US Pharm. 2012;37(5)(Oncology):8-11.
ABSTRACT: Pituitary tumors (adenomas) occur in approximately 17% of the U.S. population.1 Pituitary adenomas constitute 10% to 25% of all intracranial tumors, the majority of which are benign.2,3
Two theories have been formulated regarding the cause of pituitary
adenoma development: intrinsic abnormalities versus hormonal
stimulation.4,5 Recent technological advances in molecular
biology, however, indicate that pituitary tumors arise from a single
cell mutation followed by clonal expansion.5 Causes and risk
factors are unique to each of the tumor types identified in this
article; therefore, selection of the appropriate methods of diagnosis
and treatment remains paramount.
Pituitary tumors, or adenomas, are common neoplasms, occurring in approximately 17% of the U.S. population.1 Currently, pituitary adenomas account for 10% to 25% of all intracranial tumors.2 The majority of these tumors are benign, and the development of cancer is rare.3
Because of its ability to secrete hormones that control many glands
throughout the body, the pituitary gland is sometimes known as the
“master endocrine gland.”2 This gland is a pealike structure that is located below the hypothalamus and above the sphenoid bone.6
Surrounded by the sella turcica—a bony, saddle-shaped structure—the
pituitary gland consists of an anterior lobe and a posterior lobe. The
posterior lobe is responsible for the release of oxytocin and
antidiuretic hormone (ADH), whereas the anterior lobe synthesizes and
releases six hormones: prolactin (PRL), adrenocorticotropic hormone
(ACTH), growth hormone (GH), thyroid-stimulating hormone (TSH),
luteinizing hormone (LH), and follicle-stimulating hormone (FSH).6 Abnormal cell growth in the pituitary gland constitutes a pituitary adenoma.2 Smaller adenomas, or microadenomas, are 1 cm or less; larger adenomas, or macroadenomas, are greater than 1 cm.2
Adenomas may be graded radioanatomically as follows: <1 cm, no sella
expansion (grade 1); ≥1 cm, possible sella expansion (grade 2); ≥1 cm,
invasion of floor or suprasellar extension (grade 3); and ≥1 cm,
destruction of sella (grade 4).2
Signs, Symptoms, and Complications
Pituitary adenomas generate physical and biochemical changes. The
size of the adenoma can influence the symptoms experienced. General and
physical signs and symptoms include nausea, vomiting, vertigo, headache,
impaired vision, runny nose (cerebrospinal fluid [CSF] leak),
confusion, and seizures. Specific signs and symptoms are associated with
certain types of pituitary tumor (TABLE 1).3,5,7-9
Because of the pituitary gland’s proximity to the regions of the
brain, adenoma-associated morbidities include stroke, visual loss,
meningitis, CSF leak, and cranial palsy.10 If the adenoma is
diagnosed early, prognosis can be excellent, with surgery for total
tumor removal carrying a mortality rate of less than 1%.10
There have been two theories concerning the origin of pituitary
tumors. One hypothesis was that pituitary adenomas represented intrinsic
abnormalities within the gland itself; the other theory was that
adenomas originated from continuous stimulation by a hypothalamic
hormone or factor.5 However, recent technological advances in
molecular biology have shown that pituitary tumors arise from a single
cell mutation followed by clonal expansion. Pituitary neoplasia is a
multistep process involving dysregulation of cell growth, cell
differentiation, and hormone production.5
Causes and Risk Factors
Whereas some pituitary tumors are idiopathic, others are linked to a
rare genetic disorder, multiple endocrine neoplasia type 1 (MEN1). MEN1
can cause hyperactivity or enlargement of various endocrine glands,
including the pituitary gland. Carney complex, another genetic cause of
pituitary adenomas, is characterized by spotty skin pigmentation and
tumors of connective tissue and the endocrine glands. While each of the
aforementioned may cause pituitary tumors, other factors, such as
increasing age and certain genetic conditions, may place patients at
increased risk for developing pituitary tumors and therefore must also
Hormone measurement and imaging studies are the best methods for diagnosing pituitary adenomas.9
In addition, diagnostic tests that assess the hypersecretion of
hormones can aid in the establishment of a differential diagnosis or the
confirmation of a pituitary adenoma.
An unusually high prolactin level is almost exclusively associated
with prolactinomas, but moderate elevation may occur during pregnancy or
with the use of medications such as metoclopramide.7 In GH-secreting adenomas, an elevation of insulin-like growth factor 1 (IGF-1) is the most reliable indicator.7 The oral glucose tolerance test assesses GH levels after administration of glucose.12 Insufficient GH suppression after glucose administration is indicative of pituitary dysfunction.7 The release of IGF-binding protein-3 (IGFBP-3), which binds to IGF-1, depends upon the presence of GH.12 A determination of IGFBP-3 can be useful in diagnosing patients with normal levels of IGF-1 and GH.12
The diagnosis of ACTH-secreting adenomas relies primarily on cortisol
elevation, which often is detected during preliminary testing.7
Excessive cortisol release may be investigated by conducting 24-hour
urinary free cortisol, low-dose dexamethasone-suppression, or late-night
salivary cortisol tests.7 The differential diagnosis of
Cushing’s disease involves evaluation of plasma ACTH levels, high-dose
dexamethasone-suppression tests, and corticotropin-releasing hormone
stimulation tests.7 The most reliable tool for differential diagnosis is measurement of ACTH via venous drainage of the pituitary gland.7 TSH-secreting adenomas are characterized by increased levels of TSH, which will eventually trigger symptoms of hyperthyroidism.7
Hyperthyroidism due to TSH-secreting tumors may be distinguished from
other causes of the condition by little to no TSH response during
thyrotropin-releasing hormone stimulation and a high alpha subunit/TSH
ratio.7 Hypersecretion of hormones is rare in cases of FSH-
and LH-secreting tumors; however, free beta-FSH or alpha subunit
secretion has been observed in some cases.7 For all types of pituitary adenoma, MRI is the recommended imaging method for assessing the tumor’s size and location.7,13
Treatment of a pituitary tumor depends upon several factors,
including tumor type and size and the rate and extent of progression
into the brain.3 Tumor removal via transsphenoidal surgery or
craniotomy is required if the tumor is affecting other physiological
structures, such as the optic nerve. In transsphenoidal surgery, an
incision is made under the upper lip or at the base of the nose between
the nostrils to allow the surgical instruments to reach the pituitary
gland via the sphenoid bone.2 An endoscope is used for
viewing purposes during the procedure, and a curette is used to remove
the tumor tissue on the pituitary gland. One advantage of this type of
surgery is the re-establishment of normal function in the pituitary
gland with no visible facial scarring. Transsphenoidal surgery is not
appropriate for tumors that have invaded nearby nerves or brain tissue.3
In a craniotomy, a more invasive incision is made in the upper part
of the skull to facilitate the removal of a portion of the skull to
reveal parts of the brain.3 The invasive nature of this
procedure is a factor in some of the adverse effects associated with the
surgical removal of pituitary adenomas.10
Radiation may be used to prevent tumor cells from replicating.3
The method of radiation depends upon the tumor’s characteristics. In
external radiation, a machine beams radiation at the abnormal growth,
whereas internal radiation involves placement of a radioactive substance
directly into or near the growth. In stereotactic radiation, a head
frame attached to the patient’s skull delivers a large dose of radiation
directly to the tumor.2
The type of tumor diagnosed determines which surgical procedure is performed (TABLE 2).
Gonadotroph Adenomas: Standard therapy for gonadotroph
adenomas has not been established. Most published data are based on case
reports and anecdotal experience.8 Suppression of the
secretory activity of the adenoma occasionally is accompanied by
improvements in visual-ﬁeld defects or tumor shrinkage. Attempts at
treating nonfunctioning pituitary tumors with dopamine agonists (i.e.,
bromocriptine and cabergoline) and somatostatin analogues have been
unsuccessful, partly because only a minority of these tumors have
dopamine or somatostatin receptors. Bromocriptine typically has little
effect on tumor size, but shrinkage has been reported in a few cases.
Similarly, octreotide has been successful at improving vision in some
patients, but the response is varied, and this drug should be reserved
for therapeutically unresponsive patients. Consequently, there is no
effective medical treatment for gonadotropin-secreting tumors.8
TSH-Secreting Pituitary Adenomas: TSH-secreting pituitary adenomas are rare, accounting for 1% to 2% of all pituitary tumors.5,14 Many TSH-secreting adenomas are stage III macroadenomas.7
The goal of treatment is to establish a state of euthyroidism. Patients
with these tumors who display hyperthyroid symptoms warrant medical
treatment. Great success has been observed with somatostatin analogues,
namely octreotide.7 Octreotide is also formulated as a
long-acting injection, which has been shown to increase cure rates by
80% to 90% compared with other therapies.5 Octreotide normalizes TSH levels in 79% of diagnosed patients and reduces tumor size in 52%.7
In high doses, dopamine agonists have been used to treat TSH-secreting
pituitary tumors, but they are less effective than octreotide, perhaps
because of abnormalities in adenoma dopamine receptor function.5
GH-Secreting Pituitary Adenomas: The goal of treatment
for GH-secreting adenomas is to normalize GH and IGF-1 while preserving
pituitary function. The initial treatment is transsphenoidal surgery.7 Ninety percent of microadenomas and 50% of macroadenomas are biochemically cured after resection.7
For patients with mediocre outcomes, therapy with a somatostatin
analogue is the next option, based on proven efficacy. Sandostatin,
which is typically reserved for postsurgical adjuvant therapy, is
frequently used preoperatively in patients with cardiovascular or
respiratory complications; it also is used to prevent perioperative
complications due to elevated GH levels.7
Pegvisomant, a GH analogue, may be utilized for tumors that secrete
GH. It blocks the effects of GH, but does not inhibit GH production or
tumor size.8 Dopamine agonists offer only limited results for
GH-secreting pituitary tumors; however, these agents are particularly
useful in the treatment of pituitary tumors that cosecrete PRL and GH,
with higher dosages required for efficacy.5
Prolactinomas: Bromocriptine and cabergoline are the drugs of choice for treating prolactinomas.2
These agents have been shown to effectively decrease prolactin levels
and reduce tumor size in about 75% of patients, possibly leading to
restoration of gonadal function.7 The initial dosing of
bromocriptine is 1.25 to 2.5 mg per day. The dosage must be increased
slowly to prevent nausea and dizziness.15 Gradual increases
of 2.5 mg per day over a period of 2 to 7 days are recommended. Each
dose should be taken with a meal or bedtime snack.15 The initial dosing of cabergoline (0.25 mg) is twice per week.15 The dosage must be titrated gradually, with increases made every 4 weeks.15
In addition to nausea and dizziness, common adverse effects noted with
these agents include vomiting, constipation, postural hypotension, and
Cabergoline has a number of therapeutic advantages over bromocriptine.7
For example, cabergoline has a significantly longer half-life, which
allows it to be administered once or twice per week, while bromocriptine
must be administered daily.7 Cabergoline is reported to have
less frequent and less severe side effects and is effective against
tumors that are resistant to bromocriptine.7,15 However, bromocriptine is less expensive and has longer market tenure than cabergoline.15
Additionally, bromocriptine has a more extensive history of
investigation in pregnant patients, making it the drug of choice during
Although dopamine agonists are effective for correcting hypogonadism,
other options, such as hormone replacement therapy, serve as an
alternative for restoring reproductive function.7
Furthermore, recent studies have suggested that temozolomide, based on
its favorable safety profile and significant reduction of hormone
secretion and tumor size, could be a new option for treating aggressive
ACTH-Secreting Tumors: The treatment of ACTH-secreting
tumors includes the utilization of drugs that inhibit adrenal cortisol
secretion. The drug of choice, ketoconazole, is usually initiated at 200
mg by mouth two or three times daily, with a recommended maintenance
dosage of 400 mg by mouth two or three times daily.5,17 Dosage adjustments are determined by monitoring 24-hour urinary free cortisol levels.17
The major adverse effect associated with high doses of ketoconazole is
hepatic impairment, so liver function must be regularly monitored during
treatment.7 Other therapeutic options to suppress cortisol secretion include metyrapone, aminoglutethimide, mitotane, and etomidate (TABLE 3).7
The pituitary gland secretes hormones that control various glands
throughout the body. Abnormal cell growth within this structure can
result in hormonal imbalances, which are a major cause of morbidity
associated with pituitary adenomas. Given the multiple types of
pituitary tumors that can arise, it is crucial in the diagnostic stage
to observe the patient’s signs and symptoms and to measure hormone
levels. Current surgical and pharmacologic treatment, coupled with close
monitoring, may reduce the incidence of complications of pituitary
adenomas, leading to increased progression-free survival.
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Accessed March 25, 2012.
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Accessed December 28, 2011.
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January 22, 2011.
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15. National Endocrine and Metabolic Diseases Information Service.
Accessed December 27, 2011.
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Cushing disease. Medscape Today. www.medscape.com/viewarticle/566310_2.
Accessed December 29, 2011.
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