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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_sectitle8/13/2019 Treatment of Pituitary Gigantism With the Growth Hormone Receptor Antagonist Pegvisomant
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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#B18/13/2019 Treatment of Pituitary Gigantism With the Growth Hormone Receptor Antagonist Pegvisomant
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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_sectitle8/13/2019 Treatment of Pituitary Gigantism With the Growth Hormone Receptor Antagonist Pegvisomant
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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#B18/13/2019 Treatment of Pituitary Gigantism With the Growth Hormone Receptor Antagonist Pegvisomant
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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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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 (
8/13/2019 Treatment of Pituitary Gigantism With the Growth Hormone Receptor Antagonist Pegvisomant
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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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