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Acromegaly represents the somatic
manifestation of a pathologic excess of growth hormone secretion. When
this condition is present in childhood, before the closure of the
epiphyses of the long bones, it leads to gigantism. Acromegalic persons
and giants have been described in literature and art throughout history.
The unfortunate people afflicted with this condition have been held in
awe, and enormous strength and physical powers have been attributed to
them, although these are rarely present, at least for any extended
period of time.
Historical Aspects
Pierre Marie described acromegaly as a
medical syndrome in 1886. The causative role of the pituitary gland was
not recognized at that time, however, and the enlarged pituitaries found
at autopsy were thought by many to be just another feature of the
hypertrophy that affected many parts of the body. By 1900,
pathophysiologic correlations by Benda and others had suggested that the
hypertrophy or hyperplasia of the pituitary might be the cause of
acromegaly, and the adenomatous nature of pituitary enlargement was
ultimately documented.
Pathogenesis and Natural
History
The vast majority of cases of acromegaly
are produced by neoplasms of the somatotropic cells of the anterior
pituitary. These tumors appear to arise independently of alterations in
other hormones and tropic factors. Some tumors (20 to 30 percent) have
the ability to produce excessive amounts of both growth hormone (GH) and
prolactin. Acromegaly can also occur as a result of hyperplasia of the
somatotropes either independently or in response to excessive amounts of
growth-hormone-releasing factor. This latter syndrome has been seen in
association with a hypothalamic hamartoma, a pancreatic adenoma, and a
mediastinal carcinoid tumour.
Spontaneous remission of acromegaly may
occur but is rare and usually is associated with infarction or
haemorrhage in the tumour. Spontaneous haemorrhage may also present as
pituitary apoplexy, threatening vision and life; fortunately, apoplexy
also occurs rarely. Persistent active acromegaly is the usual course
associated with a growth-hormone-secreting pituitary tumour. Structural
changes occur in the cardiovascular system and are frequently
associated with hypertension and severe atherosclerosis. Diabetes
mellitus and its many complications are common in these patients. In
addition to morphologic changes in soft tissues with enlargement of the
digits and loss of dexterity, joints are commonly affected, resulting in
severe and progressive osteoarthritis. Early therapy is recommended to
forestall these pathophysiologic changes.
Clinical Manifestations
Patients with active acromegaly present
with a wide spectrum of symptoms and signs. Those who have elevated
growth hormone in childhood develop gigantism, with disproportionately
long arms and legs and nearly proportional increases in the size of
other body parts. The tallest accurately measured acromegalic giant was
2.3 m tall, but others undoubtedly have been taller. Once the epiphyses
close, excessive growth hormone produces acromegaly with focal
enlargement of bones and soft tissues in various parts of the body.
There is thickening of the heel and palm pads and of the soft tissues of
the fingers and toes. The facial features become characteristically
coarse, and enlargement of the nose and lips occurs. The jaw enlarges,
and the teeth become mal occluded. The tongue and heart both enlarge,
leading to partial airway obstruction on the one hand and to decreased
cardiac output on the other. The scalp may become hypertrophic enough to
appear corrugated. There is exuberant enlargement of the air sinuses in
the thickened skull, leading to a "beetle brow" appearance. Bone density
is generally increased, and joints and costochondral junctions undergo
hypertrophy. Later in life, severe degenerative osteoarthritis and
spinal stenosis may occur. The ligaments thicken, and median thenar
neuropathy from the carpal tunnel syndrome is a common presenting
complaint. The generalized effect on the cardiovascular system leads to
hypertension.
Abnormalities in glucose metabolism are
common, and diabetes mellitus is a frequent finding. Associated
hypothyroidism may occur, and a small but significant number of patients
(about 5 percent) will have a multiple endocrine neoplasia (MEN)
syndrome, most commonly with parathyroid and pancreatic adenomas. These
patients with MEN-1 (Wermer's syndrome) may suffer from hypercalcemia
and urolithiasis, hyperinsulinemia, and gastric ulcer. Because about 20
percent of acromegalic patients also have hyperprolactinemia,
premenopausal women may develop oligo-menorrhea, amenorrhea, and
galactorrhea. Other symptoms related to prolactin include loss of libido
in both sexes and impotence in men. Large tumors may produce
hypopituitarism with fatigue, anaemia, pallor, poor response to stress,
and hypogonadotropism.
Compression of the optic apparatus from
suprasellar extension of the tumour may lead to photophobia, progressive
visual loss (usually a bitemporal hemianopia), and optic atrophy. Sudden
loss of vision secondary to apoplexy within the pituitary adenoma
(haemorrhage and/or necrosis) may occur. Compression of the cavernous
sinus from lateral expansion of the tumour may lead to complaints of
trigeminal pain and diplopia. Invasive tumors may produce cerebrospinal
rhinorrhea.
Acromegaly undoubtedly has direct effects
on the nervous system, perhaps related to abnormalities of peptide
neurotransmitters. Acromegalic patients may have a greater than normal
incidence of neuropathies and myopathies, epilepsy, dementia, and
psychological disturbances. Male to female ratio is 3:2.
Therapy
Trans-sphenoidal Surgery
The first
operation on the pituitary for acromegaly was performed in
Vienna in 1908 by Hochenegg using Schloffer's trans-sphenoidal
approach. In the United States, the first such operation was
performed by Harvey Cushing in 1909. In the first
transsphenoidal operation for a pituitary tumour he used a
superior transnasal approach, resecting the upper septum and the
turbinates. He soon perfected the sublabial rhinoseptal
submucosal approach and operated on some 60 acromegalic patients
using this method.
Radiation Therapy
Radiation
therapy for acromegaly also began in 1909 and has been applied
with considerable success. Most patients have been treated with
conventional photon therapy, currently best delivered by a
linear accelerator using multiple ports and appropriate
shielding of the eyes. Interstitial radiation by implantation of
198Au
or
90y
sources has been used in the past, and heavy particle external
therapy using neutrons and alpha particles has also been
effective. Radiosurgery using stereotactically delivered focal
radiation from a Gamma Knife, linear accelerator, or proton beam
is also an effective adjunct in the management of acromegaly.
Craniotomy
craniotomy in the acromegalic
patient is made difficult by the thick cranial bone and
exuberant frontal sinuses characteristic of this condition.
Large lesions with significant suprasellar or parasellar
extension may still require craniotomy if adequate removal of
the tumour is to be accomplished. Bronson Ray became
extraordinarily skilled in the transfrontal approach and
reported his excellent results in a large series of patients.
Currently, when craniotomy is indicated, it is usually
accomplished by either the transfrontal or the pterional
approach, depending on the anatomy of the lesion.
discovery and isolation of
somatostatin (growth hormone release-inhibiting factor) gave
great promise for medical control of acromegaly. Unfortunately,
the effects of this peptide are transient, and the use of
somatostatin analogues (e.g., octreotide acetate) for control of
excessive GH secretion has numerous problems that often make it
impractical. Discovery of the fact that GH release is under
significant dopaminergic control has led to the use of the
dopamine agonist bromoergocriptine, or bromocriptine, in the
management of acromegaly. Approximately 75 percent of patients
with active acromegaly, will respond to bromocriptine treatment
with a decrease in GH production. Unfortunately, high doses (15
to 40 mg/day) are usually required, and reduction of GH levels
to normal is rare. The response to bromocriptine appears to be
most dramatic in acromegalic patients who also have
hyperprolactinemia. These patients commonly will show shrinkage
of the bulk of the tumour after bromocriptine therapy. Although
manifestations of the tumour return after bromocriptine therapy
is discontinued, continued bromocriptine therapy is thought by
many to protect against further growth of the tumour. Tumour
shrinkage is less reliable and less dramatic with the use of
octreotide, but the tumour shrinks to some degree in up to 20
percent of the patients who respond to the drug with lowered
growth hormone levels.
Results
Surgical Management
Currently, virtually all
acromegalic patients treated surgically are operated on
initially with the transsphenoidal microsurgical approach.
Criteria for a satisfactory result are clinical improvement in
the symptoms and signs of acromegaly and normalization of GH
secretion. The latter is measured by a fall in serum GH values
to less than 2 ng/ml during a glucose tolerance test. The
results are discussed within the limits of these rigid criteria.
Clinical improvement occur in 97
percent of the patients. Endocrinologic success has been more
difficult to achieve and is related to the biological and
morphologic classification of the tumour and to the preoperative
level of GH. Those patients with basal GH values less than 50
ng/ml have the best chance for normalization after surgery.
Tumors are classified as microadenomas (less than 10 mm in
diameter), diffuse (enclosed) adenomas, and invasive adenomas
according to their size and the findings at operation. Those
patients with microadenomas have the best prospects for "cure"
following surgery. The worst results are in patients with
invasive tumors and markedly elevated GH values.
Planned total hypophysectomy is
abandoned. Alcohol or Zenker's solution is not in routine use to
treat the tumour bed.
When more liberal criteria are
used for "cure" (GH less than 10 ng/ml), satisfactory results
are obtained in more than 90 percent of patients with
microadenoma.
Critical summaries of other forms
of primary management are not readily available, but reports
have been published of "success" rates of 64 percent for
craniotomy, 27 to 41 percent for radioactive implants, 76 to 86
percent for cryotherapy, 88 percent for thermocoagulation, 23
to 81 percent for conventional radiation therapy, and 53 to 91
percent for proton and heavy particle therapy. These reports
were summarized by Laws and colleagues in 1982.
Adjunctive Management of Acromegaly
It has been
the general policy to recommend postoperative radiation in
patients with tumors having suprasellar extension or invasive
characteristics. When elevation of postoperative growth hormone
levels increases over time, radiation therapy is also usually
recommended. Bromocriptine or Sandostatin therapy is considered
in cases in which active acromegaly persists despite surgery and
radiation therapy and in cases of invasive tumors that appear to
remain active or enlarge over time.
Complications of
Trans-sphenoidal Surgery for Acromegaly
There have
been no operative (30-day) deaths in E. Laws transsphenoidal
series, which included 445 acromegalies. Two arterial
injuries occurred, one of the carotid artery. which was repaired
directly, and one of the anterior cerebral artery, which was
clipped. One patient with compromised vision from a large tumour
developed further loss of vision, which later recovered. Another
patient developed optic nerve type visual loss, which resolved
after craniotomy and radiation therapy. Two patients developed
cerebrospinal rhinorrhea, which was successfully repaired in
each with a second transsphenoidal procedure. Significant
intraoperative bleeding occurred in three patients; in two the
procedure was abandoned, with later successful surgery in one,
and in the third, multiple transfusions allowed completion of
the original procedure. Loss of preoperative normal anterior
pituitary function occurred in six patients, and permanent
diabetes insipidus in four. One patient developed severe
sinusitis in the postoperative period, and another developed a
nasoseptal perforation. Fortunately, major postoperative
complications have been rare
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