Clinical Hematology
`and Oncology
`P•esen-eatio n, Diagnosis,
`and Treatanent
`
`Bruce Furie, MD
`Professor of Medicine
`Harvard Medical School
`Chief, Division of Hemostasis and Thrombosis
`Department of Medicine
`Beth Israel Deaconess Medical Center
`Boston, Massachusetts
`Peter A. cassileth, MD
`Professor of Medicine
`Division of Hematology and Oncology
`Department of Medicine
`University of Miami School of Medicine
`Miami, Florida
`Michael 8. Atkins, MD
`Professor of Medicine
`Harvard Medical School
`Deputy Director, Division of Hematology/Oncology
`Department of Medicine
`Beth Israel Deaconess Medical Center
`Boston, Massachusetts
`Robert J. Mayer, MD
`Professor of Medicine
`Harvard Medical School
`Vice Chair for Academic Affairs
`Department of Medical Oncology
`Dana-Farber Cancer Institute
`Boston, Massachusetts
`
`A)
`
`ED
`
`CHURCHILL LIVINGSTONE
`
`An Imprint of Elsevier
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`~ CHURCHILL LIVINGSTONE
`An Imprint of Elsevier
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`CLINICAL HEMATOLOGY AND ONCOLOGY
`Copyright © 2003, Elsevier Inc. (USA). All rights reserved.
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`ISBN 0-443-06556-X
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`NOTICE
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`Medicine is an ever-changing field. Standard safety precautions must be followed, but as new
`research and clinical experience broaden our knowledge, changes in treatment and drug
`therapy may become necessary or appropriate. Readers are advised to check the most current
`product information provided by the manufacturer of each drug to be administered to verify
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`Library of Congress Cataloging-in-Publication Data
`
`Clinical hematology and oncology: presentation, diagnosis, and treatment /
`Bruce Furie .. . [et al.J.-1 '' ed.
`p.; cm.
`Includes bibliographical references
`ISBN 0-443-06556-X
`1. Cancer-Handbooks, manuals, etc. 2. Blood-Diseases-Handbooks, manuals, etc.
`I. Furie, Bruce.
`I. Hematologic Diseases-diagnosis. 2. Hematologic Diseases-therapy.
`[DNLM:
`3. Hematology-methods. 4. Medical Oncology-methods. 5. Neoplasms-diagnosis.
`6. Neoplasms-therapy. WH 120 C6416 2003]
`RC262.5.C557 2003
`616.99'4-dc21
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`2003043470
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`International Standard Book Number 0-443-06556-X
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`Senior Acquisitions Editor: Dolores Meloni
`Senior Developmental Editor: Joanne Husovski
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`Printed in Hong Kong
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`Last digit is the print number: 9 8 7 6 5 4 3 2
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`

`Chapter 111
`Pituitary Tumors
`
`Robert D. Utiger
`
`Pituitary tumors are identified because the patient has
`symptoms of a pituitary mass, clinical manifestations
`of pituitary hormone excess or deficiency, or both.
`Among patients with a pituitary mass, approximately
`90% have a pituitary adenoma, 8% have a cranio(cid:173)
`pharyngioma or other cell-rest tumor (Rathke's pouch
`cyst, epidermoid cyst), and 2% have other masses,
`including metastatic tumors, aneurysms, and inflam(cid:173)
`matory masses.
`
`Pituitary Adenoma
`Pituitary adenomas are benign, slow-growing mono(cid:173)
`clonal adenomas of the different types of cells present
`in the normal anterior pituitary gland. They are
`rare, occurring with an estimated frequency of IO
`cases per 1,000,000 people per year, mostly in older
`adults. Genetic abnormalities in signal transduction
`systems or the receptors for the hormones that inhibit
`the production and secretion of particular pituitary
`hormones have been identified in some adenomas.
`Pituitary adenomas occur in approximately 40% of
`patients with multiple endocrine neoplasia type l ;
`the other components are parathyroid adenomas
`and pancreatic islet cell adenomas. Small, incidental
`pituitary adenomas are found in up to 10% of people
`at autopsy.
`
`Clinical Presentations
`Pituitary adenomas are classified according to size-as
`microadenomas (tumor diameter less than 1 cm) or
`macroadenomas (tumor diameter 1 cm or greater)(cid:173)
`and according to their secretory products.
`
`Nonsecretory Microadenomas
`Nonsecretory microadenomas do not cause symp(cid:173)
`toms and rarely cause hormonal deficiencies. They are
`usually detected incidentally by imaging in patients
`who are being evaluated for unrelated problems.
`
`Nonsecretorv Macroadenomas
`N onsecretory macroadenomas may also be detected
`incidentally, but they can cause mass effects as they
`enlarge and extend superiorly from the sella tu'rcica
`toward the hypothalamus or laterally toward the cav(cid:173)
`ernous sinuses. The major symptoms are headaches
`and visual difficulties. The headaches may be frontal,
`bitemporal, or occipital and are often relieved by
`minor analgesic drugs. The characteristic visual abnor(cid:173)
`mality is bitemporal hemianopsia, but some patients
`have quadrant defects, decreased visual acuity, sco(cid:173)
`tomas, or third or sixth nerve palsies.
`Nonsecretory macroadenomas may cause defi(cid:173)
`ciency of any pituitary hormone, including vaso(cid:173)
`pressin. The most common deficiency . is that of
`gonadotropins (follicle-stimulating hormone [FSH]
`and luteinizing hormone [LH]), which is present in
`approximately 80% of patients, followed by growth
`hormone (GH) deficiency (60%), thyrotropin (TSH)
`deficiency (40%), corticotropin (ACTH) deficiency
`(25%), and vasopressin deficiency (5%). Any of
`these can occur as an isolated deficiency or as one of
`multiple deficiencies.
`The hypogonadism that results from gonadotropin
`deficiency is easily detected in young women by the
`presence of amenorrhea, but it is not as easily detected
`in men because of the unwillingness of many men to
`describe loss of libido and other symptoms of hypo(cid:173)
`gonadism ( or the unwillingness of the physician to
`ask). Many of the symptoms of growth hormone, thy(cid:173)
`rotropin, and corticotropin deficiency are nonspecific,
`for example, muscle weakness, mental fatigue, and
`anorexia, and the presence of more specific symptoms,
`such as cold intolerance and weight loss, may go
`unnoticed because their onset is so gradual.
`Some nonsecretory macroadenomas produce and
`secrete no hormones or hormonal components, but
`many produce the common alpha subunit of follicle (cid:173)
`stimulating hormone and luteinizing hormone (and
`thyrotropin), the beta subunits of follicle-stimulating
`hormone or luteinizing hormone, or intact follicle-
`
`1139
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`section Ill: Evaluation and Treatment of Hematologic and Oncologlc Disease (cid:127) Endocrine Cancer
`sis. Most of the tumors are microadenomas, and in
`some patients, the tumor is so small that it cannot be
`detected by imaging.
`Thyrotroph adenomas are rare and are far less
`common than Graves' disease, nodular goiter, and
`thyroiditis as a cause of hyperthyroidism. In addition
`to hyperthyroidism, the patients have a diffuse goiter,
`but they do not have Graves' ophthalmopathy. Most
`of the adenomas are macroadenomas, and approx(cid:173)
`imately 40% secrete prolactin or other pituitary
`hormones.
`Gonadotroph adenomas may secrete sufficient
`follicle-stimulating hormone or luteinizing hormone
`to have clinical effects. In young women, follicle(cid:173)
`stimulating hormone hypersecretion can cause
`ovarian hyperstimulation with multiple ovarian cysts
`and oligomenorrhea or amenorrhea. In men, excess
`luteinizing hormone secretion causes high serum
`testosterone concentrations, but this has little clinical
`effect in normal men. The adenomas are nearly always
`macroadenomas.
`
`1140
`
`luteinizing hormone, as
`stimulating hormone or
`detected by mRNA and immunohistochemical analy(cid:173)
`ses of tumor tissue. These tumors often secrete one or
`both subunits, which lack biologic activity, but only
`rarely do they secrete excess amounts of intact folli(cid:173)
`luteinizing hormone.
`cle-stimulating hormone or
`Therefore, they are in fact gonadotroph adenomas.
`secretory Microadenomas and Macroadenomas
`The majority of secretory pituitary adenomas are
`microadenomas.
`Among the secretory tumors, lactotroph adeno(cid:173)
`mas (prolactinomas) are the most common (Table
`111 - 1). In young women, even moderate hyperpro(cid:173)
`lactinemia inhibits pituitary-gonadal function, causing
`infertility, oligomenorrhea or amenorrhea, and, less
`these women have
`often, galactorrhea. Most of
`microadenomas. In contrast, postmenopausal women
`and men usually present with headaches or visual
`problems and have macroadenomas. Hyperprolactine(cid:173)
`mia also inhibits pituitary-gonadal function in men,
`rarely galactorrhea.
`causing hypogonadism and
`Hyperprolactinemia does not necessarily indicate the
`presence of a lactotroph adenoma. It also can result
`from loss of tonic hypothalamic inhibition of prolactin
`secretion, for example, by interruption of hypotha(cid:173)
`lamic-pituitary blood flow.
`Somatotroph adenomas cause acromegaly, with
`thickening,
`acral enlargement, macroglossia, skin
`excessive perspiration, arthralgia, sleep apnea, hyper(cid:173)
`tension, and cardiomyopathy. Somatotroph adenomas
`are extremely slow-growing tumors. At the time of
`diagnosis, many patients have had changes attribut(cid:173)
`able to growth hormone excess for many years, and
`the majority have macroadenomas. Many soma(cid:173)
`totroph adenomas also hypersecrete prolactin.
`Corticotroph adenomas cause Cushing's disease
`and account for approximately 70% of cases of
`Cushing's syndrome. The major clinical findings are
`moon fades, plethora, central obesity, hypertension,
`myopathy, psychological disturbances, and osteoporo -
`
`Pituitary Apoplexy
`Occasional patients, most of whom have macroade(cid:173)
`nomas, present with pituitary apoplexy. It is charac(cid:173)
`terized by the sudden onset of severe headache; visual
`field deficits; third, fourth, or sixth cranial nerve
`palsies; nausea and vomiting; and decline in mental
`status. It is caused by hemorrhagic infarction of the
`adenoma.
`
`Clinical Evaluatlon
`All patients who are suspected of having a pituitary
`adenoma or other pituitary disease should undergo
`(MRI), with special
`imaging
`magnetic resonance
`attention given to the region of the sella turcica
`(Figure 111 - 1). Magnetic resonance imaging provides
`better resolution of the anatomy of this region and
`reveals more microadenomas than does computed
`tomography. Visual field testing should be done if
`there is clinical or radiologic evidence of compression
`of the optic chiasm or optic tracts.
`
`Hormonal Deficiencies
`follicle (cid:173)
`The possible deficiency of corticotropin,
`stimulating hormone and luteinizing hormone, or
`thyrotropin in a patient with a pituitary tumor should
`be assessed by simultaneous measurements of the par(cid:173)
`ticular pituitary hormone and its respective target
`gland hormone ( cortisol, estradiol or testosterone, or
`thyroxine) in serum (Table 111 -2). Pituitary hormone
`deficiency is characterized by a normal or low serum
`pituitary hormone concentration in the presence of a
`low serum concentration of the target gland hormone.
`
`rypes and Relative Frequency
`Table 111 -1 (cid:127)
`of Pituitary Adenomas
`
`Type Of Adenoma
`Nonsecretory adenoma
`Lactotroph (prolactinomal adenoma
`Somatotroph (GH-secretingl adenoma
`Corticotroph (ACTH-secreting) adenoma
`Other (thvrotroph rTSH -secretingl adenoma,
`gonadotroph !FSH- or LH-secretingll adenoma
`
`Frequency
`35%
`30%
`15%
`15%
`
`<5%
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`Chapter 111: Pituitary Tumors
`
`1141
`
`Figure 111-1 (cid:127) coronal magnetic resonance images of the head <contrast-enhanced> of a patient with a
`normal pituitary gland Ueftl and a patient with a pitUitary macroadenoma <right>. The macroadenoma fills
`the le~ side of the sella turcica and Is hypodense relative to the normal pituitary gland, and It has dis(cid:173)
`placed the pituitary stalk to the right.
`
`Growth hormone secretion need not be assessed.
`Many stimulation tests have been devised to deter(cid:173)
`mine whether secretion of pituitary hormones can
`be raised, but these tests add little and are rarely
`indicated.
`
`Hormonal Excesses
`Excess hormonal secretion also can be assessed ade(cid:173)
`quately in most patients by serum measurements of
`both the pituitary and target gland hormones or the
`pituitary hormone alone (see Table 111-2), but
`demonstration of failure of target hormones or other
`substances to inhibit pituitary hormone secretion is
`important in some patients. In patients with Cushing's
`disease, many of whom do not have a radiologically
`identifiable pituitary tumor, petrosal sinus cannula(cid:173)
`tion and measurements of plasma corticotropin before
`and after intravenous administration of corticotropin(cid:173)
`releasing hormone that reveal high petrosal; periph(cid:173)
`eral plasma ratios of corticotropin provide strong
`evidence for the presence of a corticotroph adenoma.
`Treatment
`Patients with nonsecretory microadenomas need no
`treatment but should have repeat magnetic resonance
`imaging and basal hormone measurements in six and
`12 months and then at longer intervals to be sure the
`adenoma is not enlarging. These adenomas do not
`often change during follow-up.
`
`Patients with nonsecretory macroadenomas and
`most patients with secretory microadenomas or
`macroadenomas should be treated by transsphenoidal
`resection of the tumor, but drug therapy is appropri(cid:173)
`ate for some patients with secretory adenomas (Table
`111-3). Among patients treated by transsphenoidal
`surgery, the success rate depends on the size of the
`tumor. Patients with microadenomas are considerably
`more likely to be cured than are those with macro(cid:173)
`adenomas (60% to 90% versus 30% to 50%). The
`operative mortality is very low (less than 1 % ) .
`Postoperatively, fewer than 20% of patients have new
`anterior pituitary hormone deficiencies or diabetes
`insipidus (usually transient), and approximately 1 %
`have bleeding or vascular occlusion, new visual loss,
`meningitis, sinusitis, third and sixth cranial nerve
`palsies, or hyponatremia.
`Drug therapy, in the form of dopaminergic agonist
`drugs, is the preferred initial treatment for patients
`with a prolactinoma, including those with visual
`impairment. These drugs not only decrease prolactin
`secretion, but also reduce tumor size. Similarly, long(cid:173)
`acting somatostatin analogs are gaining favor as initial
`treatment for patients with acromegaly.
`Patients with pituitary adenomas who are not
`cured by surgery or do not respond well to drugs may
`be treated with external-beam radiation, usually in a
`dose of 50 Gy. This is effective therapy, but its effect is
`slow; serum hormone concentrations usually fall at a
`rate of 10% to 20% per year, and it eventually causes
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`1142 Section Ill: Evaluation and Treatment of Hematologic and oncologic Disease (cid:127) Endocrine Cancer
`
`Table 111-2 (cid:127) Hormonal Findings in Patients
`with Pituitary Adenomas
`
`Hormonal Deficiency
`corticotropin Deficiency
`Normal or low plasma corticotropin and low serum cortisol
`concentrations (measured at 8 or 9 A.M.l
`oonadotropin <Follicle-Stimulating Hormone IFSHI and
`Luteinlzing Hormone ILHD Deficiency
`Young women with normal menstrual cycles: no tests needed
`Young women with amenorrhea: normal or low serum follicle -
`stimulating and luteinizing hormone and low serum estradiol
`concentrations
`Postmenopausal women: serum follicle-stimulating hormone
`and luteinizing hormone concentrations low for age
`Men: normal or low serum follicle-stimulating hormone and luteiniz(cid:173)
`ing hormone and low serum testosterone concentrations
`All these abnormalities may be caused by hyperprolactinemia,
`rather than destruction of gonadotrophs
`Growth Hormone
`No tests needed, unless growth hormone treatment is
`contemplated
`Prolactin
`Low serum prolactin concentration (prolactin deficiency not
`clinically important except in women who wish to lactate)
`Thyrotropin
`Normal or low serum thyrotropin and low serum free thyroxine
`concentrations
`vasopressin
`24-hour urine volume > 2000 ml
`Ratio of urine:plasma osmolality < 2 after water restriction for
`six hours or longer
`Hormonal Excess
`corticotropin Excess !Cushing's Disease>
`Screening tests: high 24-hour urine cortisol excretion, or serum
`cortisol concentration >5 µg/dL at 8 or 9 A.M. after
`administration of 1 mg dexamethasone at midnight
`Diagnosis: normal or high plasma ACTH and high serum cortisol
`concentrations !measured at 8 or 9 A.M.)
`oonadotropin Excess
`High serum follicle-stimulating hormone or luteinizing hormone
`and high serum estradiol or testosterone concentrations
`Growth Hormone Excess <Acromegalyl
`High serum growth hormone concentration two hours after
`ingestion of 75 g glucose
`High serum insulin-like growth factor I concentration
`Prolactin Excess
`High serum prolactin concentration !value may be high because
`of prolactinoma, or because another pituitary tumor blocks
`hypothalamic inhibition of prolactin secretion)
`Hyperthyroidism
`Normal or high serum thyrotropin and high serum free
`thyroxine concentrations
`
`hypopituitarism in most patients. It also has been asso(cid:173)
`ciated with psychological dysfunction and rarely
`extrapituitary brain tumors. Stereotactic radiosurgery
`using the gamma knife, in which high doses of radia(cid:173)
`tion can be delivered to small regions with little radi(cid:173)
`in more rapid
`results
`tissue,
`ation . of adjacent
`reduction in hormonal secretion and adenoma size
`than external-beam radiation and is likely safer. So far,
`it has been used mostly in patients with persistent or
`recurrent adenomas.
`Post-treatment care depends on the type and
`extent of the tumor and its secretory products. Many
`patients need treatment for one or more pituitary
`hormone deficiencies, those with hormonal hyper(cid:173)
`secretion need to be monitored periodically for hor(cid:173)
`monal recurrence, and those with macroadenomas
`the
`regrowth of
`need periodic monitoring for
`adenoma.
`
`craniopharyngioma
`Craniopharyngiomas arise from rests of squamous cells
`derived from Rathke's pouch, the diverticulum of the
`roof of the embryonic oral cavity that gives rise to the
`anterior pituitary. They originate within the sella
`turcica or, more often, in the suprasellar region. The
`
`Table 111-3 (cid:127) Treatment of Pituitary Adenomas
`
`Type of Adenoma
`Nonsecretory
`microadenoma
`Nonsecretory
`macroadenoma
`Corticotroph adenoma
`
`Gonadotroph adenoma
`Lactotroph adenoma
`
`Somatotroph adenoma
`
`Thyrotropin-secreting
`adenoma
`
`Treatment*+
`No treatment
`
`Surgery
`
`Surgery•
`Inhibitors of adrenal hormone
`synthesis (ketoconazole,
`metyrapone, mitotanel
`Surgery
`Dopamine agonist drugs
`(bromocriptine, caberogollnel
`surgery
`Surgery
`Long-acting somatostatin analogs
`Dopamine agonist drugs
`Growth hormone receptor antagonist
`drugs (pegvisomantl
`Surgery
`Long-acting somatostatin analogs
`Dopamine agonist drugs
`
`*Treatments are listed in usual order of preference.
`'Patients with any type of macroadenoma (or persistent or recurrent
`adenomal may be treated with external beam radiation therapy or
`gamma knife radiation therapy.
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`-
`
`- -
`
`Chapter 111: Pituitary Tumors
`
`1143
`
`-
`
`TREATMENT
`
`-
`
`Therapy considerations for Pituitary Tumor
`Patients with a pituitary tumor present because they
`have symptoms and signs that suggest the presence
`of a pituitary mass lesion, deficiency of one or more
`pituitary hormones, or an excess of a pituitary hormone.
`The questions that need to be considered are as
`follows:
`
`ls there a pituitary mass lesion? This is best answered by
`magnetic resonance imaging.
`Does the patient have any pituitary hormone deficiency or
`excess? A deficiency might be suspected on clinical
`grounds, but the symptoms and signs may be vague
`and nonspecific. Hormonal status can usually be
`
`accurately assessed by measurements in serum of
`the pituitary hormone and the hormone(s) produced
`by target glands.
`What treatment is indicated? Patients with a pituitary
`macroadenoma may need transsphenoidal resection
`of the tumor. Patients with pituitary deficiencies are
`usually treated with a target gland hormone, but
`administration of the pituitary hormone may on
`occasion be indicated. Patients with hormonal
`excess may be treated surgically or with one of
`several drugs, depending on the type of tumor.
`
`incidence is bimodal, with peaks in late childhood and
`adolescence and in the sixth decade; craniopharyn -
`giomas are the most common tumors of the hypotha(cid:173)
`lamic-pituitary region in children. The major clinical
`manifestations are headache, visual abnormalities,
`growth hormone deficiency,
`follicle-stimulating
`hormone and luteinizing hormone deficiency, and dia(cid:173)
`betes insipidus. Many patients have hyperprolactin(cid:173)
`emia. Magnetic resonance imaging usually reveals a
`large cystic mass, which may be calcified. Most patients
`should be treated with transsphenoidal or transfrontal
`surgery, depending on the location of the tumor, and
`external-beam radiation. The tumors are often difficult
`to resect completely, and the recurrence rate is reduced
`by postoperative radiation therapy.
`
`References
`Ben-Shlomo A, Melmed S: Acromegaly. Endocrinol Metab Clin
`North Am 2001;30:565-583.
`Ciric I, Ragin A, Baumgartner C, Pierce D: Complications of
`transsphenoidal surgery: Results of a national survey,
`review of the literature, and personal experience. Neuro(cid:173)
`surgery l 997;40:225-236.
`Donovan LE, Corenblum B: The natural history of the pituitary
`incidentaloma. Arch Intern Med 1995;155:181-183.
`
`Invitti C, Giraldi FP, De Martin M, et al: Diagnosis and manage(cid:173)
`ment of Cushing's syndrome: Results of an Italian multi(cid:173)
`centre study. J Clin Endocrinol Metab l 999;84:440-448.
`Jackson IM, Noren G: Gamma knife radiosurgery for pituitary
`tumors. Baillieres Best Pract Res Clin Endocrinol
`1999; 13:461-469.
`Laws ER Jr, Thapar K: Pituitary surgery. Endocrinol Metab Clin
`North Am 1999;28:119-131.
`Molitch ME: Disorders of prolactin secretion. Endocrinol Metab
`Clin North Am 2001;30:585-610.
`Nilsson B, Gustavsson-Kadaka E, Bengtsson B-A, Jonsson B:
`Pituitary adenomas in Sweden between 1958 and 1991:
`Incidence, survival, and mortality. J Clin Endocrinol Metab
`2000;85: 1420-1425.
`Pinzone JJ, Katznelson L, Danila DC, et al: Primary medical
`therapy of micro- and macroprolactinomas in men. J Clin
`Endocrinol Metab 2000;85:3053-3057.
`Shin JL, Asa SL, Woodhouse LJ, et al: Cystic lesions of the
`pituitary: Clinicopathological features distinguishing cran(cid:173)
`iopharyngioma, Rathke's cleft cyst, and arachnoid cyst.
`J Clin Endocrinol Metab l 999;84:3972-3982.
`Swearingen B, Barker PG II, Katznelson L, et al: Long-term
`mortality after transsphenoidal surgery and adjunctive
`therapy for acromegaly. J Clin Endocrinol Metab 1998;
`83:3419-3426.
`Verhelst J, Abs R, Maiter D, et al: Cabergoline in the treatment
`of hyperprolactinemia: A study in 455 patients. J Clin
`Endocrinol Metab l 999;84:2518-2522.
`
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