Treatment of Pituitary Gigantism With the Growth Hormone Receptor Antagonist Pegvisomant

8/13/2019 Treatment of Pituitary Gigantism With the Growth Hormone Receptor Antagonist Pegvisomant

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Treatment of Pituitary Gigantism with the Growth HormoneReceptor Antagonist Pegvisomant

Naila Goldenberg, Michael S. Racine, [...], and Ariel Barkan

Additional article information

Abstract

Context:Treatment of pituitary gigantism is complex and the results are usually

unsatisfactory.

Objective:The objective of the study was to describe the results of therapy of three

children with pituitary gigantism by a GH receptor antagonist, pegvisomant.

Design:This was a descriptive case series of up to 3.5 yr duration.

Setting:The study was conducted at a university hospital.

Patients:Patients included three children (one female, two males) with pituitary

gigantism whose GH hypersecretion was incompletely controlled by surgery,

somatostatin analog, and dopamine agonist.

Intervention:The intervention was administration of pegvisomant.

Main Outcome Measures:Plasma IGF-I and growth velocity were measured.

Results:In all three children, pegvisomant rapidly decreased plasma IGF-I

concentrations. Growth velocity declined to subnormal or normal values. Statural

growth fell into lower growth percentiles and acromegalic features resolved. Pituitary

tumor size did not change in two children but increased in one boy despite concomitant

therapy with a somatostatin analog.

Conclusions:Pegvisomant may be an effective modality for the therapy of pituitary

gigantism in children. Titration of the dose is necessary for optimal efficacy, and regular

surveillance of tumor size is mandatory.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#__ffn_sectitlehttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#__ffn_sectitlehttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#__ffn_sectitle


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Pituitary gigantism most frequently results from excess GH secretion by a somatotroph

pituitary tumor with onset during childhood, before epiphyseal closure (1). Due to the

irreversible effect of GH excess on stature rapid abolition of excessive somatic growth in

children is required. Unfortunately, the existing therapies for pituitary gigantism areunsatisfactory. Surgery alone is rarely effective and can lead to multiple hormone

deficiencies (2). Radiotherapy has delayed action (1), cannot prevent accelerated

somatic growth, and may cause significant central nervous system morbidity as well as

hypopituitarism. Somatostatin analogs are effective only in a proportion of patients with

acromegaly (3)and have not been adequately studied in children with gigantism. The

introduction of the GH receptor antagonist pegvisomant has offered a novel approach to

the treatment of acromegaly (4), but experience with this drug in pituitary gigantism is

limited (5,6,7). We present three children with pituitary gigantism treated with

pegvisomant for up to 3.5 yr.

Patients and Methods

The requirement for signed informed consent to report the data were waived by the

University of Michigan Institutional Review Board for all three patients.

Patients

Patient 1 is a 9-yr-old girl who surpassed the 95th percentile for length at 9 months of

age. Her plasma GH and IGF-I were elevated for age, and brain magnetic resonance

imaging (MRI) at 10 months demonstrated an intra- and suprasellar pituitary

macroadenoma measuring 1.8 cm. She underwent unsuccessful tumor resection by

subfrontal approach at 11 months of age. Postoperatively her plasma GH and IGF-I

remained elevated at 134 g/liter and 1419 g/liter (normal 17248), respectively.Serum prolactin was 265 g/liter (normal 123), and accelerated linear growth

continued. At 36 months of age, her tumor was debulked by transsphenoidal approach.

Immunohistochemical staining of tumor tissue confirmed GH-secreting adenoma.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B1http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B1http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B2http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B2http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B1http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B1http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B3http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B3http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B3http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B4http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B4http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B4http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B5http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B6http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B6http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B7http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B7http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B7http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B7http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B6http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B5http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B4http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B3http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B1http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B2http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B1


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The patient presented to us at age 3 yr 2 months, after her second surgery, with clinical

features of gigantism [height 110.8 cm, +3.68 SDscore (SDS)], hyperhydrosis, snoring, and

coarse facial features. Laboratory evaluation revealed plasma GH 8.9 g/liter, which

decreased to 2.7 g/liter after 50 g of oral glucose, IGF-I 390 g/liter (74202), and

prolactin of 230 g/liter. Cabergoline (0.25 mg twice weekly) did not The Journal ofClinical Endocrinology and Metabolism

The Endocrine Society

Treatment of Pituitary Gigantism with the Growth HormoneReceptor Antagonist Pegvisomant

Naila Goldenberg, Michael S. Racine, [...], and Ariel Barkan

Additional article information

Abstract

Context:Treatment of pituitary gigantism is complex and the results are usually

unsatisfactory.

Objective:The objective of the study was to describe the results of therapy of three

children with pituitary gigantism by a GH receptor antagonist, pegvisomant.

Design:This was a descriptive case series of up to 3.5 yr duration.

Setting:The study was conducted at a university hospital.

Patients:Patients included three children (one female, two males) with pituitary

gigantism whose GH hypersecretion was incompletely controlled by surgery,

somatostatin analog, and dopamine agonist.

Intervention:The intervention was administration of pegvisomant.

Main Outcome Measures:Plasma IGF-I and growth velocity were measured.

Results:In all three children, pegvisomant rapidly decreased plasma IGF-I

concentrations. Growth velocity declined to subnormal or normal values. Statural
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#__ffn_sectitlehttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#__ffn_sectitlehttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#__ffn_sectitle


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growth fell into lower growth percentiles and acromegalic features resolved. Pituitary

tumor size did not change in two children but increased in one boy despite concomitant

therapy with a somatostatin analog.

Conclusions:Pegvisomant may be an effective modality for the therapy of pituitary

gigantism in children. Titration of the dose is necessary for optimal efficacy, and regular

surveillance of tumor size is mandatory.

Pituitary gigantism most frequently results from excess GH secretion by a somatotroph

pituitary tumor with onset during childhood, before epiphyseal closure (1). Due to the

irreversible effect of GH excess on stature rapid abolition of excessive somatic growth in

children is required. Unfortunately, the existing therapies for pituitary gigantism are

unsatisfactory. Surgery alone is rarely effective and can lead to multiple hormone

deficiencies (2). Radiotherapy has delayed action (1), cannot prevent accelerated

somatic growth, and may cause significant central nervous system morbidity as well as

hypopituitarism. Somatostatin analogs are effective only in a proportion of patients with

acromegaly (3)and have not been adequately studied in children with gigantism. The

introduction of the GH receptor antagonist pegvisomant has offered a novel approach to

the treatment of acromegaly (4), but experience with this drug in pituitary gigantism is

limited (5,6,7). We present three children with pituitary gigantism treated with

pegvisomant for up to 3.5 yr.

Patients and Methods

The requirement for signed informed consent to report the data were waived by the

University of Michigan Institutional Review Board for all three patients.

Patients

Patient 1 is a 9-yr-old girl who surpassed the 95th percentile for length at 9 months of

age. Her plasma GH and IGF-I were elevated for age, and brain magnetic resonance

imaging (MRI) at 10 months demonstrated an intra- and suprasellar pituitary

macroadenoma measuring 1.8 cm. She underwent unsuccessful tumor resection by
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B1http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B1http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B2http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B2http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B1http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B1http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B3http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B3http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B3http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B4http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B4http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B4http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B5http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B6http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B6http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B7http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B7http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B7http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B7http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B6http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B5http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B4http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B3http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B1http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B2http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515082/?report=reader#B1


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subfrontal approach at 11 months of age. Postoperatively her plasma GH and IGF-I

remained elevated at 134 g/liter and 1419 g/liter (normal 17248), respectively.

Serum prolactin was 265 g/liter (normal 123), and accelerated linear growth

continued. At 36 months of age, her tumor was debulked by transsphenoidal approach.Immunohistochemical staining of tumor tissue confirmed GH-secreting adenoma.

The patient presented to us at age 3 yr 2 months, after her second surgery, with clinical

features of gigantism [height 110.8 cm, +3.68 SDscore (SDS)], hyperhydrosis, snoring,

and coarse facial features. Laboratory evaluation revealed plasma GH 8.9 g/liter,

which decreased to 2.7 g/liter after 50 g of oral glucose, IGF-I 390 g/liter (74202),

and prolactin of 230 g/liter. Cabergoline (0.25 mg twice weekly) did not suppress GH

or IGF-I levels, and her annualized growth velocity was 10 cm/yr. At 3 yr 9 months of

age, octreotide long-acting release (LAR) was started at 10 mg im every 4 wk. The dose

was gradually increased to 30 mg every 4 wk; however, the patients GH (8.2 g/liter),

IGF-I (1243 g/liter), and annualized growth velocity (10.3 cm/yr) remained elevated

(Fig. 1A1A).). At the age of 5 yr 6 months, pegvisomant 10 mg sc daily was added.

Figure 1

Clinical course of three patients with gigantism. Upper row, Actual growth curves.Middle row,

Annualized GVs.Lower row, Plasma IGF-I concentrations (shaded areasrepresent normal

ranges).Left column, Patient 1. Center column, Patient 2.Right column...

Patient 2 is a boy 13 yr 7 months old who exhibited accelerated linear growth beginning

at approximately 8 yr of age. Pituitary MRI revealed a 2.5-cm macroadenoma, and

visual field examination showed bitemporal hemianopsia. His IGF-I was 577 g/liter

(110565), and GH was 70.4 g/liter. At 9 yr 11 months, he underwent transsphenoidal

tumor debulking, which led to normalization of visual fields. Pathology revealed a GH

producing adenoma. He presented to us at 10 yr of age, measuring 153 cm (+2.09 SDS)

and exhibiting excess perspiration and coarsening of facial features. His IGF-I level was

923 g/liter and GH was 12.7 g/liter. Prolactin was 100.1 g/liter. Cabergoline 0.5 mg
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twice weekly was ineffective in lowering GH and IGF-1 concentrations and octreotide

LAR 20 mg im every 4 wk was added. His IGF-I declined to 504 g/liter, but plasma GH

remained high at 20.7 g/liter. His annualized growth velocity was 9 cm/yr (>97th

percentile for age) despite drug therapy. At the age of 10 yr 7 months, pegvisomant 20mg/day sc was added.

Patient 3 is a boy 14 yr 7 months old who developed accelerated growth and headaches

at age 9 yr. Between 10 and 11 yr of age, his height increased by almost 30 cm. A

pituitary MRI revealed a 2-cm pituitary adenoma. He presented to us at 11 1 months yr

of age. His height was 170 cm (+3.49 SDS) and he had excess perspiration, meaty hands,

and coarse facial features. His GH was 126 g/liter, IGF-I was 1963 g/liter (normal

110395), and his prolactin was less than 1 g/liter.

His tumor was debulked transsphenoidally, and immunohistochemical staining was

positive for GH. Neuroophthalmologic examination was normal before and after the

surgery. Postoperatively his GH was 37.2 g/liter, IGF-I was 2023 g/liter, and

accelerated growth continued. After three monthly injections of octreotide LAR 20 mg,

his GH and IGF-I remained elevated (32.9 and 1760 g/liter, respectively), and

annualized growth velocity was 21 cm/yr. Pegvisomant 20 mg/d was added at age 11 yr 7months.

Postoperatively, all three patients were found to have ACTH and TSH deficiency and

were given replacement therapy with hydrocortisone and L-thyroxine in standard doses.

Free T4concentrations have remained normal.

Methods

Plasma IGF-I was measured by immunoluminometric assay kit (Diagnostic Systems

Laboratories, Webster, TX) in patients 1 and 3 and by Esoterix (Calabasas Hills, CA) in

patient 2. Manufacturer-provided age/gender-adjusted normative data were used for

comparisons. Patients heights were regularly recorded using the same stadiometer and

annualized growth velocity (GV; centimeters per year) was calculated. Pituitary


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dedicated MRI studies were performed using pre- and postgadolinium contrast images.

Skeletal ages were determined by analysis of x-ray films of the left wrist and hand, using

the method of Greulich and Pyle (8).

Results

IGF-I and growth velocity

After the initiation of pegvisomant, linear growth virtually ceased for 6 months in

subjects 2 (height 157 cm between ages 10.5 and 11 yr) and 3 (177 cm between 11 yr 7

months and 12 yr 2 months) and for 1 yr in subject 1 (125 cm between 5.5 and 6.5 yr). In

patients 1 and 2, this was accompanied by subnormal and normal IGF-I levels,respectively; in patient 3 plasma IGF-I levels remained elevated for almost 2 yr after

pegvisomant was started before falling into the normal range (Fig. 11).). Administration

of pegvisomant promptly and durably abolished excessive perspiration in all children.

Within several months, diminution of soft tissue hypertrophy occurred, and within 1 yr

of therapy, the facial features of acromegaly resolved completely. Throughout the

follow-up period, liver function remained normal in all three patients, and there were no

other noticeable side effects.

In patient 1, octreotide LAR therapy was eventually terminated. Her stature followed the

75th percentile for age until the age of 8 yr 8 months when it fell to the 50th percentile.

Her IGF-I was then 154 g/liter (1 SDS)and the pegvisomant dose was decreased

further to 5 mg daily.

Subject 2 went into spontaneous puberty as was evident by 120 ng/dl testosterone at age

11 yr 5 months, but by 12 yr 7 months, his testosterone decreased to subnormal levels.

The patient and his parents declined testosterone replacement until further

consideration. Subject 3 was started on testosterone therapy after his testosterone was

unmeasurable at age 12 yr. With spontaneous or testosterone-induced puberty, GV

rapidly and temporarily increased in both boys on the same dose of pegvisomant and

then decreased spontaneously within 612 months. Octreotide LAR was stopped in
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patient 3 at the age of 13 yr 11 months but continued in patient 2 because of the larger

size of the tumor remnant.

Statural growth

In patient 1 skeletal and chronological ages were synchronous before initiation of

pegvisomant (5 yr 2 months at 5 yr of age). Due to her early bone age, calculations of

predicted height were unreliable. At the age of 7 yr, after 1.5 yr of pegvisomant therapy,

her skeletal age was 6 yr 10 months and remained similar to chronological age at 8 yr 1

months. Her predicted adult height by bone age determination(9,10)at 8 yr 1 month

was 168.9 cm. The midparental predicted target height was calculated at 155.8 9 cm

(11).

The skeletal age of patient 2, after 6 months of pegvisomant treatment, matched the

chronological age (11 yr for both). His predicted adult height by bone age was 193 cm.

His midparental target height was calculated at 180.5 9 cm.

In patient 3, after 10 months of pegvisomant and 2 months of testosterone therapy,

skeletal age was 13 yr vs. 12 yr 4 months of chronological age. At the age of 13 yr 11

months, spontaneous puberty occurred and the skeletal age advanced to 15 yr. Hiscalculated predicted height decreased from 205.4 (as calculated before the introduction

of pegvisomant) to 194.8 cm. His midparental target height was 177.4 9 cm.

Tumor size monitoring

Repeat pituitary MRI studies showed stable size of the pituitary tumor remnant

throughout the treatment period in patients 1 and 3. In patient 2, despite continued

somatostatin LAR therapy, tumor size increased between 13 and 14 yr of age and

pegvisomant was stopped. Three months after the discontinuation of pegvisomant,

tumor size did not increase further. The patient stopped octreotide LAR therapy as well

and underwent a second transsphenoidal surgery at the age of 14 yr 2 months. After

surgery and on no medications, he still had a small residual tumor within the sella, his
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random GH values were 6.6 and 9 g/liter, his plasma IGF-1 was 490 g/liter (normal 97th percentile). His parents

decided not to use pharmacological therapy but to pursue radiation therapy instead.

Discussion

Pegvisomant is a novel therapeutic agent for the treatment of acromegaly(4,12). It binds

to the GH receptor and prevents receptor dimerization and subsequent receptor-

mediated activity, thus impeding GH-dependent production of IGF-I. Administration of

pegvisomant to patients with acromegaly results in elevation of circulating GH levels by

removing the negative feedback influence of circulating IGF-I (12). This and the cross-

reactivity of pegvisomant in many GH assays make GH unsuitable as a marker oftherapeutic efficacy. However, in acromegaly and pituitary gigantism, the decline in

IGF-I generally correlates with the degree of clinical improvement (4,5,6,7,12).

In this series, administration of pegvisomant resulted in significant reduction of IGF-I,

prompt improvement in soft tissue hypertrophy and resolution of acromegalic features

in all three children. Most dramatic was the effect on growth velocity. Documentation of

clinical efficacy of therapeutic modalities in adults with acromegaly is often difficult due

to irreversible changes brought about by years of active disease. In contrast, acceleratedgrowth is a cardinal and easily quantifiable feature of gigantism. In three previously

reported cases of gigantism treated with pegvisomant (5,6,7), patients also showed

decreases in growth velocity. In all three cases reported here, pegvisomant treatment

was followed by an immediate cessation of somatic growth. Titration of the pegvisomant

dose in patient 1 allowed us to maintain growth velocity at desired rate. In patients 2

and 3, GV was kept within the expected range to maintain statures within acceptable

limits. Most importantly, disease control with pegvisomant afforded an opportunity to

delay considerations of radiotherapy until all three patients had matured further and the

dangers of central nervous system toxicity diminished.

In the two boys, spontaneous or medical increase in testosterone was followed by a brief

period of accelerated statural growth in parallel with temporary increases in plasma
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IGF-I concentrations. This is reminiscent of a similar phenomenon in individuals with

Larons type dwarfism (congenital insensitivity to GH) (13) in whom linear growth is

accelerated at the time of pubarche, despite absent GH action (14,15). We can speculate

that growth acceleration in our patients was shorter than expected due to only transientpubertal testosterone increase in subject 2 and intermittent testosterone administration

in subject 3.

Several cases of tumor expansion have been described in patients with acromegaly

treated with pegvisomant (12,16,17). Whether the increase in tumor size is due to the

removal of the negative IGF-I feedback or is a manifestation of spontaneous progression

of inherently aggressive tumors is uncertain. We initially continued therapy with

octreotide LAR in these patients despite its lack of biochemical efficacy in the hope that

it might attenuate growth potential of the tumors. Subsequently when the stability of

tumor size during combined pegvisomant/octreotide LAR was documented, the latter

was stopped in patients 1 and 3, and no further tumor growth occurred. However, in

patient 2, tumor size has expanded despite persistent octreotide LAR administration,

perhaps as a reflection of intrinsically higher aggressiveness of the tumor (Fig. 2B2B).).

It is obvious that these patients require continuous follow-up, and the decision to use

pegvisomant alone or in combination with a somatostatin analog needs to be consideredon an individual basis.

Figure 2Expansion of pituitary tumor size in patient 2.Left panel, Coronal view of the sellar area after about2 yr of combined octreotide LAR (20 mg every month) and pegvisomant (20 mg every day)therapy.Right panel, Same view after another year of therapy ...

In conclusion, pegvisomant may be an effective therapy for pituitary gigantism

in children who do not respond to other modalities, including somatostatin analogs. It

fulfills the demand for rapid and durable reduction in growth velocity and prevention of

gigantism in children. Titration of pegvisomant dose allows progression of somatic

growth at a normal rate. Caution should be exercised when using pegvisomant and

follow-up of pituitary tumor size is mandatory.
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Footnotes

This work was supported by the Department of Veterans Affairs Medical Research Service and NationalInstitutes of Health Grant R01 DK071955 (to A.B.) and Genentech Fellowship (to N.G.).

Disclosure Statement: The authors have nothing to declare.

First Published Online May 20, 2008

Abbreviations: GV, Growth velocity; LAR, long-acting release; MRI, magnetic resonance imaging;SDS, SDscore.

Article informationJ Clin Endocrinol Metab. 2008 August; 93(8): 29532956.Published online 2008 May 20. doi: 10.1210/jc.2007-2283PMCID: PMC2515082

Naila Goldenberg,Michael S. Racine,Pamela Thomas,Bernard Degnan,William Chandler,andAriel BarkanDivision of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine (N.G., M.S.R., W.C.,A.B.) and the Department of Neurosurgery (W.C., A.B.), University of Michigan Medical Center, Ann Arbor,Michigan 48109; Department of Pediatric Endocrinology (P.T.), Lutheran Childrens Hospital, Fort Wayne,Indiana 46804; and Department of Pediatric Endocrinology (B.D.), St. Johns Hospital, Detroit, Michigan 48236Address all correspondence and requests for reprints to: Ariel L. Barkan, M.D., University of Michigan MedicalCenter, Division of MEND, 1500 East Medical Center Drive, 3920 Taubman Center, SPC 5354, Ann Arbor,Michigan 48109. E-mail: abarkan/at/umich.edu.Received October 11, 2007; Accepted May 14, 2008.Copyright 2008 by The Endocrine SocietyArticles from The Journal of Clinical Endocrinology and Metabolism are provided here courtesy of TheEndocrine Society

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acromegaly resistant to long-term, high-dose somatostatin analog treatment: effect

of IGF-1 levels, tumor mass, hypertension and glucose tolerance. Eur J Endocrinol

154:467477. [PubMed]
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Pengobatan Gigantisme hipofisis dengan

Hormon Pertumbuhan Receptor Antagonis

PegvisomantNaila Goldenberg, Michael S. Racine, [...], dan Ariel Barkan

Abstrak

Konteks: Pengobatan gigantisme pituitary adalah kompleks dan hasilnya biasanya

memuaskan.

Tujuan: Tujuan dari penelitian ini adalah untuk menggambarkan hasil terapi dari

tiga anak dengan gigantisme pituitary oleh antagonis reseptor GH, pegvisomant.Desain: Ini adalah serangkaian kasus deskriptif hingga 3,5 durasi thn.

Tempat: Penelitian dilakukan di sebuah rumah sakit universitas.

Pasien: Pasien termasuk tiga anak (satu perempuan, dua laki-laki) dengan

gigantisme pituitary yang hipersekresi GH tidak lengkap dikendalikan dengan

operasi, somatostatin analog, dan agonis dopamin.

Intervensi: Intervensi adalah administrasi pegvisomant.

Main Hasil Tindakan: Plasma IGF-I dan kecepatan pertumbuhan diukur.

Hasil: Dalam semua tiga anak, pegvisomant cepat penurunan konsentrasi plasma

IGF-I. Kecepatan pertumbuhan menurun ke nilai subnormal atau normal.

Pertumbuhan Statural jatuh ke persentil pertumbuhan yang lebih rendah dan fitur

acromegalic diselesaikan. Ukuran tumor hipofisis tidak berubah dalam dua anak

namun meningkat dalam satu anak laki-laki meskipun terapi bersamaan dengan

analog somatostatin.

Kesimpulan: Pegvisomant mungkin merupakan modalitas yang efektif untuk terapi

gigantisme pituitary pada anak-anak. Titrasi dosis diperlukan untuk keberhasilan

yang optimal, dan pengawasan rutin ukuran tumor adalah wajib.

Gigantisme hipofisis paling sering hasil dari kelebihan sekresi GH oleh tumor hipofisis

somatotroph dengan onset masa kanak, sebelum penutupan epifisis (1). Karena efek

ireversibel kelebihan GH pada perawakannya penghapusan cepat pertumbuhan

somatik yang berlebihan pada anak-anak diperlukan. Sayangnya, terapi yang ada


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untuk gigantisme pituitary tidak memuaskan. Pembedahan saja jarang efektif dan

dapat menyebabkan beberapa kekurangan hormon (2). Radioterapi telah menunda

tindakan (1), tidak dapat mencegah pertumbuhan somatik dipercepat, dan dapat

menyebabkan pusat sistem saraf morbiditas signifikan serta hypopituitarism. Analog

somatostatin yang efektif hanya dalam proporsi pasien dengan acromegaly (3) dan

belum cukup diteliti pada anak dengan gigantisme. Pengenalan GH antagonis

reseptor pegvisomant telah menawarkan pendekatan baru untuk pengobatan

acromegaly (4), tapi pengalaman dengan obat ini di hipofisis gigantisme terbatas

(5,6,7). Kami menyajikan tiga anak dengan gigantisme pituitary diobati dengan

pegvisomant hingga 3,5 tahun.

Pasien dan MetodePersyaratan untuk menandatangani informed consent untuk melaporkan data

dibebaskan oleh University of Michigan Institutional Review Board untuk ketiga pasien.

Pasien

Pasien 1 adalah seorang gadis 9 thn yang melampaui persentil ke-95 untuk panjang

pada usia 9 bulan. Her GH plasma dan IGF-I yang meningkat untuk usia, dan otak

magnetic resonance imaging (MRI) pada 10 bulan menunjukkan sebuah macroadenoma

hipofisis intra dan suprasellar berukuran 1,8 cm. Dia menjalani reseksi tumor berhasil

dengan pendekatan subfrontal pada 11 bulan usia. Pasca operasi nya GH plasma dan

IGF-I tetap meningkat pada 134 mg / liter dan 1.419 mg / liter (normal 17-248), masing-

masing. Serum prolaktin adalah 265 mg / liter (1-23 normal), dan pertumbuhan linier

dipercepat terus. Pada 36 bulan, tumor nya debulked dengan pendekatan

transsphenoidal. Pewarnaan imunohistokimia jaringan tumor dikonfirmasi GH-

mensekresi adenoma.

Pasien disajikan kepada kita pada usia 3 tahun 2 bulan, setelah operasi kedua, dengan

fitur klinis gigantisme [tinggi 110,8 cm, 3,68 skor SD (SDS)], hyperhydrosis,

mendengkur, dan fitur wajah kasar. Evaluasi laboratorium mengungkapkan plasma GH

8,9 mg / liter, yang turun menjadi 2,7 mg / liter setelah 50 g glukosa oral, IGF-I 390 mg

/ liter (74-202), dan prolaktin dari 230 mg / liter. Cabergoline (0,25 mg dua kali

seminggu) tidak menekan GH atau tingkat IGF-I, dan kecepatan pertumbuhan


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tahunan-nya adalah 10 cm / tahun. Pada 3 tahun 9 bulan usia, octreotide rilis long-

acting (LAR) dimulai pada 10 mg im setiap 4 minggu. Dosis ini secara bertahap

meningkat menjadi 30 mg setiap 4 minggu, namun, GH pasien (8,2 mg / liter), IGF-I

(1243 mg / liter), dan kecepatan pertumbuhan tahunan (10,3 cm / tahun) tetap

meningkat (Gambar 1A1A ).). Pada usia 5 tahun 6 bulan, pegvisomant 10 mg sehari sc

ditambahkan.

Gambar 1

Perjalanan klinis tiga pasien dengan gigantisme. Atas baris, kurva pertumbuhan aktual.

Barisan tengah, GVS Annualized. Baris bawah, konsentrasi IGF-I Plasma (berbayang

daerah merupakan rentang normal). Kolom kiri, Pasien 1. Pusat kolom, Pasien 2. Kolom

kanan ...Pasien 2 adalah seorang anak 13 thn berusia 7 bulan yang menunjukkan pertumbuhan

linier dipercepat dimulai pada sekitar 8 tahun usia. Pituitary MRI mengungkapkan

macroadenoma 2,5 cm, dan pemeriksaan bidang visual menunjukkan hemianopsie

bitemporal. IGF-I nya 577 mg / liter (110-565), dan GH adalah 70,4 mg / liter. Pada 9

thn 11 bulan, ia menjalani debulking tumor transsphenoidal, yang menyebabkan

normalisasi bidang visual. Patologi mengungkapkan memproduksi adenoma GH. Dia

disajikan kepada kita pada 10 tahun usia, berukuran 153 cm (2,09 SDS) dan

menunjukkan kelebihan keringat dan merendahkan fitur wajah. IGF-I tingkat nya

adalah 923 mg / liter dan GH adalah 12,7 mg / liter. Prolaktin adalah 100,1 mg / liter.

Cabergoline 0,5 mg dua kali seminggu tidak efektif dalam menurunkan GH dan IGF-1

konsentrasi dan octreotide LAR 20 mg im setiap 4 minggu ditambahkan. IGF-I tidak

bersedia 504 mg / liter, tetapi plasma GH tetap tinggi pada 20,7 mg / liter. Kecepatan

pertumbuhan tahunan nya adalah 9 cm / tahun (> 97 persentil untuk usia) meskipun

terapi obat. Pada usia 10 tahun 7 bulan, pegvisomant 20 mg / hari sc ditambahkan.

Pasien 3 adalah seorang anak 14 thn berusia 7 bulan yang mengembangkan

pertumbuhan yang pesat dan sakit kepala pada usia 9 tahun. Antara 10 dan 11 tahun

usia, tinggi badannya meningkat hampir 30 cm. Sebuah hipofisis MRI mengungkapkan

adenoma hipofisis 2 cm. Dia disajikan kepada kita pada 11 bulan 1 tahun usia. Tingginya

170 cm (3,49 SDS) dan ia memiliki kelebihan keringat, tangan gemuk, dan fitur wajah


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kasar. GH nya adalah 126 mg / liter, IGF-I adalah 1963 mg / liter (110-395 normal), dan

prolaktin nya kurang dari 1 mg / liter.

Tumor Nya debulked transsphenoidally, dan pewarnaan imunohistokimia positif untuk

GH. Pemeriksaan Neuroophthalmologic normal sebelum dan sesudah

operasi. Pasca operasi GH nya adalah 37,2 mg / liter, IGF-I adalah 2023 mg / liter, dan

pertumbuhan dipercepat terus. Setelah tiga suntikan bulanan octreotide LAR 20 mg,

nya GH dan IGF-I tetap meningkat (32,9 dan 1760 mg / liter, masing-masing), dan

kecepatan pertumbuhan tahunan adalah 21 cm / tahun. Pegvisomant 20 mg / d

ditambahkan pada usia 11 tahun 7 bulan.

Pasca operasi, ketiga pasien ditemukan memiliki kekurangan ACTH dan TSH dan diberi

terapi pengganti dengan hidrokortison dan L-tiroksin dalam dosis standar. Konsentrasi

T4 bebas tetap normal.

Metode

Plasma IGF-I diukur dengan immunoluminometric assay kit (Diagnostik Sistem

Laboratories, Webster, TX) pada pasien 1 dan 3 dan oleh Esoterix (Calabasas Hills, CA)

pada pasien 2. Produsen yang disediakan usia / gender disesuaikan normatif data yang

digunakan untuk perbandingan. Ketinggian pasien secara teratur direkam

menggunakan stadiometer yang sama dan kecepatan pertumbuhan tahunan (GV;

sentimeter per tahun) dihitung. Pituitary studi MRI khusus dilakukan dengan

menggunakan gambar kontras pra-dan postgadolinium. Usia Skeletal ditentukan

dengan analisis film x-ray pergelangan tangan kiri dan tangan, menggunakan metode

Greulich dan Pyle (8).

Hasil

IGF-I dan kecepatan pertumbuhan

Setelah inisiasi pegvisomant, pertumbuhan linier hampir berhenti selama 6 bulan

dalam mata pelajaran 2 (tinggi 157 cm antara usia 10,5 dan 11 thn) dan 3 (177 cm antara

11 thn 7 bulan dan 12 tahun 2 bulan) dan untuk 1 tahun dalam subjek 1 (125 cm antara

5,5 dan 6,5 thn). Pada pasien 1 dan 2, ini disertai dengan IGF-I tingkat subnormal dan

normal, masing-masing; pada pasien 3 kadar plasma IGF-I tetap meningkat selama

hampir 2 tahun setelah pegvisomant dimulai sebelum jatuh ke kisaran normal (Gbr. 11).


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). Administrasi pegvisomant segera dan tahan lama dihapuskan keringat berlebih pada

semua anak. Dalam beberapa bulan, penurunan hipertrofi jaringan lunak terjadi, dan

dalam 1 tahun terapi, fitur wajah acromegaly diselesaikan sepenuhnya. Selama masa

tindak lanjut, fungsi hati tetap normal dalam tiga pasien, dan tidak ada efek samping

terlihat lain.

Pada pasien 1, octreotide terapi LAR akhirnya dihentikan. Perawakannya nya mengikuti

persentil 75 untuk usia sampai usia 8 tahun 8 bulan ketika jatuh ke persentil ke-50.

IGF-I nya kemudian 154 mg / liter (-1 SDS) dan dosis pegvisomant itu menurun

menjadi 5 mg sehari.

Subyek 2 pergi ke pubertas spontan seperti terbukti dengan 120 ng / dl testosteron pada

usia 11 thn 5 bulan, tetapi dengan 12 tahun 7 bulan, testosteronnya menurun ke tingkat

bawah normal. Pasien dan orangtuanya menolak penggantian testosteron sampaipertimbangan lebih lanjut. Subjek 3 dimulai pada terapi testosteron setelah testosteron

nya terukur pada usia 12 tahun. Dengan pubertas spontan atau testosteron-diinduksi,

GV cepat dan untuk sementara meningkat di kedua anak laki-laki pada dosis yang sama

pegvisomant dan kemudian menurun secara spontan dalam waktu 6-12 bulan.

Octreotide LAR dihentikan pada pasien 3 pada usia 13 tahun 11 bulan tapi terus pada

pasien 2 karena ukuran yang lebih besar dari sisa-sisa tumor.

Pertumbuhan Statural

Pada pasien usia 1 rangka dan kronologis yang sinkron sebelum memulai pegvisomant

(5 thn 2 bulan pada 5 thn usia). Karena usia tulang awal, perhitungan ketinggian

diperkirakan tidak dapat diandalkan. Pada usia 7 tahun, setelah 1,5 tahun terapi

pegvisomant, usia tulang nya 6 tahun 10 bulan dan tetap sama dengan usia kronologis

pada 8 thn 1 bulan. Dia memprediksi tinggi dewasa dengan penentuan usia tulang

(9,10) pada 8 thn 1 bulan adalah 168,9 cm. The midparental tinggi Target diprediksi

dihitung pada 155,8 9 cm (11).

Usia kerangka pasien 2, setelah 6 bulan pengobatan pegvisomant, cocok usia kronologis

(11 thn untuk keduanya). Tinggi dewasa diperkirakan Nya dengan usia tulang adalah

193 cm. Target tinggi midparental nya dihitung pada 180,5 9 cm.

Pada pasien 3, setelah 10 bulan dan 2 bulan pegvisomant terapi testosteron, usia tulang

adalah 13 thn vs 12 tahun 4 bulan usia kronologis. Pada usia 13 tahun 11 bulan, pubertas


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spontan terjadi dan usia kerangka maju ke 15 tahun. Tinggi dihitung Nya diperkirakan

menurun dari 205,4 (yang dihitung sebelum pengenalan pegvisomant) ke 194,8 cm.

Target tinggi midparental Nya adalah 177.4 9 cm.

Pemantauan ukuran tumor

Ulangi studi MRI hipofisis menunjukkan ukuran stabil dari sisa-sisa tumor hipofisis

selama periode pengobatan pada pasien 1 dan 3. Pada pasien 2, meskipun terus

somatostatin LAR terapi, ukuran tumor meningkat antara 13 dan 14 tahun usia dan

pegvisomant dihentikan. Tiga bulan setelah penghentian pegvisomant, ukuran tumor

tidak meningkat lebih lanjut. Pasien berhenti octreotide terapi LAR juga dan menjalani

operasi transsphenoidal kedua pada usia 14 tahun 2 bulan. Setelah operasi dan tidak

ada obat-obatan, ia masih memiliki sisa tumor kecil di dalam sella itu, nilai-nilai GH

acak nya adalah 6,6 dan 9 mg / liter, plasma nya IGF-1 adalah 490 mg / liter (normal 97th

persentil). Orang tuanya memutuskan untuk tidak menggunakan terapi farmakologi

tapi untuk mengejar terapi radiasi sebagai gantinya.

Diskusi

Pegvisomant adalah agen terapi baru untuk pengobatan acromegaly (4,12). Berikatan

dengan reseptor GH dan mencegah dimerisasi reseptor dan aktivitas reseptor-mediated

berikutnya, sehingga menghambat produksi GH-tergantung dari IGF-I. Administrasi

pegvisomant kepada pasien dengan Akromegali menghasilkan elevasi tingkat sirkulasi

GH dengan menghapus pengaruh umpan balik negatif beredar IGF-I (12). Ini dan

reaktivitas silang dari pegvisomant dalam banyak tes GH membuat GH cocok sebagai

penanda keberhasilan terapi. Namun, dalam acromegaly dan hipofisis gigantisme,

penurunan IGF-I biasanya berkorelasi dengan tingkat perbaikan klinis (4,5,6,7,12).

Dalam seri ini, administrasi pegvisomant mengakibatkan penurunan yang signifikan

dari IGF-I, peningkatan cepat dalam hipertrofi jaringan lunak dan resolusi fitur

acromegalic dalam semua tiga anak. Paling dramatis adalah efek pada kecepatan

pertumbuhan. Dokumentasi keberhasilan klinis modalitas terapi pada orang dewasa

dengan Akromegali sering sulit karena perubahan ireversibel dibawa oleh tahun

penyakit aktif. Sebaliknya, pertumbuhan dipercepat adalah fitur kardinal dan mudah

diukur dari gigantisme. Dalam tiga sebelumnya melaporkan kasus gigantisme diobati


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dengan pegvisomant (5,6,7), pasien juga menunjukkan penurunan kecepatan

pertumbuhan. Dalam semua tiga kasus yang dilaporkan di sini, pengobatan

pegvisomant diikuti oleh penghentian segera pertumbuhan somatik. Titrasi dosis

pegvisomant pada pasien 1 memungkinkan kita untuk mempertahankan kecepatan

pertumbuhan pada tingkat yang diinginkan. Pada pasien 2 dan 3, GV disimpan dalam

kisaran diharapkan untuk mempertahankan ketetapan-ketetapan dalam batas yang

dapat diterima. Yang paling penting, pengendalian penyakit dengan pegvisomant

diberikan kesempatan untuk menunda pertimbangan radioterapi sampai ketiga pasien

telah jatuh tempo lebih lanjut dan bahaya toksisitas sistem saraf pusat berkurang.

Dalam dua anak laki-laki, peningkatan spontan atau medis testosteron diikuti oleh

periode singkat dipercepat pertumbuhan statural secara paralel dengan peningkatan

sementara konsentrasi plasma IGF-I. Hal ini mengingatkan kita pada fenomena serupapada individu dengan Laron itu jenis dwarfisme (ketidakpekaan bawaan ke GH) (13) di

antaranya pertumbuhan linier dipercepat pada saat pubarche, meskipun ada tindakan

GH absen (14,15). Kita dapat berspekulasi bahwa percepatan pertumbuhan pada pasien

kami lebih pendek dari yang diharapkan karena hanya sementara peningkatan

testosteron pubertas pada subjek 2 dan administrasi testosteron intermiten dalam

subjek 3.

Beberapa kasus ekspansi tumor telah dijelaskan pada pasien dengan acromegaly diobati

dengan pegvisomant (12,16,17). Apakah peningkatan ukuran tumor ini disebabkan

penghapusan negatif IGF-I umpan balik atau merupakan manifestasi dari

perkembangan spontan tumor agresif inheren tidak pasti. Kami awalnya melanjutkan

terapi dengan octreotide LAR pada pasien ini meskipun kurangnya kemanjuran

biokimia dengan harapan bahwa mungkin melemahkan potensi pertumbuhan tumor.

Selanjutnya ketika stabilitas ukuran tumor selama pegvisomant / octreotide LAR

didokumentasikan gabungan, yang terakhir dihentikan pada pasien 1 dan 3, dan tidak

ada pertumbuhan tumor lebih lanjut terjadi. Namun, pada pasien 2, ukuran tumor telah

berkembang meskipun octreotide gigih LAR administrasi, mungkin sebagai refleksi dari

agresivitas intrinsik lebih tinggi tumor (Gambar 2B2B).). Hal ini jelas bahwa pasien ini

membutuhkan terus menerus tindak lanjut, dan keputusan untuk menggunakan

pegvisomant sendiri atau dalam kombinasi dengan analog somatostatin perlu

dipertimbangkan secara individual.


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Gambar 2

Perluasan ukuran tumor hipofisis pada pasien 2. Panel sebelah kiri, pandangan Coronal

daerah sellar setelah sekitar 2 tahun dari octreotide gabungan LAR (20 mg setiap bulan)

dan pegvisomant (20 mg setiap hari) terapi. Panel sebelah kanan, pandangan yang sama

setelah satu tahun lagi terapi ...

Sebagai kesimpulan, pegvisomant mungkin merupakan terapi yang efektif untuk

gigantisme pituitary pada anak-anak yang tidak menanggapi modalitas lainnya,

termasuk analog somatostatin. Ini memenuhi permintaan untuk pengurangan cepat dan

tahan lama dalam kecepatan pertumbuhan dan pencegahan gigantisme pada anak-

anak. Titrasi dosis pegvisomant memungkinkan perkembangan pertumbuhan somatik

pada tingkat normal. Perhatian harus dilakukan ketika menggunakan pegvisomant dantindak lanjut dari ukuran tumor hipofisis wajib.

Catatan kaki

Karya ini didukung oleh Departemen Veterans Affairs Medical Research Service dan

National Institutes of Health Hibah r01 DK071955 (ke AB) dan Genentech Fellowship

(untuk NG).

Pernyataan Pengungkapan: Para penulis tidak perlu mendeklarasikan.

Pertama Publikasi Online 20 Mei 2008

Singkatan: GV, kecepatan pertumbuhan, LAR, rilis long-acting, MRI, magnetic

resonance imaging, SDS, SDscore.

Informasi Pasal

J Clin Endocrinol Metab. Agustus 2008, 93 (8): 2953-2956.

Diterbitkan online 2008 20 Mei. doi: 10.1210/jc.2007-2283

PMCID: PMC2515082

Naila Goldenberg, Michael S. Racine, Pamela Thomas, Bernard Degnan, William

Chandler, dan Ariel Barkan

Divisi Metabolisme, Endokrinologi, Diabetes dan, Departemen of Internal Medicine

(NG, MSR, WC, AB) dan Departemen Bedah Saraf (WC, AB), Universitas Michigan

Medical Center di Ann Arbor, Michigan 48109, Departemen Pediatric Endokrinologi (


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PT), Rumah Sakit Lutheran Anak, Fort Wayne, Indiana 46804, dan Departemen

Pediatrik Endokrinologi (BD), Rumah Sakit St John, Detroit, Michigan 48236

Alamat semua korespondensi dan permintaan untuk cetak ulang ke: Ariel L. Barkan,

MD, dari University of Michigan Medical Center, Divisi MEND, 1500 East Medical

Center Drive, 3920 Taubman Center, SPC 5354, Ann Arbor, Michigan 48109. E-mail:

abarkan / di / umich.edu.

Diterima 11 Oktober 2007, diterima 14 Mei 2008.

Hak Cipta 2008 oleh The Endocrine Society

Artikel dari The Journal of Clinical Endokrinologi dan Metabolisme yang disediakan di

sini courtesy of The

Endocrine Society

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Treatment of Pituitary Gigantism With the Growth Hormone Receptor Antagonist Pegvisomant

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