
Rarely, a pituitary tumor secreting GH may be too tiny to detect
even with a sensitive MRI scan.
[Top]
How is acromegaly treated?
Currently, treatment options include surgical removal of the
tumor, medical therapy, and radiation therapy of the pituitary.
Goals of treatment are to
- reduce excess hormone production to normal levels
- relieve the pressure that the growing pituitary tumor may be
exerting on the surrounding brain areas
- preserve normal pituitary function or treat hormone
deficiencies
- improve the symptoms of acromegaly
Surgery
Surgery is the first option recommended for most people with
acromegaly, as it is often a rapid and effective treatment. The
surgeon reaches the pituitary via an incision through the nose or
inside the upper lip 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 rapid 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
45 ng/ml before the operation and with pituitary tumors no larger
than 10 millimeters (mm) in diameter. Success depends in large part
on the skill and experience of the surgeon, as well as the location
of the tumor. Even with the most experienced neurosurgeon, the
chance of a cure is small if the tumor has extended into critical
brain structures or into the cavernous sinus where surgery could be
risky.
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-I levels. The overall rate of remission—control of the
disease—after surgery ranges from 55 to 80 percent. (See
For More Information to locate a board-certified
neurosurgeon.)
A possible complication of surgery is damage to the surrounding
normal pituitary tissue, which requires lifelong use of pituitary
hormone replacement. The part of the pituitary that stores
antidiuretic hormone—a hormone important in water balance—may be
temporarily or, rarely, permanently damaged and the patient may
require medical therapy. Other potential problems include
cerebrospinal fluid leaks and, rarely, meningitis. Cerebrospinal
fluid bathes the brain and can leak from the nose if the incision
area doesn’t heal well. Meningitis is a bacterial or viral infection
of the meninges, the outer covering of the brain.
Even when surgery is successful and hormone levels return to
normal, people with acromegaly must be carefully monitored for years
for possible recurrence of the disease. More commonly, hormone
levels improve, but do not return to normal. Additional treatment,
usually medications, may be required.
Medical Therapy
Medical therapy is most often used if surgery does not result in
a cure and sometimes to shrink large tumors before surgery. Three
medication groups are used to treat acromegaly.
Somatostatin analogs (SSAs) are the first medication group used
to treat acromegaly. They shut off GH production and are effective
in lowering GH and IGF-I levels in 50 to 70 percent of patients.
SSAs also reduce tumor size in around 0 to 50 percent of patients
but only to a modest degree. Several studies have shown that SSAs
are safe and effective for long-term treatment and in treating
patients with acromegaly caused by nonpituitary tumors. Long-acting
SSAs are given by intramuscular injection once a month.
Digestive problems—such as loose stools, nausea, and gas—are a
side effect in about half of people taking SSAs. However, the
effects are usually temporary and rarely severe. About 10 to 20
percent of patients develop gallstones, but the gallstones do not
usually cause symptoms. In rare cases, treatment can result in
elevated blood glucose levels. More commonly, SSAs reduce the need
for insulin and improve blood glucose control in some people with
acromegaly who already have diabetes.
The second medication group is the GH receptor antagonists
(GHRAs), which interfere with the action of GH. They normalize IGF-I
levels in more than 90 percent of patients. They do not, however,
lower GH levels. Given once a day through injection, GHRAs are
usually well-tolerated by patients. The long-term effects of these
drugs on tumor growth are still under study. Side effects can
include headaches, fatigue, and abnormal liver function.
Dopamine agonists make up the third medication group. These drugs
are not as effective as the other medications at lowering GH or
IGF-I levels, and they normalize IGF-I levels in only a minority of
patients. Dopamine agonists are sometimes effective in patients who
have mild degrees of excess GH and have both acromegaly and
hyperprolactinemia—too much of the hormone prolactin. Dopamine
agonists can be used in combination with SSAs. Side effects can
include nausea, headache, and lightheadedness.
Agonist: A drug that binds to a receptor of
a cell and triggers a response by the cell, mimicking the action
of a naturally occurring substance.
Antagonist: A chemical that acts within the
body to reduce the physiological activity of another chemical
substance or hormone.
Radiation Therapy
Radiation therapy is usually reserved for people who have some
tumor remaining after surgery and do not respond to medications.
Because radiation leads to a slow lowering of GH and IGF-I levels,
these patients often also receive medication to lower hormone
levels. The full effect of this therapy may not occur for many
years.
The two types of radiation delivery are conventional and
stereotactic. Conventional radiation delivery targets the tumor with
external beams but can damage surrounding tissue. The treatment
delivers small doses of radiation multiple times over 4 to 6 weeks,
giving normal tissue time to heal between treatments.
Stereotactic delivery allows precise targeting of a high-dose
beam of radiation at the tumor from varying angles. The patient must
wear a rigid head frame to keep the head still. The types of
stereotactic radiation delivery currently available are proton beam,
linear accelerator (LINAC), and gamma knife. With stereotactic
delivery, the tumor must be at least 5 mm from the optic chiasm to
prevent radiation damage. This treatment can sometimes be done in a
single session, reducing the risk of damage to surrounding tissue.
All forms of radiation therapy cause a gradual decline in
production of other pituitary hormones over time, resulting in the
need for hormone replacement in most patients. Radiation also can
impair a patient’s fertility. Vision loss and brain injury are rare
complications. Rarely, secondary tumors can develop many years later
in areas that were in the path of the radiation beam.
[Top]
Which treatment for acromegaly is most effective?
No single treatment is effective for all patients. Treatment
should be individualized, and often combined, depending on patient
characteristics such as age and tumor size.
If the tumor has not yet invaded surrounding nonpituitary
tissues, removal of the pituitary adenoma by an experienced
neurosurgeon is usually the first choice. Even if a cure is not
possible, surgery may be performed if the patient has symptoms of
neurological problems such as loss of peripheral vision or cranial
nerve problems. After surgery, hormone levels are measured to
determine whether a cure has been achieved. This determination can
take up to 8 weeks because IGF-I lasts a long time in the body’s
circulation. If cured, a patient must be monitored for a long time
for increasing GH levels.
If surgery does not normalize hormone levels or a relapse occurs,
an endocrinologist should recommend additional drug therapy. With
each medication, long-term therapy is necessary because their
withdrawal can lead to rising GH levels and tumor re-expansion.
Radiation therapy is generally reserved for patients whose tumors
are not completely removed by surgery, who are not good candidates
for surgery because of other health problems, or who do not respond
adequately to surgery and medication.
Points to Remember
-
Acromegaly is a hormonal disorder that results from too much
growth hormone (GH) in the body.
-
In most people with acromegaly, a benign tumor of the
pituitary gland produces excess GH.
-
Common features of acromegaly include abnormal growth of the
hands and feet; bone growth in the face that leads to a
protruding lower jaw and brow and an enlarged nasal bone; joint
aches; thick, coarse, oily skin; and enlarged lips, nose, and
tongue.
-
Acromegaly can cause sleep apnea, fatigue and weakness,
headaches, impaired vision, menstrual abnormalities in women,
and erectile dysfunction in men.
-
Acromegaly is diagnosed through a blood test. Magnetic
resonance imaging (MRI) of the pituitary is then used to locate
and detect the size of the tumor causing GH overproduction.
-
The first line of treatment is usually surgical removal of
the tumor. Medication or radiation may be used instead of or in
addition to surgery.
[Top]
Hope through Research
Researchers continue to study treatment options for people with
acromegaly. Studies are examining the safety and effectiveness of
different types, dosages, dosing schedules, and combinations of
somatostatin analogs and GH receptor antagonists, both before and
after transsphenoidal surgery. Another study is evaluating the
effects of GH replacement in adults with a history of acromegaly who
are now growth hormone deficient. Other research seeks to identify
new genes that predispose people to endocrine tumors.
[Top]
For More Information
American Association of Neurological Surgeons
5550 Meadowbrook Drive
Rolling Meadows, IL 60008
Phone: 1–888–566–AANS (2267) or 847–378–0500
Email: info@AANS.org
Internet:
www.NeurosurgeryToday.org
For information about pituitary conditions:
www.neurosurgerytoday.org/what/patient_e/pituitary.asp
To locate a board-certified neurosurgeon:
www.neurosurgerytoday.org/findaneuro
The Hormone Foundation
8401 Connecticut Avenue, Suite 900
Chevy Chase, MD 20815–5817
Phone: 1–800–HORMONE (467–6663)
Fax: 301–941–0259
Email:
hormone@endo-society.org
Internet:
www.hormone.org
The Pituitary Society
VA Medical Center
423 East 23rd Street, Room 16048aW
New York, NY 10010
Phone: 212–263–6772
Fax: 212–447–6219
Internet:
www.pituitarysociety.org