pituitary tumors - cecity · disclosures: baha m. arafah, md, current author of this module, has no...

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Pituitary Tumors View online at http://pier.acponline.org/physicians/diseases/d263/d263.html

Module Updated: 2013-01-29

CME Expiration: 2016-01-29

Author

Baha M. Arafah, MD

Table of Contents

1. Screening ..........................................................................................................................2

2. Diagnosis ..........................................................................................................................3

3. Consultation ......................................................................................................................12

4. Hospitalization ...................................................................................................................15

5. Non-drug Therapy ..............................................................................................................16

6. Drug Therapy .....................................................................................................................20

7. Patient Counseling ..............................................................................................................23

8. Follow-up ..........................................................................................................................26

References ............................................................................................................................29

Glossary................................................................................................................................38

Tables ...................................................................................................................................39

Figures .................................................................................................................................48

http://pier.acponline.org/physicians/diseases/d263/d263.html

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1. Screening Top

Screen patients with MEN-I for the presence of pituitary adenomas.

1.1 Screen patients with a family history of MEN-I and at least one component of MEN-I (usually hyperparathyroidism) for the presence of

pituitary adenomas.

Recommendations

• Consider prolactin measurements and MRI to detect the presence of a prolactinoma or other types

of pituitary adenomas.

Evidence

• About 30% to 40% of patients with MEN-I will have pituitary adenomas; of these, well over 50%

will have prolactinomas (1; 2; 3). Such tumors may be more aggressive than sporadic

prolactinomas (4).

Rationale

• Patients with MEN-I who have pituitary adenomas can be screened with MRI; those with

prolactinomas will be hyperprolactinemic.

Comments

• Among patients with MEN-I, the risk for Cushing's disease and acromegaly is sufficiently low;

therefore, only symptomatic patients should be screened.

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2. Diagnosis Top

Diagnosis relies on clinical signs and symptoms of hormone hypersecretion or hyposecretion and/or neurologic dysfunction.

2.1 Look for abnormalities in reproductive function.

Recommendations

• In women, look for galactorrhea, oligomenorrhea, or amenorrhea of more than 6 months' duration;

loss of libido; and infertility.

• In men, look for infertility, loss of libido, and impotence.

Evidence

• About 10% to 25% of women with galactorrhea alone, 15% to 20% with amenorrhea alone, 30%

to 35% with infertility, and 75% with galactorrhea plus amenorrhea will be found to be

hyperprolactinemic when tested (5; 6; 7).

Many will ultimately prove to have a prolactin-secreting tumor, especially if the serum prolactin level is greater than 100 ng/mL.

• Correction of hyperprolactinemia causes restoration of normal gonadal and reproductive function

and cessation of galactorrhea.

• A small minority of people with reproductive symptoms will have other types of pituitary tumors

causing gonadotropin deficiency (5).

Rationale

• Hyperprolactinemia interferes with the reproductive axis primarily by inhibiting the pulsatile release

of GnRH by the hypothalamus. This interference can cause anovulation with amenorrhea and

infertility in women, and infertility and impotence in men. High prolactin levels can also stimulate

inappropriate breast milk production in both sexes (rarely in men).

• A large pituitary tumor (functioning or nonfunctioning) can lead to decreased gonadotropin

secretion as a result of compression of the portal vessels or pituitary stalk or because of ischemic

necrosis (8; 9; 10) of the gonadotrophs.

2.2 Look for distinctive morphologic abnormalities suggestive of acromegaly.

Recommendations

• Ask about headaches and increased sweating (less specific).

• Ask about excessive snoring and symptoms of sleep apnea.

• Document

Enlargement of hands (increased ring or glove size) and feet (increased shoe size)

Coarsening of facial features (in serial photographs)

Deepending of voice

Increased spacing of teeth (in dental x-rays) and poor-fitting dentures.

Evidence

• Acromegaly is a rare disease; annual incidence is about 3 new case-patients per million, and the

overall population prevalence is about 60 case-patients per million (11; 12).

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• Excessive GH levels stimulate IGF-I production in the liver and locally in other tissues; the effects

of GH overproduction are due primarily to this IGF-I but there may also be an effect of GH itself

(13).

• In general, the signs and symptoms of acromegaly correlate well with IGF-I levels (14; 15) and are

ameliorated when GH levels are lowered (16; 17; 18).

• Although the specificity of each of the signs and symptoms of acromegaly are not high, their high

rate of coincidence in patients with acromegaly (acral/facial changes in 98%, headaches in 55%,

sweating in 64%) makes this a diagnosis worth considering when they occur (12).

Rationale

• Excessive GH levels can stimulate the production of IGF-I (formerly somatomedin C) in the liver

and locally.

• IGF-I and possibly GH itself can stimulate cartilage growth, causing increases in hand and foot size

and changes in facial features.

• The earlier the diagnosis, the better the prognosis with treatment.

Comments

• GH hypersecretion before puberty and closure of the epiphyses can result in gigantism.

• Approximately 30% of patients with GH hypersecretion have elevated serum prolactin levels;

therefore, patients can present with symptoms and signs of hyperprolactinemia.

• Because GH is a lactogenic hormone, some patients can present with galactorrhea even when their

serum prolactin levels are normal.

2.3 Look for signs and symptoms of thyroid dysfunction.

Recommendations

• Look for signs and symptoms of hyperthyroidism.

Tachycardia

Tremor

Diffuse goiter

Warm, moist skin

Palpitations

Heat intolerance

Weight loss

Tremor

Irritability

Evidence

• Nearly 90% of hyperthyroid patients with elevated thyroid hormone levels and normal or elevated

TSH levels have TSH-secreting tumors (19; 20; 21).

Rationale

• TSH-secreting adenomas are very rare causes of hyperthyroidism, and are suspected only when a

nonsuppressed TSH level is found or if a hyperthyroid patient has associated symptoms of a mass

lesion.

• Patients with autonomously hyperfunctioning thyroid glands always have suppressed TSH levels.

Comments

• These patients are rare and should be referred to an endocrinologist.

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2.4 Look for signs and symptoms of Cushing's disease in patients suspected

of having a pituitary tumor.

Recommendations

• Ask about recent weight gain, depression, emotional lability, menstrual irregularities, hirsutism,

muscle weakness, and skin fragility.

• Document facial rounding and plethora, centripetal obesity, increased dorsal and supraclavicular fat

pads, pigmented stretch marks, ecchymoses, proximal muscle weakness, hirsutism, and

hypertension.

• See module Hypercortisolism.

• See figure Cushing Syndrome.

Evidence

• Cushing's disease is the most common cause of naturally occurring (endogenous) Cushing's

syndrome, accounting for more than two thirds of cases (22). The exogenous use of large doses of

corticosteroids to treat various illnesses can cause exogenous Cushing's syndrome.

• The signs and symptoms of Cushing's disease are due to excessive cortisol secretion and are not

specific to the cause of the Cushing's syndrome. However, the excessive levels of ACTH in

Cushing's disease may, in rare instances, cause an increase in skin pigmentation, particularly

where skin healing is occurring (e.g., a recent scar) (22; 23).

• Clustering of obesity, hypertension, and glucose intolerance is common in patients with “insulin-

resistance syndrome”; these symptoms are nonspecific. Centripetal fat distribution, ecchymoses,

pigmented striae, and proximal muscle weakness are symptoms that should trigger a diagnostic

evaluation for Cushing's syndrome (22; 23).

• Once Cushing's syndrome is diagnosed with appropriate screening, the specific cause must be

established through detailed biochemical suppression and stimulation testing (22; 23; 24; 25; 26;

27; 28).

Rationale

• In Cushing's disease, there is increased production of ACTH by a pituitary tumor, which causes an

increased production of cortisol by the adrenal cortex.

• These increases in cortisol are the cause of such signs and symptoms as recent weight gain,

depression, muscle weakness, skin fragility, facial rounding, stretch marks, proximal muscle

weakness, hypercoagulable state (29), and hypertension and are also found in patients with

cortisol-secreting primary adrenal tumors.

• The earlier the diagnosis, the better the chances of reversal with treatment.

Comments

• Among the presenting signs and symptoms of Cushing's disease, the most distinguishing features

include proximal myopathy, unexplained osteoporosis, prominent supraclavicular fat pad, and

unexplained bruising.

In children, stunted growth is among the most important features of Cushing's disease.

2.5 Look for signs and symptoms of a mass lesion near the sella turcica; if

symptoms are present, evaluate patient for a clinically nonfunctioning adenoma.

Recommendations

• Screen patient for the following:

Progressive headaches


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Visual disturbances, decreased visual acuity, visual field loss, and diplopia

Symptoms compatible with hypopituitarism (e.g., reproductive symptoms/signs, weakness, fatigue, cold intolerance, and anorexia)

• See module Hypopituitarism.

• See figure Visual Field Defect.

Evidence

• Patients with evidence of visual field loss commonly have mass lesions compressing the optic

chiasm. Acquired hypopituitarism is commonly caused by mass lesions in these areas. Of patients

diagnosed with large, clinically nonfunctioning adenomas, 66% to 78% have visual field defects,

58% to 75% have hypopituitarism, and 36% to 56% have headaches (10; 30; 31; 32; 33; 34;

35).

• There is a wide differential diagnosis for mass lesions in the hypothalamic-pituitary area (36; 37;

38; 39; 40; 41; 42; 43). About three quarters of clinically nonfunctioning adenomas are actually

gonadotroph adenomas, but the clinical differentiation is of little practical consequence at present.

Rationale

• Large lesions in this area might compress the optic chiasm (causing visual field loss), and the

hypothalamus, pituitary, or hypothalamic-pituitary stalk (causing hypopituitarism and diabetes

insipidus).

• Invasive tumor can extend into the cavernous sinus and present with ocular dysmotility, primarily

VI and III nerve palsies.

• These patients need not have evidence of pituitary hormone hypersecretion.

Comments

• Most of these clinically nonfunctioning adenomas do not secrete FSH or LH; they secrete the FSH-

beta subunit, which is not measured in conventional assays. There are very rare FSH- or LH-

secreting tumors that secrete the complete molecule; in this case, the levels of the gonadotropin

would be elevated.

2.6 Establish the diagnosis of hyperprolactinemia through repeated testing,

and evaluate the cause by appropriate biochemical and radiologic testing.

Recommendations

• Measure serum prolactin at least twice to confirm hyperprolactinemia.

• Exclude other causes of hyperprolactinemia by careful history and physical exam.

• Perform MRI of the pituitary if no extrapituitary cause of hyperprolactinemia can be identified.

• See table Laboratory and Other Studies for Pituitary Tumors.

• See table Major Causes of Hyperprolactinemia.

Evidence

• Depending on the doses used, 10% to 75% of patients taking psychotropic agents, protease

inhibitors, and antihypertensive agents may have hyperprolactinemia (6; 7; 44; 45; 46; 47; 48).

• All pregnant women develop progressive hyperprolactinemia during gestation, but those taking oral

contraceptives do not (6; 7; 48).

• More than 50% of patients with end-stage renal disease develop hyperprolactinemia, and 10% to

50% of those with serum creatinine levels greater than 2.0 mg/dL develop hyperprolactinemia (6;

7).


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• Only 10% of those with cirrhosis, 25% of those with hypothyroidism, and a modest but unspecified

percentage of those with adrenal insufficiency develop hyperprolactinemia (6; 7).

• Depending upon their anatomic extent, up to 60% of those patients with large mass lesions or

infiltrative disease of the hypothalamic-pituitary area may develop hyperprolactinemia (6; 7).

• As many as 21% of patients with hyperprolactinemia may have macroprolactinemia, a high-

molecular-weight form of no physiologic or clinical significance. Symptoms and neuroimaging

abnormalities may be unrelated to macroprolactin, making misinterpretation of the prolactin levels

possible. Commercial assays vary in their ability to distinguish normal (monomeric) prolactin from

macroprolactin (49; 50; 51; 52).

Rationale

• Several medications frequently cause mild hyperprolactinemia (< 100 ng/mL) by interfering with

the normal dopamine inhibition of prolactin; such medications include psychotropic agents

(butyrophenones and phenothiazines, MAO inhibitors, tricyclic antidepressants), protease

inhibitors, and antihypertensive agents (verapamil, methyldopa).

• Very high levels of estrogen in pregnancy cause progressive hyperprolactinemia, but the modest

estrogen content of oral contraceptives does not cause hyperprolactinemia.

• Altered hypothalamic inhibition of prolactin also occurs in patients with renal insufficiency, hepatic

cirrhosis, hypothyroidism, and adrenal insufficiency.

• Anatomic lesions also cause hyperprolactinemia when they interfere by mass effect or by

infiltration (e.g., sarcoidosis or Langerhans' cell histiocytosis) with the normal inhibitory pathways

in the hypothalamic-pituitary stalk.

• Hyperprolactinemia may be caused by abnormal forms of prolactin—macroprolactin—that are of no

clinical significance.

Comments

• To distinguish medication-induced hyperprolactinemia from tumor-induced hyperprolactinemia in a

patient with a microadenoma, consider stopping the medication or changing to an alternative to

see if the hyperprolactinemia resolves. With psychoactive medications, consult the patient's

psychiatrist first.

• It is important to run the prolactin undiluted and at 1:100 dilution when there is a mass lesion in

the hypothalamic-pituitary area to exclude very high prolactin levels that may read artifactually low

with two-site assays (53). Patients with hypothalamic disease and those with prolactinomas should

be referred to an endocrinologist.

2.7 Establish the diagnosis of acromegaly by documenting nonsuppressible

serum GH levels and elevated serum IGF-I levels.

Recommendations

• Measure GH during an oral glucose tolerance test.

A finding that levels cannot be suppressed to <2.0 ng/mL (if RIA is used) is evidence of active disease.

A finding that levels cannot be suppressed to <1.0 ng/mL (if a two-site immunoradiometric or chemiluminescent assay is used) is evidence of active disease.

• Note that an elevated (age-corrected) IGF-I is evidence of active acromegaly.

• Ideally, obtain both measurements to make the diagnosis.

Evidence

• Growth hormone levels suppress to <2.0 ng/mL (RIA) in about 90% to 95% of normal people, but

do not suppress with hyperglycemia to <2.0 ng/ml in virtually all patients with acromegaly at the

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time of diagnosis (12; 16; 54). With newer, more sensitive assays, lower cutoffs are often used but

these vary by assay method (55; 56; 57; 58; 59; 60).

• The degree of elevation of IGF-I correlates well with clinical features (14) and with mean 24-hour

GH secretion (12).

• Rare false-positives occur with the oral glucose tolerance test in patients with cirrhosis, renal

failure, anorexia, and diabetes mellitus, but such patients will have low, rather than elevated, IGF-I

levels (12; 13; 54; 61; 62).

Rationale

• Growth hormone secretion is normally pulsatile, thus single measurements are not diagnostic.

• Lack of GH suppressibility is critical.

• In normal persons, GH can be suppressed by hyperglycemia; however, this does not occur in

acromegaly.

• Increased GH levels stimulate the production of IGF-I by the liver.

• Rare false-positive results occur with the oral glucose suppression test in patients with cirrhosis,

renal failure, anorexia nervosa, and diabetes mellitus, but these patients will have low or normal,

rather than elevated, IGF-I levels.

Comments

• For initial screening for GH excess, measurement of plasma IGF-1 level is recommended.

2.8 Evaluate hyperthyroid patients who do not have suppressed TSH levels

for the presence of a TSH-secreting adenoma.

Recommendations

• Evaluate hyperthyroid patients with elevated thyroid hormone levels and nonsuppressed TSH levels

for a TSH-secreting tumor by measurement of the glycoprotein α subunit/TSH molar ratio.

• Perform an MRI of the pituitary.

Evidence

• The α subunit/TSH molar ratio is increased in about 80% of patients with TSH-secreting adenomas,

but is rarely elevated in those with thyroid hormone resistance (19; 20; 21; 63).

• A total of 75% to 90% of TSH-secreting adenomas are macroadenomas (19; 20; 21; 63; 64; 65).

Rationale

• In considering the differential diagnosis, it is important to exclude patients with generalized or

selective pituitary resistance to thyroid hormone. In patients with TSH-secreting tumors, the α

subunit/TSH molar ratio is elevated, but it is not usually elevated in those with resistance to

thyroid hormone. It is also important to exclude patients with heterophile antibody interfering with

the TSH assay.

• MRI may show a TSH-secreting adenoma.

• TSH-secreting tumors release TSH as well as the common alpha subunit (common to TSH, LH, FSH,

and placental hCG).

• TSH-secreting tumors typically secrete a molar excess of α subunit compared to TSH, so that the

molar ratio of α subunit to TSH is >1.

Comments

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• Hyperthyroid patients with an “inappropriately” normal TSH level should be screened for family

history of thyroid illnesses and other autoimmune diseases, a strong presence of which should

prompt measurement of heterophil antibody interfering with the TSH assay.

2.9 Perform MRI in patients with signs or symptoms of a mass lesion in the

pituitary and hypothalamic area, whether or not there is evidence of pituitary hypersecretion.

Recommendations

• Perform MRI with gadolinium enhancement to detect a pituitary tumor or other mass lesion in the

hypothalamic and pituitary area.

• See figure Pituitary Prolactinoma.

Evidence

• Displacement of normal structures and enhancement are seen with mass lesions in the area (66;

67).

Rationale

• MRI with gadolinium can determine the anatomic extent of a pituitary tumor and other mass

lesions.

Comments

• When a lesion is shown to abut the optic chiasm, formal visual field testing should also be

performed.

2.10 In patients with symptoms and signs of Cushing's syndrome, document the presence of hypercortisolism and then evaluate them specifically for

Cushing's disease.

Recommendations

• Screen for the diagnosis of Cushing's syndrome by demonstrated elevated levels of urinary free

cortisol, by showing nonsuppressibility of cortisol production by dexamethasone, or by elevated 11

pm salivary cortisol levels.

• Establish the specific cause by ACTH measurements and a combination of other tests, including:

Dexamethasone suppression testing

CRH testing

Inferior petrosal sinus sampling for ACTH levels

• See module Hypercortisolism.

Evidence

• Overproduction of cortisol is first established by showing elevated levels of urinary free cortisol and

has a diagnostic sensitivity and specificity of 90% to 100%, and 85% to 95%, respectively, in

separating patients with Cushing's syndrome from normal and obese persons (23; 68). However,

about 10% of patients with established Cushing's syndrome have had a normal free cortisol at least

once (69; 70; 71; 72).

• Autonomy of cortisol secretion may be screened for with an overnight dexamethasone (1 mg)

suppression test and confirmed with a 2-day, low-dose (0.5 mg every 6 hours) dexamethasone

test (23). However, the latter low-dose test had only 74% specificity, 79% sensitivity, and 71%

diagnostic accuracy; another study also found its sensitivity to be limited (25). The overnight, 1-

mg dexamethasone suppression test usually has been preferred for screening purposes because of

its ease of use and the difficulty of accurately collecting a 24-hour urine specimen. Patients with

Cushing's syndrome exhibit an absence of diurnal rhythm of plasma cortisol. The concentration of


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cortisol in the saliva is in equilibrium with the free (active) cortisol in the plasma. Measurement of

salivary cortisol levels at 11 pm to detect an elevated late-night plasma cortisol level can be a

useful screening test (69; 70; 71; 72; 73; 74).

• Separation of primary adrenal vs. ACTH-dependent causes of Cushing's syndrome is done by

finding low vs. normal-to-high serum ACTH levels along with elevated cortisol levels. In the latter

case, CRH stimulation results in a further elevation of ACTH by more than 35% with a diagnostic

accuracy of 85% to 90% (22; 23; 68; 71).

• Most ACTH-secreting pituitary tumors are microadenomas and also may be undetectable by MRI.

Inferior petrosal sinus sampling (IPSS) with CRH stimulation is usually necessary to distinguish

between pituitary ACTH hypersecretion and an occult ectopic source of ACTH with a diagnostic

accuracy approaching 100%, but false-positive IPSS sampling may occur in the rare patient with

an ectopic CRH-producing tumor (22; 68).

Rationale

• The initial step of evaluation is to show overproduction of cortisol by the adrenals, which is not

suppressible.

• Excessive cortisol production can be caused by primary adrenal overproduction by adenomas or

carcinomas, resulting in suppressed ACTH levels.

• Excessive cortisol production can be caused by increased ACTH production due to a pituitary

adenoma, a cancer (ectopic ACTH), or because of increased CRH production by another tumor.

Comments

• Cushing's syndrome due to ACTH-secreting macroadenomas tends to have more pronounced

hypercortisolism and more severe disease than those due to ACTH-secreting microadenomas.

• Tests used to define the cause of Cushing's syndrome (e.g., CRH test, inferior petrosal sinus

catheterization) should be performed only in patients with established hypercortisolism.

2.11 Evaluate pituitary adenomas found incidentally on MRI or CT scans done

for other reasons.

Recommendations

• For patients with incidentally found pituitary adenomas, test for hormone hypersecretion.

• For patients with incidentally found macroadenomas, test for hormone hyposecretion.

• If these tumors are clinically nonfunctioning adenomas, determine tumor growth by repeating the

imaging test initially at 6- to 12-month intervals, and at less-frequent intervals thereafter.

Evidence

• Approximately 5% of incidentally found tumors referred for evaluation hypersecrete pituitary

hormones, likely an overestimate of actual prevalence (75; 76).

• Approximately 5% of microadenomas and from 25% to as many as 50% of untreated, clinically

nonfunctioning macroadenomas grow (37; 75; 77; 78; 79).

• Tumors that hypersecrete hormones should be treated, and nonsecreting tumors should be

resected if there is evidence of significant growth (80).

Rationale

• Tumors that hypersecrete hormones may cause few symptoms at an early point in their

development.

• Early detection of tumor growth facilitates surgical removal.

• Pituitary adenomas are incidentally found in up to 10% to 20% of MRI or CT examinations.

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Comments

• The extent of evaluation for hormonal hypersecretion in an asymptomatic patient with an

incidentaloma is controversial (75; 80).

2.12 In hyperprolactinemic patients with amenorrhea and/or galactorrhea

and normal results on pituitary MRI, rule out other causes of hyperprolactinemia.

Recommendations

• Take a careful drug history.

• Test for pregnancy.

• Perform routine laboratory studies.

• Perform thyroid function tests.

• See table Differential Diagnosis of Pituitary Tumors.

Evidence

• Cases of primary hypothyroidism masquerading as pituitary prolactin-secreting tumors have been

reported (6; 7).

• Prolactin may also be elevated due to pituitary disinhibition in patients with nonprolactin-secreting

pituitary tumors (81).

Rationale

• Many drugs can cause hyperprolactinemia (rarely levels as high as 200 ng/mL).

• Pregnancy must always be ruled out.

• Severe hypothyroidism can cause hyperprolactinemia and enlargement of the pituitary due to

hyperplasia of the thyrotropes.

2.13 In hyperprolactinemic patients with amenorrhea and/or galactorrhea

and normal results on pituitary MRI, and in whom other causes of hyperprolactinemia have been ruled out, consider the diagnosis of idiopathic

hyperprolactinemia.

Recommendations

• Be aware that MRI does not exclude small (<3 mm) pituitary microadenomas.

• Consider idiopathic hyperprolactinemia as a diagnosis of exclusion.

• Consider macroprolactinemia as a potential diagnosis.

Evidence

• Most patients with apparent idiopathic hyperprolactinemia do not develop radiologically evident

tumors on follow-up, and prolactin levels return to normal in about one third (6; 7).

Rationale

• Patients with idiopathic hyperprolactinemia may have amenorrhea and galactorrhea and may

require medical therapy.

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3. Consultation Top

Consider endocrine consultation when routine testing does not establish the diagnosis clearly, when initial diagnosis suggests hormone-secreting pituitary tumors, and in patients with large macroadenomas or parasellar lesions. Consider consultation with an endocrinologist for overall management of complex patients with pituitary tumors and with appropriate specialists when surgery or radiotherapy is required.

3.1 Consider endocrine consultation when preliminary testing does not clearly

establish the diagnosis.

Recommendations

• Consider consulting an endocrinologist when the results of preliminary testing are equivocal and

when additional, more complex testing is required to confirm or exclude an accurate diagnosis.

Evidence

• These conditions are uncommon and are rarely seen by the average internist or primary care

physician (82).

Rationale

• Confounding factors may alter test results in a variety of circumstances; experience in dealing with

a large number of such patients and familiarity with testing is needed to perform additional tests to

establish the diagnosis.

3.2 Consider endocrine consultation in patients believed to have hormone-

secreting adenomas, clinically nonfunctioning adenomas, or other lesions in the hypothalamic or pituitary area.

Recommendations

• Consider endocrine consultation to confirm the diagnosis and evaluate residual pituitary function.

Evidence

• Large tumors commonly cause hypopituitarism and visual field defects; also, they may cause other

hypothalamic dysfunction. Furthermore, large tumors might be at risk for apoplexy (78; 83; 84).

• Specific treatments vary depending upon tumor type, tumor size, and patient characteristics (85).

Treatment for nontumorous lesions differs from that of tumors (38; 86).

Rationale

• Many of these conditions are relatively uncommon and rarely seen by most internists and primary

care physicians.

• Nontumorous lesions may mimic features of pituitary adenomas.

3.3 Refer appropriate patients for transsphenoidal surgical resection.

Recommendations

• Refer for transsphenoidal surgery patients with:

Resistance to or intolerance of dopamine agonists

GH-secreting adenomas

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TSH-secreting adenomas

Clinically nonfunctioning adenomas that are causing symptoms because of mass effects or that are shown to be growing on serial MRI

• For treatment of ACTH-secreting tumors, see module Hypercortisolism.

Evidence

• Surgical cures can be obtained in about 50% to 60% of microprolactinomas, 25% of

macroprolactinomas (87; 88; 89), 60% to 80% of GH-secreting tumors, 60% to 90% of ACTH-

secreting tumors (90), about 33% of TSH-secreting tumors (63), and 25% to 50% of clinically

nonfunctioning adenomas (91).

• Considerable benefit may accrue even from partial resection of GH-, ACTH-, and TSH-secreting

tumors, making them more receptive to irradiation and medical treatment (63; 92).

• The availability of an experienced neurosurgeon influences this decision, as the percentage of

operations resulting in complications significantly decreases with increasing experience (93).

Rationale

• Substantial benefit can be obtained in most patients with pituitary adenomas and a proportion

cured by surgical resection.

3.4 Refer patients who have not responded to surgery or medical therapy for radiation therapy.

Recommendations

• Refer patients for radiotherapy when their tumors continue to enlarge or oversecreted hormone

levels do not decrease appropriately despite surgery or medical therapy.

• When available, consider focused beam (stereotactic) radiation therapy administered by linear

accelerator or “gamma knife” cobalt machines which may be more effective than conventional

radiation therapy; it should be considered especially when the tumor has invaded the cavernous

sinuses.

Evidence

• Tumor control is generally good with conventional radiation therapy, but success in normalizing PRL

levels is only about 20% to 30%, and experience with focused beam radiation therapy is limited

(94).

• For patients with GH-secreting tumors, normalization of IGF-I levels occurs in 10% to 60% over a

period of 10 to 15 years with conventional irradiation (95; 96), and occurs more rapidly with

focused beam irradiation (92; 97; 98; 99; 100).

• For patients with ACTH-secreting tumors, external pituitary irradiation can cause a remission in

83% of patients within a median of 42 months (101).

• For patients with clinically nonfunctioning adenomas, control of tumor growth with conventional

radiation therapy is more variable, because the only way to measure growth is with MRI and CT,

not hormone levels. The regrowth rate of about 50% for tumor visible postoperatively can be

decreased to about 10% with radiation therapy, and the regrowth rate of about 20% to 30% for

tumor visible postoperatively can be decreased to <5% with radiation therapy (102; 103; 104;

105; 106; 107).

• For patients with TSH-secreting tumors, about two thirds have thyroid hormone levels in the

normal range after a combination of surgery plus irradiation, but only one third had normal levels

with surgery alone (63). Experience with focused beam irradiation for TSH-secreting tumors is very

limited.


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• It should be recognized that the risk of hypopituitarism occurring as a result of conventional

radiation therapy may be as high as 50% and may take years to occur (105). The risk of

hypopituitarism with focused beam radiation therapy is not yet known (108).

• Overall, given the relatively high efficacy rate, speed of response, and predicted lower complication

rate, focused beam radiation therapy is becoming the preferred type of radiation therapy for many

patients when such treatment is indicated and when such equipment is available (100; 108; 109).

• For patients with clinically nonfunctioning pituitary adenomas, gamma knife radiosurgery appears

to be effective in 50% to 90% of cases (100; 110; 111; 112).

Rationale

• Radiation therapy may be necessary to halt tumor growth and may impair their function, so that

oversecreted hormone levels decrease.

Comments

• All patients treated with any form of irradiation for a pituitary tumor are at high risk for acquiring

partial or complete hypopituitarism at some point in the future. These patients should be followed

indefinitely and screened for pituitary hormone deficits.

3.5 Consider consultation with an endocrinologist for most patients with pituitary adenomas for appropriate follow-up and long-term management.

Recommendations

• Refer the following patients for endocrinologic consultation for management assistance:

Patients with prolactinomas who have side effects or who do not respond to dopamine agonists

Patients with suspected GH-, ACTH-, or TSH-secreting adenomas

Patients with secretory and clinically nonfunctioning adenomas who might be panhypopituitary (including central diabetes insipidus) preoperatively and/or after surgery or radiotherapy (See module Hypopituitarism.)

Evidence

• Consensus.

Rationale

• Endocrinologists are likely to have expertise in the management of pituitary disease and the

sequelae of surgery and radiation therapy, especially in areas such as the pharmacotherapy of

hyperprolactinemia, acromegaly, TSH-secreting tumors, and panhypopituitarism.


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4. Hospitalization Top

Hospitalize patients for pituitary tumor apoplexy or surgery.

4.1 Hospitalize patients if they have acute pituitary tumor apoplexy.

Recommendations

• Hospitalize patients experiencing acute, severe headache often associated with visual disturbance

and altered level of consciousness in the ICU under an experienced endocrinologist's care, with

consultation by neurosurgery.

Evidence

• More than 50% of these patients develop hypopituitarism acutely and 25% to 50% will require

surgical decompression (83; 84; 113; 114).

Rationale

• These patients often have acute hypopituitarism and need treatment with steroids

(glucocorticoids), and they may also have an expanding mass from a hemorrhage that requires

surgical decompression.

Comments

• Although surgical decompression of an apoplectic tumor is often recommended, patients with

minimal and improving symptoms can be managed conservatively, especially those without visual

compromise.

4.2 Hospitalize patients who undergo transsphenoidal surgery and monitor

them closely in the perioperative period.

Recommendations

• Admit patients the morning of surgery and then observe closely in the hospital for several days for

signs and symptoms of postoperative infection, hypopituitarism, and diabetes insipidus (transient

or permanent).

Evidence

• In experienced centers, there is a cumulative incidence of postoperative complications of

approximately 2% for microadenomas and approximately 6% for macroadenomas, with transient

diabetes insipidus occurring in up to 10% of cases (93; 115; 116; 117).

Rationale

• These complications can be life-threatening and demand immediate treatment.

Comments

• There is wide variation in surgical outcomes (59; 118). In a national study of transsphenoidal

surgery for pituitary tumors (1996-2000), postoperative complications were observed in 26.5% of

cases. Median length of stay overall was 4 days. Complication rates and lengths of stay were

shorter with higher-volume surgeons and hospitals than with lower-volume hospitals (119).

Currently, most patients treated at experienced centers are discharged home within 48 hours of

surgery.

• Perioperative care of patients undergoing transsphenoidal surgery presents special challenges (21;

120; 121; 122).

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5. Non-drug Therapy Top

In patients with pituitary tumors, consider criteria for observation, transsphenoidal surgery, or irradiation in addition to drug therapy.

5.1 Consider observation without specific treatment in women with

microprolactinomas (tumors <10 mm) and normal menses, but note that surgery or irradiation may be required in others who do not respond to or who

are intolerant of dopamine agonists.

Recommendations

• Carefully observe women with normal menses and estrogen status (in whom galactorrhea is not

bothersome, and whose MRI findings are normal or show only microadenomas) without specific

treatment and followed with yearly PRL levels.

• Consider repeating a pituitary MRI yearly for 1 to 2 years, or less frequently if PRL levels are

stable.

• For patients requiring therapy for a prolactinoma, consider a dopamine agonist as first-line

treatment.

• Consider surgery for those patients not responding to or intolerant of dopamine agonists.

• Consider irradiation only in those patients with aggressive invasive tumors in whom dopamine

agonists or surgery are ineffective.

Evidence

• The normal estrogen state prevents hyperprolactinemia from being a risk factor for osteopenia

(123).

• The progression of microadenoma to macroadenoma occurs in only about 7% of patients, and is

almost always accompanied by a rise in PRL levels (6; 7).

• Transsphenoidal surgery is less effective, with only about 50% of patients with microadenomas

having normal PRL levels several years after surgery, and an even smaller percentage for patients

with macroadenomas (87; 88; 124; 125).

Rationale

• Women with normal menses are not at risk for osteopenia.

• Women with microadenomas are at very low risk for tumor enlargement.

• Women with irregular menses or amenorrhea should be treated.

Comments

• All forms of irradiation should be avoided in patients with prolactinomas, except those with

invasive, aggressive tumors that do not respond favorably to dopamine agonist therapy or surgery.

5.2 Initially treat with surgery virtually all patients with acromegaly to decrease GH levels unless lifespan is considerably limited.

Recommendations

• Aim for a normal IGF-I level and a serum GH level <2 ng/mL (RIA), preferably with suppression

during an oral glucose tolerance test to <1 ng/mL (RIA).

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• Be aware that initial treatment is normally transsphenoidal surgery to attempt curative resection or

debulking, thereby making subsequent medical treatment with dopamine agonists and/or

somatostatin analogues or irradiation more efficacious.

• Consider that the relative roles of dopamine agonists, somatostatin analogues, and irradiation, and

the sequence of their use in patients not cured by surgery is controversial.

Evidence

• Mortality, increased two- to three-fold in acromegaly, can be reduced to normal with reduction of

GH to <2.5 ng/mL and normalization of IGF-I levels (12; 17).

• With surgery, these levels can be achieved in over 90% of microadenomas and close to 50% of

macroadenomas (12; 126; 127; 128; 129).

• When surgery is not curative, GH/IGF-I levels can be normalized in approximately 33% of patients

with cabergoline, 55% to 68% with the somatostatin analogue octreotide (130; 131), and nearly

90% of patients using the new GH receptor blocker pegvisomant (132; 133).

• The newer, long-acting preparations of somatostatin analogs (such as octreotide-LAR and

lanreotide) are successful in postoperative patients who have not been cured (134; 135; 136). The

new GH receptor antagonist pegvisomant is also highly effective (130; 132; 133; 137).

• Conventional irradiation can normalize GH/IGF-I levels in about three fourths of previously

operated patients by 10 years after irradiation (95; 96; 138), but the new technique of focused

beam irradiation (also called stereotactic radiosurgery) appears to achieve this effect within 3 years

(42; 92; 97; 98; 139; 140).

• All forms of irradiation are associated with the gradual subsequent development of hypopituitarism.

Rationale

• Surgery may be curative.

• Normalization of GH/IGF-I levels decreases illness and death.

• Even lowered, but still abnormal, basal GH levels after surgery are clinically beneficial.

• Debulking the tumor may make medical treatment with dopamine agonists, somatostatin analogs,

or irradiation more efficacious.

Comments

• The prevalence of colon polyps and colon cancer appears to be increased in acromegaly; mortality

from colon cancer is increased particularly in patients with higher postoperative GH levels. Regular

colonoscopy and polypectomy would seem advisable (141; 142; 143).

• Morbidity persists even after adequate therapy (144; 145; 146).

• The relative roles of dopamine agonists, somatostatin analogues, and irradiation, and the sequence

of their use in patients not cured by surgery, are controversial (57; 58; 60).

5.3 Initially treat with surgery patients with TSH-secreting tumors to normalize thyroid hormone and TSH levels.

Recommendations

• Consider transsphenoidal surgery to try for curative resection or debulking, thereby making

subsequent medical treatment with somatostatin analogues or irradiation more efficacious.

• Aim for normal thyroid hormone levels and a normal TSH <2 ng/mL.

• Consider a trial of dopamine agonist therapy in patients who are resistant to somatostatin

analogues.

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Evidence

• Transsphenoidal surgery can normalize TSH/T4/T3 levels in about one third of patients (19; 20;

21; 63).

• Irradiation can cure an additional 40% to 50% of patients after noncurative surgery but may take

years to have a full effect (19; 20; 21; 63; 147).

• Somatostatin analogues, given as adjunctive treatment after surgery can reduce thyroid hormone

levels to normal in 95% of patients (19; 20; 20; 21; 63).

Rationale

• Persistent hyperthyroidism may cause atrial fibrillation, muscle wasting, etc.

• Treatment with surgery and, if the patient is not cured, somatostatin analogs and irradiation may

be necessary to achieve normal thyroid hormone levels.

5.4 Refer patients with ACTH-secreting tumors for transsphenoidal surgery to remove the tumors.

Recommendations

• Consider transsphenoidal resection of the pituitary adenoma.

• Aim for the long-term normalization of serum ACTH and cortisol levels with restoration of normal

suppressibility of cortisol levels by dexamethasone.

• For guidance on ACTH-secreting tumors, see module Hypercortisolism.

Evidence

• Tumor resection can be curative in about 90% of patients with microadenomas and 50% to 60% of

patients with macroadenomas (90; 148; 149; 150; 151; 152). Late recurrence is possible (153).

• Irradiation after incomplete tumor resection results in remission in 80% to 85% of patients (101;

154).

• Medical therapy with ketoconazole in patients not cured by surgery can result in normalization of

urinary free cortisol levels in 43% of patients and a substantial reduction of levels in 42% of

patients (155).

Rationale

• Tumor resection may be curative.

• Successful tumor resection will reverse the clinical manifestations of hypercortisolism.

• Successful tumor resection will be followed by a period of secondary adrenal insufficiency that may

last for several months.

• Tumor debulking may make secondary therapies such as irradiation or medical treatment more

successful.

Comments

• Morbidity persists even after adequate therapy (3; 156; 157).

• Preliminary data suggest that some of the newer somatostatin receptor blockers are effective in

lowering plasma ACTH levels in patients with Cushing's disease and thereby decreasing cortisol

secretion by the adrenals in these patients.

5.5 Follow patients with incidentally found clinically nonfunctioning adenomas without therapy under certain circumstances, but note that

adenomas causing mass effects require surgery and possibly irradiation.


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Recommendations

• Follow patients with microadenomas and small, noninvasive macroadenomas with MRI at 6 months

and yearly thereafter.

If there is no evidence of enlargement after 3 to 5 years, then continue to follow patients clinically.

Note that macroadenomas may require repeated imaging at less frequent intervals for longer periods of

time.

• Consider surgical resection of enlarging pituitary adenomas, especially those with mass effects

such as headaches or those approaching the optic chiasm.

• Consider surgical resection of all pituitary adenomas initially causing mass effects (these require

surgery to reduce the mass effects and possibly effect cure):

Visual field defects

Headaches

Hypopituitarism

• Consider irradiation for all patients with pituitary tumors who have evidence on MRI of residual

tumor or continuing hormonal excess after surgery.

Evidence

• Less than 5% of microadenomas and about 25% of macroadenomas will enlarge over time;

therefore, the majority do not require surgery (37; 75; 80).

• When mass effects occur, surgery, usually through the transsphenoidal route, is indicated.

Transcranial surgery is reserved for extremely large tumors that are invading the brain and that

cannot be removed by the transsphenoidal route. Depending on the size of the tumor, cure by

surgery alone can occur in 25% to 50% of patients (117; 91).

• When postoperative scans show no residual tumor, the tumor recurrence rate is about 10% to 20%

(102; 103; 158), and this recurrence rate can be reduced to almost 0% with postoperative

irradiation (102; 159; 160).

• When postoperative scans show residual tumor, tumor regrowth occurs in 50% of patients (102);

this figure can be reduced to 20% with irradiation (102; 161).

Rationale

• Unless there is evidence of hormonal hypersecretion, tumor compression of adjacent structures, or

evidence of enlargement, the mere presence of an adenoma is insufficient to warrant surgery.

Comments

• The availability of an experienced neurosurgeon influences this decision, as the percentage of

operations resulting in complications significantly decreases with increasing experience (93).

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6. Drug Therapy Top

In patients with pituitary tumors, consider drug therapy as primary or adjunctive therapy to surgery.

6.1 Consider dopamine agonists to be the initial treatment of choice for patients with micro- or macro-prolactinomas.

Recommendations

• In patients with low estrogens and/or macroadenomas and in almost all men, initiate treatment

with dopamine agonists first (cabergoline is preferred to bromocriptine).

• See table Drug Treatment for Pituitary Tumors.

Evidence

• In hyperprolactinemic women with amenorrhea due to low estrogen levels, osteopenia may

progress, but can be reversed by treatment of the hyperprolactinemia (123).

• Tumor size reduction of >50% occurs in about 45% of bromocriptine-treated patients and about

60% of cabergoline-treated patients (162; 163).

• A randomized, prospective trial of hyperprolactinemic, amenorrheic women showed normalization

of PRL levels in 59% of bromocriptine-treated women and in 83% of cabergoline-treated women;

12% of the former and 3% of the latter discontinued treatment because of drug intolerance (164).

Rationale

• Treatment with dopamine agonists will normalize menses and prolactin levels, and reduce the size

of pituitary prolactinomas.

Comments

• In patients with prolactin-secreting microadenomas, long-term remission may follow withdrawal of

dopamine agonist therapy (7; 165; 166).

6.2 Consider drug therapy in all patients with acromegaly.

Recommendations

• Treat patients with acromegaly who have continuing active disease after surgery with the

somatostatin analogue octreotide, with a dopamine agonist such as cabergoline, or with a GH

receptor antagonist such as pegvisomant.


Evidence

• Signs and symptoms of acromegaly improve with lowered GH levels (167). Octreotide will

normalize GH in about 50% to 60% of patients, and cabergoline will normalize GH in about 30% of

patients (134; 135; 136; 168).

• The new GH receptor antagonist pegvisomant is highly effective because it normalizes IGF-1 levels

in over 80% of patients (132; 133; 137; 169).

Rationale

• Persistently elevated IGF-I or GH is associated with increased morbidity and mortality from

cardiovascular disease.

Comments

• Most patients with acromegaly due to a pituitary macroadenoma will require postoperative drug

therapy.

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• Particularly close follow-up is warranted for patients with predictors of treatment-resistant tumor

growth, such as young patients with large tumors, patients with extrasellar extension of their

tumors, and patients with high pretreatment GH levels (170).

6.3 Start hormonal replacement therapy once specific hormone deficiencies

have been documented in patients with pituitary tumors.

Recommendations

• Although the replacement dose of hydrocortisone is approximately 15 to 25 mg/d for most patients

in divided doses, individualize it based on clinical assessment and increase it in times of stress.

• Base the replacement doses of thyroid hormone on clinical assessment and the serum T4 or free T4

level, because serum TSH levels may not be helpful in patients with pituitary disease.

• Administer estrogen/progesterone replacement the same way as for normal postmenopausal

women; avoid progesterone in women with large prolactinomas.

• Administer testosterone by intramuscular injection or transdermal patch or gel, and adjust doses

on the basis of clinical symptoms and peak and trough serum testosterone levels.

• Monitor serum lipid levels in hypogonadal men because LDL often increases after testosterone

therapy.

• Administer desmopressin in patients with established diabetes insipidus on the basis of clinical

symptoms and measurements of serum sodium and osmolality.

• Be aware that GH replacement is controversial and should be handled by an endocrinologist.

• See module Hypopituitarism for further details.


Evidence

• The exact dose of glucocorticoid is difficult to determine with laboratory testing and should be

based on clinical response (171; 172).

• The glucocorticoid dose should be increased 2- to 10-fold when the patient experiences stress

(173).

• Serum testosterone should be mid-normal 1 week after IM testosterone, and 8 to 12 hours after

transdermal testosterone. Older males should have monitoring of serum PSA at 3 to 6 months and

yearly thereafter (174). Hemoglobin and hematocrit should also be monitored because of the

increased frequency of secondary erythropoiesis (174).

• Adequate estrogen replacement in hypogonadal, premenopausal women requires 0.625 to 1.25 mg

of conjugated estrogen or equivalent per day, plus progestin (5 to 10 mg), either continuous or

cyclical, in women with an intact uterus (175).

• Improved muscle mass, bone density, and quality of life have been shown in several studies of

adult GH deficiency (176; 177).

Rationale

• Failure to treat hypoadrenalism and hypothyroidism or severe vasopressin deficiency may have

life-threatening consequences.

• Treatment of hypogonadism is important in the prevention of cardiovascular disease and

osteoporosis and in improving quality of life.

6.4 Consider drug therapy in patients with ACTH-secreting pituitary tumors

who are not cured by surgery.


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Recommendations

• Treat with drugs patients with active Cushing's disease after surgery to normalize excess cortisol

secretion.


Evidence

• Therapy with ketoconazole, an inhibitor of cortisol biosynthesis, can normalize or lower cortisol

levels in most patients with Cushing's disease (178).

Rationale

• Untreated hypercortisolism leads to excess morbidity and mortality. (See module

Hypercortisolism.)

Comments

• Ketoconazole therapy may eventually become ineffective due to ACTH secretion by the tumor

overriding the drug-induced enzymatic blockade. Ketoconazole is not FDA-approved for the

treatment of Cushing's syndrome.

• Patients with persistent hypercortisolism after surgical removal of ACTH-secreting pituitary

adenomas should be referred to experienced endocrinologists.

• Other inhibitors of glucocorticoid synthesis or blockers of glucocorticoid action can be used in

patients resistant to ketoconazole therapy. Referral to an experienced endocrinologist is highly

recommended in such instances.

• Newer preliminary data suggest that some somatostatin analogues can suppress ACTH secretion

from ACTH-producing pituitary tumors and lead to improvement in the state of hypercortisolism.


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7. Patient Counseling Top

Inform patients about the importance of achieving normal hormone levels, the need for continued surveillance, how pregnancy might affect tumor progression, and awareness of symptoms of tumor growth.

7.1 Inform patients with hormone-secreting tumors that without treatment

their symptoms will worsen progressively, and that with proper therapy they can improve their symptoms with the potential for cure.

Recommendations

• Inform patients with GH-, ACTH-, and TSH-secreting tumors and with clinically non-functioning

tumors that without treatment their respective symptoms of acromegaly, Cushing's syndrome,

hyperthyroidism, or mass effects will worsen progressively, and that with proper therapy they will

achieve improvement in their symptoms with the potential for cure.

• Inform patients with ACTH-secreting tumors about the steroid withdrawal syndrome that follows

successful tumor resection.

Evidence

• Mortality, increased two- to three-fold in acromegaly, can be reduced to normal with reduction of

GH to <2.5 ng/mL and normalization of IGF-I levels (16; 179; 180).

• With surgery, such levels can be achieved in more than 90% of GH-secreting microadenomas and

nearly 50% of macroadenomas (126).

• When surgery is not curative, GH/IGF-I levels can be normalized in about one third of patients with

cabergoline and in 55% to 68% of patients with the somatostatin analogue octreotide. Even when

complete remission cannot be achieved, clinical features may improve (181).

• Newer, long-acting preparations of somatostatin analogues, such as octreotide-LAR and lanreotide,

are successful in postoperative patients who have not been cured (134).

• Conventional irradiation can normalize GH/IGF-I levels in about three fourths of previously

operated patients by 10 years after irradiation (95; 96), but the new technique of focused beam

irradiation (stereotactic radiosurgery) appears to achieve this effect within 3 years (92; 97; 98).

• Tumor resection can be curative in about 90% of patients with ACTH-secreting microadenomas and

50% to 60% of patients with macroadenomas (90; 148; 149; 155).

• Irradiation after incomplete ACTH-secreting tumor resection results in remission in 80% to 85% of

patients (101).

• Medical therapy with ketoconazole in patients with ACTH-secreting tumors not cured by pituitary

surgery can result in normalization of urinary free cortisol levels in 43% of patients with substantial

reduction in another 42%. Bilateral adrenalectomy may be necessary in some patients (182).

• Persistent hyperthyroidism may cause atrial fibrillation and muscle wasting (183).

• Transsphenoidal surgery for TSH-secreting tumors can normalize TSH, T4, and T3 levels in about

one third of patients (19; 20; 63; 184).

• Irradiation can cure an additional 40% to 50% of patients with TSH-secreting tumors after

noncurative surgery but may take years to have a complete effect (19; 20; 63; 184).

• Somatostatin analogues, given as adjunctive treatment after surgery, can reduce thyroid hormone

levels to normal in 95% of patients with TSH-secreting pituitary tumors (19; 20; 63; 184).

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Rationale

• The combination of surgery, irradiation, and medical treatment can improve substantially the

symptoms of acromegaly, Cushing's disease, hyperthyroidism, and mass effects.

Comments

• Morbidity from chronic hormonal hypersecretion may persist even after adequate therapy (144;

145; 156; 185).

7.2 Inform patients that continued surveillance is needed to detect tumor

growth or regrowth after surgical resection.

Recommendations

• Inform patients with hormone-secreting tumors that they must have periodic measurements of

hormone levels and MRI.

• Inform patients with clinically nonfunctioning adenomas that they must have periodic MRI (yearly

first, less frequently thereafter).

• Inform patients of the need to return for follow-up even when they appear to have been cured.

Evidence

• Tumor growth occurs in about 25% of incidentally found, clinically nonfunctioning macroadenomas

(37; 186).

• Tumor recurrence after apparent initial surgical cure occurs in 20% to 40% of prolactinomas (87;

88; 89), 5% to 10% of GH-secreting tumors (12; 56; 128; 129), and 20% to 30% of clinically

nonfunctioning adenomas (104; 105).

Rationale

• Tumor growth is common in macroadenomas, and tumor recurrence is common after surgical

resection.

7.3 For women with prolactinomas already receiving dopamine agonists and

contemplating pregnancy, provide information about the various therapeutic options for treatment during the pregnancy.

Recommendations

• Advise women with prolactin-secreting microadenomas who are taking cabergoline to consider

switching to bromocriptine, and then to withdraw bromocriptine at the time of the first missed

menses and subsequent confirmation of pregnancy.

• Advise women with macroadenomas that the risk of tumor enlargement during pregnancy makes

several options appropriate:

Withdrawing bromocriptine when pregnancy is diagnosed

Debulking the tumor before pregnancy

Continuing bromocriptine throughout the pregnancy

Evidence

• Bromocriptine used as above causes no increase in fetal malformations, multiple births, preterm

deliveries or perinatal disorders (187; 188).

• There is a 23% risk of substantial macroadenoma enlargement during pregnancy that can be

lowered to 3% with surgery or irradiation before pregnancy. However, in tumors that enlarge

during pregnancy, bromocriptine is usually successful in decreasing tumor size (187; 188).

Rationale

• The safety record for bromocriptine, but not cabergoline, is established under these circumstances.

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• The estrogen milieu of pregnancy can stimulate tumor enlargement.

Comments

• Although the cabergoline database for pregnancy is small, there is no reason to suspect that there

may be problems. If a patient cannot tolerate bromocriptine, cabergoline could be used instead

(187; 188).

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8. Follow-up Top

Because tumors may recur and complications of treatment may occur, patients need careful follow-up of hormone levels and MRI and CT.

8.1 Ensure immediate assessment for hypopituitarism and diabetes insipidus

after pituitary surgery and periodically after pituitary radiotherapy.

Recommendations

• Assess the pituitary hormone function 1 to 6 weeks postoperatively for those patients with

macroadenomas and then every 6 to 12 months for those patients receiving postoperative

radiation therapy.

• Evaluate for the presence of residual tumor with MRI 3 to 6 months after surgery and at some

point afterward depending on the initial results.

• See module Hypopituitarism for more details.

Evidence

• Depending on the size of the tumor, the extent of initial surgery, and the experience of the

surgeon, loss of pituitary hormone function may occur in 7% to 20% of patients after surgery (93).

• Similarly, loss of pituitary hormone function may occur in more than 50% of patients after

radiation therapy, although this may be a slow process over the years, necessitating repeated

testing at 6- to 12-month intervals (105; 106).

Rationale

• Loss of pituitary function may occur after transsphenoidal surgery of large tumors and slowly after

radiation therapy of pituitary tumors.

Comments

• Morbidity persists after therapy (3; 17; 189; 190; 191; 192; 193; 194; 195).

8.2 Adjust replacement hormonal therapy periodically, once loss of specific

hormones has been determined.

Recommendations

• Assess adequacy of therapy for central hypothyroidism, hypoadrenalism, hypogonadism, and

diabetes insipidus.

Adjust thyroid hormone doses based on free hormone levels as well as clinical assessment of the patient.

• Adjust glucocorticoid doses based on clinical assessment of the patient; increases are needed when

patient experiences stress.

• Administer estrogen/progesterone replacement in the same way as standard hormone replacement

in postmenopausal women.

• Administer testosterone by intramuscular injection or transdermal patch, and adjust dose based on

peak and trough serum testosterone levels.

• Understand that GH replacement is controversial and can be carried out in selected patients under

the guidance of an endocrinologist.

• See module Hypopituitarism for more details.

Evidence



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• Sex steroid hormone replacement is required to prevent osteoporosis in men and women.

Hypogonadal patients have rapid loss of bone mineral and a higher fracture rate than persons with

normal gonadal function (171).

• A review found that hypopituitarism is not a rare disease and should be considered by primary care

physicians when considering related, nonspecific symptoms (196).

• Reviews summarize diagnostic and therapeutic approaches to anterior pituitary hormone

deficiencies (196; 197; 198).

Rationale

• It is vital to detect and treat hypopituitarism.

• Failure to detect and treat hypoadrenalism and hypothyroidism can have life-threatening

consequences.

• Untreated patients with hypogonadism may have serious morbidity from osteoporosis, as well as a

lower quality of life.

• For diabetes insipidus, close attention is needed for adjustment of desmopressin doses and fluid

intake to avoid extremes of hyper- and hyponatremia.

Comments

• Guidelines have been published for use of GH replacement by the GH Research Society and the

Endocrine Society (199), as has a review (200).

8.3 Check hormone levels periodically to detect relapse.

Recommendations

• Once PRL levels have been stabilized in the normal or near-normal range, check them every 6 to

12 months to detect relapse and to determine whether the dose of medication can be decreased.

• For patients with GH-secreting tumors, check GH and IGF-I levels 1 to 6 weeks after surgery to

determine cure.

• For patients not cured after focused beam radiotherapy, check GH and IGF-I levels at 6- to 12-

month intervals.

• For patients treated with octreotide, check GH and IGF-I levels every 2 months to adjust octreotide

doses.

• For patients with clinically nonfunctioning adenomas, obtain α-subunit measurements

preoperatively at 6 to 12 months, which may be helpful in following patients with elevated levels.

• For patients with TSH-secreting tumors, check measurements of TSH and free T4 levels 1 to 2

weeks postoperatively; follow patients that appear to be cured at 6- to 12-month intervals

thereafter.

Evidence

• The dose of dopamine agonist can be reduced over time and withdrawn without a rise in PRL levels

or an increase in tumor size in more than 20% to 30% of patients with prolactinomas (7; 201;

202), especially those with macroprolactinomas. Variable success was reported in withdrawing

dopamine agonist therapy from patients with macroprolactinomas (201; 202).

• Too few case-patients have been analyzed to know the recurrence rate after apparent surgical cure

in patients with TSH-secreting adenomas.

Rationale

• Tumors that have not been completely resected may regrow at rates of 10% to 30%.

http://www.eje-online.org/cgi/content/abstract/157/6/695

http://jcem.endojournals.org/cgi/content/abstract/91/5/1621

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• In patients with prolactinomas, the medication dose can often be reduced over time and the

medication even withdrawn without a rise in PRL levels. Tumors very rarely enlarge without a

preexisting increase in PRL levels.

• In these situations, a rise in GH, TSH, or PRL levels can often be the initial sign of tumor

recurrence.

Comments

• Particularly close follow-up is warranted for patients with predictors of treatment-resistant tumor

growth, such as young patients with large tumors and patients with high pretreatment GH levels

(170).

8.4 Initiate periodic follow-up assessment of tumor regrowth in all patients.

Recommendations

• Repeat MRI (or CT if MRI is unavailable) if hormone levels begin to rise in patients with PRL-, GH-,

and TSH-secreting tumors.

• For patients with clinically nonfunctioning adenomas, order 4- to 6-month postoperative imaging to

assess postoperative tumor size and then yearly imaging to assess for tumor regrowth.

Evidence

• Tumor regrowth is virtually always preceded by rising hormone levels in patients with PRL-

secreting (7); GH-secreting (12), and TSH-secreting tumors; therefore, such tumors can be

followed with hormone levels and MRI, which are repeated only if hormone levels are rising.

• Patients with clinically nonfunctioning adenomas only uncommonly secrete LH, FSH, or α-subunit in

increased levels; therefore, they must be followed with postoperative imaging at yearly intervals

(104; 105).

• Time to tumor growth or recurrence is variable and may exceed 10 years. Long-term follow-up is

important (203).

Rationale

• Growth in hormone-producing tumors almost never occurs without prior increase in hormone

levels; therefore, follow-up imaging should be performed only when hormone levels have risen.

• Patients with clinically nonfunctioning adenomas have no elevated hormone level to follow (except

in those patients with elevated LH, FSH, or α-subunit); thus, periodic imaging is needed to detect

tumor regrowth.

Comments

• Patients with acromegaly, nonfunctional pituitary adenomas, or hypopituitarism appear to have a

higher mortality rate from cardiovascular and cerebrovascular disease (204). This should be

considered in follow-up.

• In patients with acromegaly treated with the GH receptor antagonist pegvisomant, hormonal

follow-up can be accomplished only by obtaining IGF-I levels (205).

• Somatostatin receptor scintigraphy may be helpful in differentiating recurrent tumor from scar

tissue (206).

• Repeated transsphenoidal surgery is a more effective treatment for residual or recurrent mass than

persistent or recurrent hormonal hypersecretion (207).

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Glossary Top

ACTH adrenocorticotropic hormone

CRH corticotropin-releasing hormone

CT computed tomography

FDA Food and Drug Administration

FSH

follicle-stimulating hormone

GH

growth hormone

GHRH growth hormone-releasing hormone

GnRH gonadotropin releasing hormone

ICU

intensive care unit

IGF insulin-like growth factor

IPSS inferior petrosal sinus sampling

im intramuscular

LH luteinizing hormone

MEN-1 multiple endocrine neoplasia, type 1

MRI magnetic resonance imaging

PRL

prolactin

PSA prostate-specific antigen

sc subcutaneous

TFT

thyroid function test

TSH thyroid-stimulating hormone

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Tables Top

History and Physical Examination Elements for Pituitary Adenomas

Category Element Notes

History Amenorrhea Found with PRL excess and/or gonadotropin deficiency

History Galactorrhea Found with PRL excess; sometimes with GH excess

History Infertility Found with PRL excess and/or gonadotropin deficiency

History Impotence Found with PRL excess and/or gonadotropin deficiency

History Decreased libido Found with PRL excess and/or gonadotropin deficiency

History Increased hand size Patients with acromegaly

History Increased foot size Negative result. Patients with acromegaly

History Facial feature coarsening Patients with acromegaly

History Increased sweating Patients with acromegaly or TSH-secreting tumor

History Headaches Patients with large tumors

History Increased teeth spacing Patients with acromegaly

History Heat intolerance Patients with TSH-secreting tumor

History Weight loss Patients with TSH-secreting tumor

History Decreased need for sleep Patients with TSH-secreting tumor

History Increased frequency of bowel movements Patients with TSH-secreting tumor

History Loss of peripheral vision Present often when large tumors with suprasellar extension abut

the optic chiasm

History Development of thin limbs with truncal obesity Patients with Cushing's syndrome

History Development of facial rounding with erythema Patients with Cushing's syndrome

History Development of pigmented stretch marks Patients with Cushing's syndrome

History Development of ecchymoses Patients with Cushing's syndrome

History Development of muscle weakness Patients with Cushing's syndrome

Physical exam Expressible galactorrhea Patients with prolactinomas

Physical exam Hirsutism Women with prolactinoma, Cushing's disease

Physical exam Decreased facial and body hair Males with prolactinomas

Males with impaired gonadal function

Physical exam Coarsening/enlargement of facial features (nose, brow, jaw, Patients with acromegaly

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tongue)

Physical exam Gigantism GH-secreting tumors beginning before puberty

Physical exam Increased spacing between teeth Patients with acromegaly

Physical exam Enlarged hands and feet Patients with acromegaly

Physical exam Goiter Patients with thyrotropinoma or acromegaly

Physical exam Tremor Patients with thyrotropinoma

Physical exam Brisk reflexes Patients with thyrotropinoma

Physical exam Optic atrophy Patients with large adenomas

Physical exam Decreased visual acuity/visual field loss Due to large visual field cuts from tumors abutting or compressing

the optic chiasm

Physical exam Centripetal obesity with increased supraclavicular and dorsal fat

pads

Patients with Cushing's syndrome

Physical exam Facial rounding with erythema (“moon facies”) Patients with Cushing's syndrome

Physical exam Pigmented skin striae Patients with Cushing's syndrome

Physical exam Proximal muscle weakness Patients with Cushing's syndrome

Physical exam Hypertension Patients with Cushing's syndrome

GH = growth hormone; PRL = prolactin; TSH = thyroid-stimulating hormone.

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Laboratory and Other Studies for Pituitary Tumors

Test Sensitivity (%) Specificity (%) Likelihood Ratio Positive Likelihood Ratio Negative Notes

Serum prolactin Elevated in patients with

prolactinomas, but also in many

other conditions

Creatinine To exclude renal insufficiency as

a cause of hyperprolactinemia

Bilirubin To exclude cirrhosis as a cause

of hyperprolactinemia

TSH To exclude hypothyroidism as a

cause of hyperprolactinemia. To

detect and follow-up in TSH-

secreting tumors

Growth hormone during oral

glucose tolerance test

>85 90-95 Lack of suppression diagnostic

of acromegaly

IGF-I >95 Elevated in acromegaly

Glycoprotein α subunit/TSH

molar ratio

Increased α subunit/TSH molar

ratio in TSH-secreting tumors

(19)

MRI of pituitary Delineate the anatomic extent of pituitary tumors

Formal visual fields Determine whether a tumor abutting the optic chiasm is

causing optic tract dysfunction

FSH and LH Usually normal or low in

pituitary tumors, except for the

very rare gonadotropin-

secreting tumors. Elevated

gonadotropin levels are also the

hallmark of primary gonadal

failure

1 mg dexamethasone

suppression test

85-95 80-95 11.6 (5.8-23.1) 0.07 (0.05-0.14) Establish diagnosis of

hypercortisolism (70; 71; 72)

Midnight salivary cortisol 92-100 93-100 8.8 (3.5-21.8) 0.07 (0.00-1.20) Establish diagnosis of


Urinary free cortisol 90-99 85-95 10.6 (5.5-20.5) 0.16 (0.07-0.33) Establish diagnosis of


Basal ACTH Normal-to-elevated with

Cushing's disease

ACTH response to CRH 93 100 Increased response with

Cushing's disease

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IPSS testing for ACTH with CRH

stimulation

85 100 100 45 Increased central gradient with

Cushing's disease

ACTH = adrenocorticotropic hormone; CRH = corticotropin-releasing hormone; FSH = follicle-stimulating hormone; IGF = insulin-like growth factor; IPSS = inferior petrosal sinus sampling; LH = luteinizing hormone; MRI = magnetic resonance imaging; TSH = thyroid-stimulating hormone.

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Differential Diagnosis of Pituitary Tumors

Disease Characteristics

Medication use Cause mild hyperprolactinemia (PRL levels usually <100 ng/mL)

Medications include: neuroleptics, butyrophenones, MAO inhibitors, tricyclic antidepressants,

metoclopramide, verapamil, methyl dopa, reserpine

Renal insufficiency Cause mild hyperprolactinemia (PRL levels usually <100 ng/mL)

Hypothyroidism Cause mild hyperprolactinemia (PRL levels usually <100 ng/mL)

Cirrhosis Cause mild hyperprolactinemia (PRL levels usually <100 ng/mL)

Polycystic ovarian disease Cause mild hyperprolactinemia (PRL levels usually <100 ng/mL)

Patients have signs and symptoms of androgen excess: hirsutism, acne, and usually obesity

Pregnancy PRL levels gradually rise through pregnancy to levels >200 ng/mL

Hypothalamic lesions Cause mild hyperprolactinemia (PRL levels usually <100 ng/mL)

Include mass lesions, infiltrative disease, aneurysms, empty sella

Mass lesions other than pituitary adenomas Can be confused with pituitary adenomas on MRI and CT scans

Includes meningiomas, craniopharyngiomas, Rathke's cleft cysts, gliomas, dysgerminomas,

granulomas, hypophysitis, metastases

Thyroid hormone resistance Elevated free thyroid hormone and TSH levels

Due to resistance to the action of thyroid hormone because of a thyroid hormone receptor mutation.

Usually a family history

Dysalbuminemic hyperthyroxinemia Elevated total thyroxine levels, but normal free thyroxine levels with non-suppressed TSH levels

Need to measure free hormone levels

Primary gonadal dysfunction Elevated gonadotropin levels and low steroid hormone levels

No clinical evidence of pituitary disease, and prolactin levels are normal

Ectopic hormone secretion Clinical and laboratory features of acromegaly, but pituitary MRI showing normal or minimally enlarged

pituitary

Rare pancreatic GH and GHRH-secreting tumors have been reported.

CT = computed tomography; GH = growth hormone; GHRH = growth hormone-releasing hormone; MRI = magnetic resonance imaging; PRL = prolactin; TSH = thyroid-stimulating hormone.

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Drug Treatment for Pituitary Tumors

Drug or Drug Class Dosing Side Effects Precautions Clinical Use

Cabergoline 0.5-3 mg PO once weekly Nausea, constipation, orthostatic

hypotension, dizziness, drowsiness.

Long-term use: cardiac valvulopathy,

pulmonary fibrosis

Avoid with: pregnancy, uncontrolled

hypertension. Caution with psychiatric

disorders. Decrease dose with severe

hepatic disease

Micro- or macro-prolactinomas

Bromocriptine (Parlodel) 2.5-15 mg PO qd Nausea, constipation, orthostatic

hypotension, dizziness, drowsiness,

nasal congestion, visual impairment.

Long-term use: pulmonary fibrosis

Avoid with: pregnancy, uncontrolled

hypertension. Caution with: hepatic

disease, psychiatric disorders

Micro- or macro-prolactinomas

Octreotide (Sandostatin, Sandostatin

LAR)

SC: 100-500 mcg tid.

Depot suspension: 10-30 mg IM every 4 weeks

Abdominal pain, diarrhea, vomiting,

injection site reactions, cholelithiasis, hypothyroidism, bradycardia, vitamin

B12 deficiency

Caution with: diabetes, cardiac

disease, severe CKD. Inhibits CYP3A4

Acromegaly

Pegvisomant (Somavert) 40 mg SC loading dose, then 10 mg SC

qd. May increase to 30 mg qd

Edema, hypertension, infection,

nausea, diarrhea, pain, injection site

reactions, hepatotoxicity

Caution with: hepatic disease,

hypercholesterolemia, diabetes

Acromegaly

Hydrocortisone (Cortef) Maintenance: 15-25 mg PO total daily

dose, dosed bid-qid

Physiologic replacement doses should

not cause adverse effects. Long-term

pharmacologic doses can lead to

adrenocortical atrophy and generalized

protein depletion

Adrenocortical insufficiency

Ketoconazole (Nizoral) 400-800 mg PO qd Vomiting, QT prolongation, TdP Hepatotoxicity, drug interactions.

Avoid with pregnancy. Caution with

hepatic disease. Substrate and potent

inhibitor of CYP3A4

Cushing's disease

= first-line agent; = black box warning; bid = twice daily; CKD = chronic kidney disease; CNS = central nervous system; CrCl = creatinine clearance; CYP = cytochrome P450 isoenzyme; GI = gastrointestinal; IM = intramuscular; IV = intravenous; PO = oral; qd = once daily; qid = four times daily; SC = subcutaneous; TdP = torsade de pointes; tid = three times daily.

PIER provides key prescribing information for practitioners but is not intended to be a source of comprehensive drug information.

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Elements of Follow-up for Pituitary Tumors

Category Issue How? How Often? Notes

History Recurrence of original symptoms By query Every 6-12 months Positive response results in laboratory

testing of specific hormone

History Development of symptoms of

hypopituitarism, including symptoms of

hypothyroidism (fatigue, lethargy, cold

intolerance, constipation),

hypoadrenalism (fatigue, anorexia,

nausea, orthostatic symptoms), and

hypogonadism (amenorrhea in women, decreased libido, impotence in men)

(see module Hypopituitarism)

By query Every 6-12 months Positive response results in laboratory


History Recurrence of mass lesion causing

visual problems such as diplopia and

field cuts

By query Every 6-12 months Ask about difficulties in driving and

automobile accidents, which can occur

in patients with abnormal visual fields

or decreased visual acuity

Physical exam Recurrence of original symptoms

related to hormone oversecretion (see

above)

On examination Every 6-12 months Positive finding results in laboratory


Physical exam Development of findings of

hypopituitarism, including

hypothyroidism (bradycardia, dry skin,

delayed reflexes), hypoadrenalism

(pallor, orthostatic hypotension), and hypogonadism (decreased body hair,

breast atrophy, testicular atrophy)


On examination Every 6-12 months Positive finding results in laboratory


Physical exam Recurrence of mass lesion with

invasion of cavernous sinuses or

suprasellar region

Extraocular movements, visual fields

by confrontation, fundoscopic exam

Every 6-12 months

Laboratory testing If prior history of hormone

oversecretion, retest

Prolactin, GH/IGF-I, TSH/free T4, as

appropriate

Every 6-12 months Positive findings results in repeat MRI

scan

Laboratory testing After surgery and/or irradiation, screen

for hypopituitarism

Low levels of free T4, morning cortisol,

plasma IGF-1, sodium, sex steroids


1-6 weeks after transsphenoidal

surgery and yearly after irradiation

Positive findings necessitate

replacement hormone treatment (see

module Hypopituitarism)

Other tests Tumor size MRI scan (CT if MRI is not available) of

pituitary with gadolinium

When indicated with evidence of

hormone over secretion or yearly in

patients with clinically nonfunctioning

adenomas

Positive findings necessitate repeat

surgery, irradiation, or institution of

medical therapy, as appropriate

Other tests Visual fields Visual field testing For patients with macroadenomas with

baseline abnormalities, repeat at 2-6 month intervals until stable to assess

for recovery

If fields returned to normal, only

repeat if evidence of chiasmal compression on repeat MRI





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Drug therapy Hormone oversecretion and tumor size Dopamine agonist (prolactinoma),

octreotide (GH- and TSH-secreting adenomas)

Assess for return of hormone levels to

normal and for adjustment of drug dose every 1-3 months until stable;

after 1-2 years, try to reduce dose

Drug therapy Hypopituitarism Replacement with L-thyroxine,

glucocorticoids, estrogen/testosterone,

and possibly GH, when deficits are

found (see module Hypopituitarism)

Replace when deficits are found at

testing as indicated above

Dose adjustments generally needed

periodically (see module

Hypopituitarism)

CT = computed tomography; GH = growth hormone; IGF = insulin-like growth factor; MRI = magnetic resonance imaging; TSH = thyroid-stimulating hormone.



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Major Causes of Hyperprolactinemia

Pituitary Tumors

Prolactinomas

Growth hormone secreting tumors

Nonfunctioning pituitary tumors

Non-pituitary Sellar and Parasellar Lesions

Craniopharyngioma

Hypothalamic disease (sarcoidosis, Langhans' cell histiocytosis, lymphoma)

Metastatic tumors to pituitary/hypothalamus

Neurogenic

Chest wall or spinal cord disease

Drugs

Psychotropic agents (butyrophenones and phenothiazines, MAO inhibitors, tricyclic antidepressants), and antihypertensive agents (verapamil, alpha methyldopa). Protease inhibitors. Estrogen in conventionally

used doses does not cause hyperprolactinemia.

Other

Pregnancy

Hypothyroidism

Chronic renal failure

Cirrhosis

Polycystic ovarian disease

Macroprolactinemia

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Figures Top

Pituitary Prolactinoma

The CT image of a prolactinoma often is visualized as a discrete area of hypolucency in an otherwise normal sized pituitary gland of homogenous density.

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Visual Field Defect

Visual field showing bitemporal hemianopsia, consistent with a pituitary tumor compression of the optic chiasm.

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Cushing Syndrome

Classic features of Cushing syndrome in a patient with an adrenocorticotropic hormone?secreting pituitary adenoma. Central obesity and striae are evident (top). A close-up view of the striae (bottom) reveals their wide, violaceous nature.

pituitary tumors - cecity · disclosures: baha m. arafah, md, current author of this module, has no...

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