Acromegaly & Gigantism

Essentials of Diagnosis
• Excessive growth of hands, feet, jaw, and internal organs; or gigantism
before closure of epiphyses.
• Amenorrhea, headaches, visual field loss, weakness.
• Soft, doughy, sweaty handshake.
• Elevated IGF-I.
• Serum GH not suppressed following oral glucose.
General Considerations
GH exerts much of its growth-promoting effects through the release of IGF-1
produced in the liver and other tissues.
Acromegaly is nearly always caused by a pituitary adenoma. These tumors
may be locally invasive, particularly into the cavernous sinus. Less than 1%
are malignant. Most are macroadenomas (over 1 cm in diameter).
Acromegaly is usually sporadic but may rarely be familial. The disease may
be associated with endocrine tumors of the parathyroids or pancreas (MEN
1). Acromegaly may also be seen in McCune–Albright syndrome and as part
of Carney's complex (atrial myxoma, acoustic neuroma, and spotty skin
pigmentation). Acromegaly is rarely caused by ectopic growth hormone-
releasing hormone (GHRH) or GH secreted by a lymphoma, hypothalamic
tumor, bronchial carcinoid, or pancreatic tumor.
Clinical Findings
Symptoms and Signs
Excessive GH causes tall stature and gigantism if it occurs before closure of
epiphyses. Afterward, acromegaly develops. The term "acromegaly,"
meaning extremity enlargement, seriously understates the manifestations.
The hands enlarge and a doughy, moist handshake is characteristic (see
photograph). The fingers widen, causing patients to enlarge their rings.
Carpal tunnel syndrome is common. The feet also grow, particularly in shoe
width. Facial features coarsen since the bones and sinuses of the skull
enlarge; hat size increases. The mandible becomes more prominent, causing
prognathism and malocclusion. Tooth spacing widens (see photograph).
Macroglossia occurs, as does hypertrophy of pharyngeal and laryngeal
tissue; this causes a deep, coarse voice and sometimes makes intubation
difficult. Obstructive sleep apnea may occur. A goiter may be noted.
Hypertension (50%) and cardiomegaly are common. At diagnosis, about 10%
of acromegalic patients have overt heart failure, with a dilated left ventricle
and a reduced ejection fraction. Weight gain is typical, particularly of muscle
and bone. Insulin resistance is usually present and frequently causes
diabetes mellitus (30%). Arthralgias and degenerative arthritis occur.
Overgrowth of vertebral bone can cause spinal stenosis. Colon polyps are
common, especially in patients with skin papillomas. The skin may also
manifest hyperhidrosis, thickening, cystic acne, and areas of acanthosis
nigricans.
GH-secreting pituitary tumors usually cause some degree of hypogonadism,
either by cosecretion of PRL or by direct pressure upon normal pituitary
tissue. Decreased libido and impotence are common, as are irregular menses
or amenorrhea. Secondary hypothyroidism sometimes occurs;
hypoadrenalism is unusual. Headaches are frequent. Temporal hemianopia
may occur as a result of the optic chiasm being impinged by a suprasellar
growth of the tumor.
Laboratory Findings
The patient should be fasting for at least 8 hours (except for water), not
acutely ill, and should not have exercised on the day of testing. A serum
specimen is obtained and assayed for the following: IGF-I (increased to over
five times normal in most acromegalics), PRL (cosecreted by many GH-
secreting tumors), glucose (diabetes is common in acromegaly), liver
enzymes and blood urea nitrogen (BUN) (hepatic or renal failure can
misleadingly elevate GH), serum calcium (to screen for
hyperparathyroidism), serum inorganic phosphorus (frequently elevated),
serum free T4, and TSH (secondary hypothyroidism is common in
acromegaly; primary hypothyroidism may increase PRL, and hyperthyroidism
may occur as a result of excess TSH).
Glucose syrup (75 g) is then administered orally, and serum GH is measured
60 minutes afterward; acromegaly is excluded if the serum GH is less than 1
ng/L (immunoradiometric assay [IRMA] or chemiluminescent assays) or less
than 2 ng/L (older radioimmunoassays) after glucose syrup, and if the serum
IGF-I is normal.
Imaging
MRI shows a pituitary tumor in 90% of acromegalics. MRI is generally
superior to CT scanning, especially in the postoperative setting. Radiographs
of the skull may show an enlarged sella and thickened skull (see x-ray).
Radiographs may also show tufting of the terminal phalanges of the fingers
and toes (see x-ray). A lateral view of the foot shows increased thickness of
the heel pad.
Differential Diagnosis
Active acromegaly must be distinguished from familial coarse features, large
hands and feet, and isolated prognathism and from inactive ("burned-out")
acromegaly in which there has been a spontaneous remission due to
infarction of the pituitary adenoma. GH-induced gigantism must be
differentiated from familial tall stature and from aromatase deficiency. (See
Osteoporosis.)
Misleadingly high serum GH levels can be caused by exercise or eating just
prior to the test; acute illness or agitation; hepatic or renal failure;
malnourishment; diabetes mellitus; or concurrent treatment with estrogens,
-blockers, or clonidine.

Complications
Complications include hypopituitarism, hypertension, glucose intolerance or
frank diabetes mellitus, cardiac enlargement, and cardiac failure. Carpal
tunnel syndrome may cause thumb weakness and thenar atrophy. Arthritis
of hips, knees, and spine can be troublesome. Cord compression may be
seen. Visual field defects may be severe and progressive. Acute loss of vision
or cranial nerve palsy may occur if the tumor undergoes spontaneous
hemorrhage and necrosis (pituitary apoplexy). Patients with acromegaly are
more likely to develop colon polyps.
Treatment
Endoscopic transnasal, transsphenoidal pituitary microsurgery removes the
adenoma while preserving anterior pituitary function in most patients.
Surgical remission is achieved in about 70% of patients followed over 3
years. GH levels fall immediately; diaphoresis and carpal tunnel syndrome
often improve within a day after surgery. Transsphenoidal surgery is usually
well tolerated, but complications occur in about 10% of patients including
infection, cerebrospinal fluid leak, and hypopituitarism. Hyponatremia can
occur 4–13 days postoperatively and is manifested by nausea, vomiting,
headache, malaise, or seizure. It is prudent to monitor sodium levels
postoperatively. Dietary salt supplements for 2 weeks postoperatively may
prevent this complication.
Patients who do not have a clinical or biochemical remission after surgery
are treated with a dopamine agonist (eg, cabergoline), somatostatin analogs,
pegvisomant, or a combination of these medications. Cabergoline may be
used first, since it is an oral medication. Cabergoline therapy is most
successful for tumors that secrete both PRL and GH, but can also be effective
for patients with normal serum PRL levels. Therapy with cabergoline will
shrink one-third of such tumors by more than 50%. The initial dose is 0.25
mg orally twice weekly, which is gradually increased to a maximum dosage
of 1 mg twice weekly, if tolerated by the patient based upon serum GH and
IGF-I levels. Side effects of cabergoline include nausea, fatigue, constipation,
abdominal pain, and dizziness. Cabergoline is expensive.
Octreotide and lanreotide are somatostatin analogs that are given by
subcutaneous injection. Short-acting octreotide acetate in doses of 50 mcg is
injected three times daily. Responders who tolerate the drug are switched to
long-acting octreotide acetate injectable suspension in a dosage of 20 mg
intragluteally per month. The dosage may be adjusted—up to a maximum of
40 mg monthly—to maintain the serum GH between 1 and 2.5 ng/mL,
keeping IGF-I levels normal. Lanreotide SR (not available in the United
States) is given by subcutaneous injection at a dosage of 30 mg every 7–14
days. Lanreotide Autogel (not available in the United States) is a newer
formulation that is administered by deep subcutaneous injection in doses of
60–120 mg every 28 days; this preparation is better tolerated than
lanreotide SR. All somatostatin analogs are expensive and must be continued
indefinitely or until other treatment has been effective. Octreotide long-
acting release (LAR) preparations (Sandostatin LAR depot) are superior to
shorter-acting octreotide, ultimately achieving serum GH levels under 2
ng/mL in 79% of patients and normal serum IGF-I levels in 53% of patients.
Headaches often improve, and tumor shrinkage of about 30% may be
expected. Acromegalic patients with pretreatment serum GH levels
exceeding 20 ng/mL are less likely to respond to octreotide therapy. Side
effects are experienced by about one-third of patients and include injection
site pain, loose acholic stools, abdominal discomfort, or cholelithiasis.
Pegvisomant is a GH receptor antagonist that blocks the effects of GH.
Pegvisomant therapy produces symptomatic relief and normalizes serum
IGF-I levels in over 90% of acromegalic patients. The starting dosage is 10
mg subcutaneously daily. The maintenance dosage can be increased by 5–10
mg every 4–6 weeks, based on serum IGF-I levels and liver transaminase
levels; the maximum dosage is 30 mg subcutaneously daily. Pegvisomant
does not shrink GH-secreting tumors. Patients need to be monitored carefully
with visual field examinations, GH levels, and MRI scanning of the pituitary.
Side effects of pegvisomant can include injection site reactions, hepatitis,
edema, flu-like syndrome, nausea, and hypertension. In acromegalic
diabetics, hypoglycemic drugs are reduced to avoid hypoglycemia during
pegvisomant therapy. The effectiveness of pegvisomant is reduced by
coadministration of opioids or propoxyphene. Pegvisomant is extraordinarily
expensive.
Acromegalic patients who have not had a complete remission with
transsphenoidal surgery or medical therapy may be treated with
stereotactic radiosurgery administered by gamma knife, heavy particle
radiation, or adapted linear accelerator. Some medical centers are using
pituitary gamma knife radiosurgery as the initial treatment with reported
success rates of 20–90%. Radiosurgery precisely radiates the pituitary tumor
in a single session and reduces radiation to the normal brain. However, it
cannot be used for pituitary tumors with suprasellar extension due to the risk
of damaging the optic chiasm. Radiosurgery can be used for pituitary tumors
invading the cavernous sinus, since cranial nerves III, IV, V, and VI are less
susceptible to radiation damage. Radiosurgery can also be used for patients
who have not responded to conventional radiation therapy.
Prognosis
Patients with acromegaly have increased morbidity and mortality from
cardiovascular disorders; those who are treated and have a glucose-
suppressed serum GH level less than 2.5 ng/mL (radioimmunoassay) or
under 1 ng/mL (immunofluorometric assay) and normal age-adjusted serum
IGF-I levels have reduced morbidity and mortality. Patients with untreated or
persistent acromegaly tend to have premature cardiovascular disease and
progressive acromegalic symptoms. Transsphenoidal pituitary surgery is
successful in 80–90% of patients with tumors less than 2 cm in diameter and
GH levels less than 50 ng/mL. Extrasellar extension of the pituitary tumor,
particularly cavernous sinus invasion, reduces the likelihood of surgical cure.
Adjuvant medical therapy has been quite successful in treating patients who
are not cured by pituitary surgery. Postoperatively, normal pituitary function
is usually preserved. Soft tissue swelling regresses but bone enlargement is
permanent. Hypertension frequently persists despite successful surgery.
Conventional radiation therapy (alone) produces a remission in about 40% of
patients by 2 years and 75% of patients by 5 years after treatment. Gamma
knife or cyberknife radiosurgery reduces GH levels an average of 77%, with
20% of patients having a full remission after 12 months. Patients with
pituitary adenomas that abut the optic chiasm can be treated with
cyberknife radiosurgery, controlling tumor growth and preserving vision in
most patients. Heavy particle pituitary radiation produces a remission in
about 70% of patients by 2 years and 80% of patients by 5 years. Radiation
therapy eventually produces some degree of hypopituitarism in most
patients. Conventional radiation therapy may cause some degree of organic
brain syndrome and predisposes to small strokes. Patients must receive
lifelong follow-up, with regular monitoring of serum GH and IGF-I levels.
Serum GH levels over 5 ng/mL and rising IGF-I levels usually indicate a
recurrent tumor.
Hypopituitarism may occur, due to the tumor itself, pituitary surgery, or
radiation therapy. Hypopituitarism may develop years following radiation
therapy, so patients must have regular clinical monitoring of their pituitary
function.