Abstract
Pituitary tumors are frequently encountered intracranial neoplasms. They present with a variety of
clinical manifestations that include symptoms and signs of excessive hormone secretion by the tumor,
signs of hormone decits by the normal pituitary gland and others related to expansion of the tumor
mass and the resulting compression of surrounding structures such as the optic chiasm and cranial
nerves. Advances in molecular biology, immunocytochemical staining and imaging, and the
introduction of new treatment options have improved our understanding of the natural history of these
adenomas and their management. Available treatments include surgical, medical and radiation
therapy. Although the primary treatment for each tumor type may vary, it is important to consider all
available options and select the most applicable for that patient. The interaction of all members of
management team, including the primary care provider, the endocrinologist and the neurosurgeon in
selecting the treatment course can only improve therapeutic outcome. Regardless of the initial choice
of treatment, follow-up of all patients should be maintained indenitely. The managing physician
should be familiar with the natural history and long-term complications of pituitary adenomas, and
with the side effects of treatments given over the years.
Endocrine-Related Cancer (2001) 8 287305
Introduction
Pituitary tumors are the most commonly encountered
intracranial neoplasms. The prevalence of these tumors in
autopsy series is reported to be 520%, with most series
estimating the prevalence to be approximately 10% (Burrows
et al. 1981, Molitch & Russell 1990). It is interesting to note
the vast majority of these tumors discovered at autopsy are
small (<10 mm) or microadenomas. The use of magnetic
resonance imaging (MRI), in otherwise healthy individuals
revealed a similar prevalence of incidentally discovered
pituitary adenomas (Hall et al. 1994). Although the
frequency or prevalence of clinically recognized tumors are
not clearly established, they are estimated to be lower than
those reported in autopsy studies. Advances in biochemical
testing and neuroimaging techniques over the past two
decades have facilitated early recognition of pituitary tumors
and revolutionized their management. The introduction of
immunocytochemical methods and more recently the
renements in techniques in molecular biology, have led to
changes in the classication and better appreciation of the
pathogenesis of these tumors. In this article, we will review
the current classication, pathogenesis and biologic behavior
Prevalence
(% of all tumors)
Hormone staining
Clinical manifestations
4045
20
Prolactin
GH prolactin
Signs of hyperprolactinemia
Acromegaly
1012
ACTH others
Hypercortisolism
15
510
12
PRL, prolactin
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Pathophysiology of clinical
manifestations
Patients with pituitary tumors present with a variety of signs
and symptoms that can be divided into any of the following
categories:
1) Signs and symptoms related to, or caused by,
excessive hormone production: e.g., symptoms and signs of
hypercortisolism in patients with ACTH-secreting adenomas
or signs of acromegaly in patients with GH-secreting
adenomas.
2) Signs and symptoms related to the mechanical effects
of an expanding tumor within the sella turcica. Such
symptoms include headaches, visual disturbances and cranial
nerve palsies.
3) Signs and symptoms of impaired normal pituitary
function (i.e., partial or panhypopituitarism). This is almost
always seen in patients with macroadenomas, the main
exception to this being when the impairment in pituitary
function is functional in nature, resulting from the effects of
excess hormone secretion. A common example of the latter
is the nding of hypogonadism in patients with
prolactin-secreting adenomas.
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Surgical treatment
The
primary
approach,
transsphenoidal
surgical
adenomectomy, is very effective, with low morbidity and
mortality. Normal pituitary function is most often preserved
(Hout et al. 1988) and recovery of lost function is common
(Arafah et al. 1994). Despite the enormous size of some
tumors, the transsphenoidal approach is preferred by most
neurosurgeons. A subsequent craniotomy may be necessary
in some patients with residual, suprasellar tumor that did not
descend during the transsphenoidal approach. Surgical
treatment results in improvement of visual symptoms in at
least 7080% of patients with preoperative chiasmal
compression (Young et al. 1996).
Complete tumor removal can be achieved in most, but
not all patients. The outcome of surgery is determined by the
surgeons experience, the size of the adenoma and the degree
of its extension beyond the sella turcica (Freda & Wardlaw
1999, Shimon & Melmed 1998). Extension of the tumor into
the cavernous sinus is almost always associated with
incomplete removal. Recurrence of pituitary adenoma after
apparent complete surgical resection is reported to occur in
1025% of patients, usually within the rst 4 years.
However, recurrences and continued tumor growth have been
seen after long-term follow-up. Therefore, periodic hormonal
testing and repeat imaging studies are recommended
annually. The initial MRI follow-up after surgery is usually
done 34 months later, to allow time for healing and removal
of post-operative debris. Transsphenoidal surgery is
generally well tolerated with minimal morbidity and
mortality. The complication rate is usually low, in
experienced hands, and is inuenced by size and location of
the adenoma, in addition to the patients medical condition.
Commonly encountered side-effects or complications include
diabetes insipidus in 515% of patients, which is often
transient, and, less commonly, infection and leakage of
cerebrospinal uid.
The hypopituitarism found in the majority of patients at
presentation can very often be reversible. Recovery of
pituitary function can be documented to occur immediately
after operation (Arafah et al. 1994). This is even true in
patients with pituitary tumor apoplexy, in whom recovery of
pituitary function has also been demonstrated immediately
after operation (Arafah et al. 1997). It is, therefore, important
to monitor pituitary function after surgery and assess the
potential for recovery, and to document persistence of
previous function.
Radiation therapy
Radiation therapy has been advocated as a treatment option,
for different reasons. In earlier studies preceding recent
advances in neurosurgical techniques, radiation therapy was
recommended as a primary treatment for all types of pituitary
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Medical treatment
Primary medical treatment is available for most pituitary
tumors. It is well tolerated in general, but usually entails
several years of therapy at least. There are various
medications available depending on the different hormones
secreted and on the specic level of action of the drug along
the hypothalamicpituitaryend-organ axis. The specic
therapies will be discussed under each tumor type.
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Drugs
Dopamine receptor antagonists
Inhibitors of dopamine synthesis and release
Estrogens
Hypothalmic disease
Tumors
Irradiation
Inlitrative disease
Inammation
Granulomas
Neurogenic
Chest wall/spinal cord lesions/injury
Breast stimulation
Suckling
Treatment options
Specic treatment depends to a large degree on the size of
the tumor, its extent, the patients preference and the
available expertise for the managing physician (Besser 1993,
Molitch et al. 1997). Generally, the two main therapeutic
options include surgical and medical treatments, as will be
detailed here. Both options should be presented and
discussed with the patient before a decision is made.
Although radiation therapy is still an option, it is rarely used
in patients with prolactinomas, particularly those with
microadenomas. The availability of effective surgical and
medical treatments have limited the need for using radiation
to patients with large tumors that are resistant to standard
treatment.
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Others
Primary hypothyroidism
Renal failure
Idiopathic
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GH-secreting adenomas
Clinical manifestations and diagnosis
These tumors account for approximately 20% of all pituitary
tumors and present with the clinical syndrome of acromegaly
in adults and gigantism in children. The incidence of
acromegaly is 34 cases per million, with a prevalence of
4060 cases per million (Lissett et al. 1998). There are no
known sex, ethnic or racial differences. The peak incidence
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Medical therapy
Several pharmacologic approaches are used in the adjunctive
therapy of patients with hypercortisolism (Arafah & Pearson
1985, Tsigos et al. 1995). Drugs that inhibit adrenal cortisol
secretion include ketoconazole, which is known to inhibit
cytochrome P450 enzymes involved in steroid synthesis. In
doses of 6001200 mg/day, ketoconazole is relatively
effective in controlling hypercortisolism. Its effects are
reversible once the drug is discontinued. Hence, medical
therapy is provided to supplement other forms of treatments
such as irradiation.
Other drugs used to control hypercortisolism include
aminoglutathemide and metyrapone. Both agents are also
used as adjunctive treatments and are more expensive, less
effective and have more side effects than ketoconazole.
Another agent used occasionally in patients with Cushings
disease is mitotane (Lysodren or o,p-DDD). This agent
results in adrenal atrophy and is used predominantly in
patients with adrenal carcinoma. It has signicant side effects
that would limit its routine use in patients with Cushings
disease. Despite initial favorable reports, medical treatment
of excessive secretion of ACTH with cyproheptadine, a
serotonin and histamine antagonist, or with the dopamine
agonist, bromocriptine, have been disappointing and rarely,
if ever, effective.
Octreotide is not effective in the medical management of
Cushings disease caused by ACTH-secreting pituitary
adenomas. However, it is reported to be very effective in the
treatment of ectopic ACTH secretion by carcinoid tumors
and in patients with food-dependent or gastric inhibitory
peptide-mediated hypercortisolism (Lacroix et al. 1992,
Herder & Lamberts 1999).
Nelsons syndrome
This syndrome is seen in patients with Cushings disease
who were previously treated with bilateral adrenalectomies
to control the state of hypercortisolism. Removal of the
source of hypercortisolism leads to further increases in
plasma ACTH concentrations from previously known, or at
times unrecognized, ACTH-secreting pituitary adenomas.
Studies showed that pituitary irradiation after bilateral
adrenalectomies does not necessarily prevent the development of Nelsons syndrome. The clinical manifestations of
Nelsons syndrome include hyperpigmentation, in addition to
signs and symptoms related to the growth of the tumor (i.e.
headaches and visual symptoms). Such tumors can be very
invasive, extending into surrounding structures such as
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Radiation therapy
In patients with gonadotroph tumors, radiation therapy can
be used in patients whose adenomas could not be removed
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Management
Patients education about their disease is an important aspect
in the management of hypopituitarism that is often
overlooked. Patients should understand the impact of
hormone decit on their daily lives and activities, and to be
fully aware that treatment may need to be modied in the
event of intercurrent illnesses, accidents or surgical
procedures. A medic-alert bracelet or necklace, identifying
the patient as hypopituitary and receiving glucocorticoids,
should be always worn.
Treatment of hypopituitarism should not be rigid but,
instead, always individualized. Management should take into
consideration the patients age, sex, work schedule,
education, original disease process and clinical history.
Either hydrocortisone (cortisol) or cortisone acetate in two
or, preferably, three divided doses totaling 1525 mg of the
former steroid, represent the usual glucocorticoid
replacement therapy. The goal is to provide the least amount
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Acknowledgements
The authors wish to acknowledge the valuable help of all
personnel of The Clinical Research Center for conducting
the studies, and Paul Hartman and Elizabeth Smith for their
technical assistance.
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