GIGANTISM AND ACROMEGALY the absence of growth hormone–releasing

hormone (GHRH). A few cases of ectopic

Gigantism and acromegaly are GHRH-producing tumors, especially of the
syndromes of excessive secretion of growth pancreas and lung, also have been described.
hormone (hypersomatotropism) that are nearly
always due to a pituitary adenoma. Before Pituitary gigantism
closure of the epiphyses, the result is
gigantism. Later, the result is acromegaly, This rare condition occurs if GH
which causes distinctive facial and other hypersecretion begins in childhood, before
features. Diagnosis is clinical, by skull and closure of the epiphyses. Skeletal growth
hand x-rays, and by measurement of levels of velocity and ultimate stature are increased,
growth hormone and insulin-like growth factor but little bony deformity occurs. However,
1. Treatment involves removal or destruction soft-tissue swelling occurs, and the peripheral
of the responsible adenoma, and sometimes nerves are enlarged. Delayed puberty or
also other treatment modalities. hypogonadotropic hypogonadism is also
frequently present, resulting in a eunuchoid
Growth hormone (GH) stimulates habitus (ie, a body build that is tall and
somatic growth and regulates metabolism. slender with long extremities).
Growth hormone–releasing hormone (GHRH)
is the major stimulator and somatostatin is
the major inhibitor of the synthesis and Acromegaly
release of GH. GH controls synthesis of
insulin-like growth factor 1 (IGF-1, also called In acromegaly, GH hypersecretion
somatomedin-C), which largely controls usually starts between the 20s and 40s. When
growth. Although IGF-1 is produced by many GH hypersecretion begins after epiphyseal
tissues locally, the liver is the major source of closure, the earliest clinical manifestations are
circulating IGF-1. The metabolic effects of GH coarsening of the facial features and soft-
are biphasic. GH initially exerts insulin-like tissue swelling of the hands and feet.
effects, increasing glucose uptake in muscle Appearance changes, and larger rings, gloves,
and fat, stimulating amino acid uptake and and shoes are needed. Photographs of the
protein synthesis in liver and muscle, and patient are important in delineating the course
inhibiting lipolysis in adipose tissue. Several of the disease.
hours later, more profound anti–insulin-like
metabolic effects occur. They include
inhibition of glucose uptake and use, causing
In adults with acromegaly, coarse body
blood glucose and lipolysis to increase, which
hair increases, and the skin thickens and
increases plasma free fatty acids.
frequently darkens. The size and function of
GH-secreting tumors are largely sebaceous and sweat glands increase, such
sporadic, but genetic abnormalities in the X that patients frequently complain of excessive
chromosome (X-linked acrogigantism), perspiration and offensive body odor.
overexpression of the pituitary tumor Overgrowth of the mandible leads to
transforming gene (PTTG), and mutations in protrusion of the jaw (prognathism) and
the aryl hydrocarbon receptor–interacting malocclusion of teeth. Cartilaginous
protein (AIP) have been discovered. Many GH– proliferation of the larynx leads to a deep,
secreting adenomas contain a mutant form of husky voice. The tongue is frequently enlarged
the Gs protein, which is a stimulatory and furrowed. In long-standing acromegaly,
regulator of adenylate cyclase. Cells with the costal cartilage growth leads to a barrel chest.
mutant form of Gs protein secrete GH even in Articular cartilaginous proliferation occurs
early in response to GH excess, with the
articular cartilage possibly undergoing  Insulin-like growth factor 1 (IGF-1)
necrosis and erosion. Joint symptoms are levels
common, and crippling degenerative arthritis
may occur.  Usually growth hormone levels

Peripheral neuropathies occur Diagnosis can be made from the characteristic

commonly because of compression of nerves by clinical findings. MRI of the sella is the
adjacent fibrous tissue and endoneural fibrous imaging test of choice for diagnosis of pituitary
proliferation. Headaches are common because adenoma. CT, MRI, or skull x-rays disclose
of the pituitary tumor. Bitemporal hemianopia cortical thickening, enlargement of the frontal
may develop if suprasellar extension sinuses, and enlargement and erosion of the
compresses the optic chiasm. The heart, liver, sella turcica. X-rays of the hands show tufting
kidneys, spleen, thyroid gland, parathyroid of the terminal phalanges and soft-tissue
glands, colon, and pancreas are larger than thickening.
normal; thyroid enlargement may be Serum IGF-1 should be measured in patients
generalized or multinodular. Cardiac disease with suspected acromegaly; IGF-1 levels are
(eg, coronary artery disease, cardiomegaly, typically substantially elevated (3-fold to 10-
valvular insufficiencies, fold), and because IGF-1 levels do not
sometimes cardiomyopathy) occurs in perhaps fluctuate like GH levels do, they are the
one third of patients, with a doubling in the simplest way to assess GH hypersecretion.
risk of death due to cardiac IGF-1 levels also can be used to monitor
disease. Hypertension occurs in up to one third response to therapy.
of patients. Snoring is a common symptom,
and obstructive sleep apnea occurs in 40 to Plasma GH levels are typically elevated. Blood
50% of patients. Colonic polyps are increased should be taken before the patient eats
as a result of GH excess. The risk of cancer, breakfast (basal state); in normal people, basal
particularly of the gastrointestinal tract, GH levels are low or undetectable. Transient
increases 2-fold to 3-fold. GH increases tubular elevations of GH are normal, due to the
reabsorption of phosphate and leads to mild pulsatile secretion of GH, and must be
hyperphosphatemia. Impaired glucose distinguished from pathologic hypersecretion.
tolerance occurs in nearly half the patients The degree of GH suppression after a glucose
with acromegaly and in gigantism, but load remains the standard and thus should be
clinically significant diabetes mellitus occurs in measured in patients with elevated plasma
only about 10% of patients. GH; however, the results are assay-dependent,
and the cutoff for normal suppression is
Galactorrhea occurs in some women controversial. Secretion in normal people is
with acromegaly, usually in association suppressed to < 1 ng/mL ([< 1 mcg/L] a cutoff
with hyperprolactinemia. However, of < 0.4 ng/mL [< 0.4 mcg/L] is often used)
galactorrhea may occur with GH excess alone, within 120 minutes of oral administration of
because GH itself stimulates lactation. 75 g of glucose. Most patients with acromegaly
Decreased gonadotropin secretion often occurs have substantially higher values. In some
with GH-secreting tumors. About one third of cases, basal plasma GH levels are also used in
men with acromegaly develop erectile monitoring response to therapy.
dysfunction, and nearly all women develop
menstrual irregularities or amenorrhea. CT or MRI of the sella should be done to look
for a tumor. If a tumor is not visible, excessive
Diagnosis of Gigantism and Acromegaly secretion of pituitary GH may be due to a non-
 CT or MRI central nervous system tumor producing
excessive amounts of ectopic GHRH.
Demonstration of elevated levels of plasma normal range seems to reduce mortality rates
GHRH can confirm the diagnosis. Lungs and to normal.
pancreas may be first evaluated in searching
for the sites of ectopic production. Medical therapy

Screening for complications, In general, drug therapy is indicated if surgery

including diabetes, heart disease, and is contraindicated, if surgery or radiation
gastrointestinal cancer, should be done at the therapy has not been curative, or if radiation
time of diagnosis. Fasting plasma glucose therapy is being given time to work. Drugs
levels, glycosylated Hb (HbA1C), or an oral available for the treatment of acromegaly
glucose tolerance test can be done to test for include those that target tumor secretion of
diabetes. Electrocardiography and, preferably, GH and one that blocks GH at the level of the
echocardiography are done to detect heart GH receptor.
disease. Colonoscopy is done to detect colon Somatostatin receptor ligands are a mainstay
cancer. Follow-up screening depends on the of therapy because they decrease GH secretion
results of the initial testing and the patient's from the pituitary tumor mediated through
response to treatment. interactions predominately with the
Treatment of Gigantism and Acromegaly somatostatin subtype receptor-2 (SSTR-2).
Drugs in this class
 Surgery or radiation therapy include octreotide and lanreotide, which have
high affinity for the SSTR-2 and come in
 Sometimes pharmacologic suppression short-acting (octreotide) and long-acting
of GH secretion or activity (octreotide LAR and lanreotide)
Surgical therapy preparations. Pasireotide, a somatostatin
receptor ligand with affinity for SSTR-1, 2, 3,
Selective removal of the pituitary tumor with and 5, is also available in short- and long-
surgery is considered first-line therapy for acting preparations. All somatostatin receptor
most patients. Patients with comorbidities that ligands may also cause tumor shrinkage.
prevent safe surgical resection and those with
unresectable tumors may be treated with Octreotide is started with a 20-mg
primary medical therapy. Rates of remission intramuscular injection delivered monthly and
after surgical resection are dependent on the titrated to an effective dose after the third
size and degree of invasion of the pituitary injection. Effective doses range from 10 to 40
adenoma and the experience of the mg monthly. Lanreotide is given in doses of 60
neurosurgeon. to 120 mg monthly, with the possibility of
extended dosing (120 mg every 6 to 8 weeks)
Surgical removal of the tumor is likely to have in patients with well-controlled
been curative if GH levels measured after a disease Pasireotide is generally considered
glucose load and IGF-1 levels reach normal if octreotide or lanreotide is unsuccessful in
values. If one or both values are abnormal, returning IGF-I levels to normal. Octreotide is
further therapy is usually needed. If GH also available in an oral preparation given
excess is poorly controlled, hypertension, twice daily.
heart failure, and an increased mortality
occur. Predictors of mortality in acromegaly Cabergoline, a dopamine agonist, has been
include hypertension, age, use of radiation, used alone or in combination with a
and hypopituitarism, especially somatostatin receptor ligand and works by
adrenocorticotropic hormone deficiency. suppressing GH secretion at the
Reduction of IGF-I and GH levels to the pituitary. Cabergoline is typically used in mild
disease and has the advantage of being an  Gigantism occurs if GH hypersecretion
oral drug. begins in childhood, before closure of the
epiphyses.
Pegvisomant, the GH receptor antagonist, is
given as a daily subcutaneous injection and  Acromegaly involves GH hypersecretion
decreases IGF-I levels and symptoms but does beginning in adulthood; a variety of bony and
not decrease GH levels or act on the pituitary soft tissue abnormalities develop.
tumor. Pegvisomant is given with a loading
dose 40 mg subcutaneously under physician  Diagnose by measuring insulin-like growth
supervision followed by a maintenance dose of factor 1 and GH levels; do central nervous
10 mg subcutaneously once a day and titrated system imaging to detect a pituitary tumor.
by 5-mg increments every 4 to 6 weeks,  Remove pituitary tumors surgically or using
depending on IGF-I levels. radiation therapy.
Radiation therapy  If tumors cannot be removed,
Radiation therapy may be used at any step of give octreotide or lanreotide to suppress GH
treatment but is typically used as primary secretion.
therapy only when surgery is not available.
Timing of radiation in the treatment of
patients with acromegaly varies among What causes acromegaly?
institutions. Stereotactic radiation, delivering
about 5000 cGy to the pituitary, is used, but A benign (noncancerous) tumor that produces
GH levels may not fall to normal for several too much growth hormone, called
years. Treatment with accelerated protons an adenoma, is the cause of acromegaly. The
(heavy particle radiation) permits delivery of adenoma is in the pituitary, a tiny gland
larger doses of radiation (equivalent to 10,000 located near the bottom of the brain. The
cGy) to the pituitary; such therapy poses pituitary regulates how the body makes
higher risk of cranial nerve and hypothalamic several hormones, in addition to growth
damage and is available only in a few centers. hormone.

Hypopituitarism commonly develops several What are the symptoms of acromegaly?

years after irradiation. Because radiation
Acromegaly affects the body’s bones and
damage is cumulative, proton beam therapy
tissues and causes them to grow in abnormal
should not be used after conventional gamma-
ways. In children, acromegaly causes
irradiation. A combined approach with both
gigantism (unusual growth). When a child or
surgery and radiation therapy is indicated for
young adult has too much growth hormone in
patients with progressive extrasellar
his or her body, gigantism can cause their
involvement by a pituitary tumor and for
bones to grow at an increased rate. Some
patients in whom the entire tumor cannot be
people with gigantism reach 8 feet tall.
resected, which is often the case.
Adults with acromegaly do not grow tall, but
Key Points
may have the following symptoms:
 Gigantism and acromegaly are usually
 Enlarged or swollen body parts, such as the
caused by a pituitary adenoma that secretes
hands, feet or chest
excessive amounts of growth hormone (GH);
rarely, they are caused by non-pituitary  Changes in the face, including a prominent
tumors that secrete growth hormone–releasing jaw, nose or forehead
hormone (GHRH).
 Excessive sweating or oily skin There are several treatment options for
acromegaly. Your doctor will consider your
 Numbness or “pins and needles” in the hands symptoms and circumstances before deciding
 Joint pain which treatment(s) are right for you.

 Carpal tunnel syndrome or spinal cord The most common treatments for acromegaly
problems are surgery, medication and radiation therapy:

 Muscle weakness  Surgery: In many cases, surgery greatly

improves acromegaly symptoms or corrects
 Headaches the condition entirely. The specifics of the
surgery will depend on the size and location of
 Sleep apnea, a condition that causes the body a tumor. The goal of surgery is to remove all of
to stop breathing for short bursts of time a tumor that is causing excess growth
during sleep hormone production. If doctors remove
enough of the tumor, you may not need
 Changes in vision or voice
further treatment. If doctors can remove only
Acromegaly symptoms often start slowly and a part of a tumor, you may need medication or
may be difficult to notice at first. Some people radiation therapy to manage your symptoms
only notice their hands have grown in size and reduce the production of growth hormone.
when their wedding ring feels tight.
 Medication: Injection medications such as
How is acromegaly diagnosed? somatostatin analogs (Sandostatin®) can help
manage hormone levels. Medications work in
Symptoms of acromegaly often show up very different ways to normalize the body’s growth
slowly, over many years. This makes it hard to hormone levels and improve your symptoms.
diagnose.
In some cases, a person may take medication
Doctors who suspect acromegaly may order until a tumor has shrunk. This can allow
these tests to diagnose the condition: doctors to safely remove it with surgery. Other
people may need to take medication long-term
 Blood tests: Growth hormone and IGF-I blood
to effectively manage growth hormone levels
tests measure different types of growth
and symptoms.
hormone levels in your blood. If these levels
are high, your doctor might order a glucose  Radiation therapy: Radiation therapy can
tolerance test to confirm an acromegaly help lower growth hormone levels when
diagnosis. Glucose tolerance tests tell doctors medications aren’t effective. Radiation therapy
whether your body’s growth hormone levels uses specialized equipment to target the
react to glucose (sugar) the way they should. tumor with radiation beams. This therapy
For this test, you’ll have blood taken at works slowly. It may require several treatment
different intervals after you drink a glucose courses, with breaks in between, and may
solution. take several years for full effect.
 Imaging tests: If blood tests confirm that you
have acromegaly, your doctor will probably
recommend an MRI scan, which can clearly
show the size and location of a tumor and help
determine the proper treatments.

How is acromegaly treated?