Treatment of Pituitary Gigantism with the Growth Hormone Receptor 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.

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 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 SD score (SDS)], hyperhydrosis, snoring, and coarse facial features. Laboratory evaluation revealed plasma GH 8.9 g/liter, which prolactin of 230 g/liter. Cabergoline (0.25 mg twice weekly) did not The decreased to 2.7 g/liter after 50 g of oral glucose, IGF-I 390 g/liter (74202), and

Journal of

Clinical Endocrinology and Metabolism

The Endocrine Society

Treatment of Pituitary Gigantism with the Growth Hormone Receptor 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. 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

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 SD score (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 areas represent 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

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 20 mg/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 7 months. 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 T4 concentrations 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

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

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. His calculated 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

random GH values were 6.6 and 9 g/liter, his plasma IGF-1 was 490 g/liter (normal < 540), and his growth velocity was 9.4 cm/yr (at or > 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 receptormediated 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 crossreactivity of pegvisomant in many GH assays make GH unsuitable as a marker of therapeutic 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, accelerated growth 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

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 transient pubertal 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 considered on an individual basis.

Figure 2 Expansion of pituitary tumor size in patient 2. Left panel, Coronal view of the sellar area after about 2 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.

Footnotes
This work was supported by the Department of Veterans Affairs Medical Research Service and National Institutes 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 information
J Clin Endocrinol Metab. 2008 August; 93(8): 29532956. Published online 2008 May 20. doi: 10.1210/jc.2007-2283 PMCID: PMC2515082 Naila Goldenberg, Michael S. Racine, Pamela Thomas, Bernard Degnan, William Chandler, and Ariel Barkan Division 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 48236 Address all correspondence and requests for reprints to: Ariel L. Barkan, M.D., University of Michigan Medical Center, 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 Society Articles from The Journal of Clinical Endocrinology and Metabolism are provided here courtesy of The Endocrine Society

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5. Rix M, Laurberg P, Hoejberg AS, Brock-Jacobsen B2005 Pegvisomant therapy in pituitary gigantism: successful treatment in a 12 year old girl. Eur J Endocrinol 153:195 201. [PubMed] 6. Mssig K, Gallwitz B, Honegger J, Strasbuerg CJ, Bidlingmaier M, Machicao F, Bornemann A, Ranke MB, Hring HU, Petersenn S2007 Pegvisomant treatment in gigantism caused by a growth hormone-secreting giant pituitary adenoma. Exp Clin Endocrinol Diabetes 115:198202. [PubMed] 7. Ali O, Banerjee S, Kelly DF, Lee PDK2007 Management of type 2 diabetes mellitus associated with pituitary gigantism. Pituitary 10:359364. [PubMed] 8. Greulich W, Pyle S1999 Radiographic atlas of skeletal development of the hand and wrist. 2nd ed. Palo Alto, CA: Stanford University Press. 9. Tanner JM, Landt KW, Cameron N, Carter BS, Patel J1983 Prediction of adult height from height and bone age in childhood. A new system of equations (TW Mark II) based on a sample including very tall and very short children. Arch Dis Child 58:767776. [PMC free article] [PubMed] 10. Tanner JM, Whitehouse RH, Marshall WA, Carte 11. Tanner JM, Whitehouse RH, Marshall WA, Carter BS1975 Prediction of adult height from height, bone age, and occurrence of menarche, at ages 4 to 16 with allowance for midparent height. Arch Dis Child 50:1426. [PMC free article][PubMed] 12. Wales JKH, Wit J-M, Rogol A2003 Pediatric endocrinology and growth. 2nd ed. Philadelphia: Saunders. 13. Parkinson C, Trainer PJ1999 Growth hormone receptor antagonists therapy for acromegaly. Bailleres Best Pract Res Clin Endocrinol Metab 13:419430. [PubMed] 14. Laron Z, Sarel R, Pertzelan A1980 Puberty in Laron type dwarfism. Eur J Pediatr 134:7983. [PubMed] 15. Aynsley-Green A, Zachmann M, Prader A1976 Interrelation of the therapeutic effects of growth hormone and testosterone on growth in hypopituitarism. J Pediatr 89:992999. [PubMed] 16. Borski RJ, Tsai W, DeMott-Friberg R, Barkan AL1996 Regulation of somatic growth and the somatotropic axis by gonadal steroids: primary effect on insulin-like growth factor 1 gene expression and secretion. Endocrinology 137:32533259.[PubMed] 17. Trainer PJ2003 Lessons from 6 years of GH receptor antagonist therapy for acromegaly. J Endocrinol Invest 26:4452. [PubMed] 18. Colao A, Pivonello R, Auriemma RS, De Martino MC, Bidlingmaier M, Briganti F,
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Pengobatan Gigantisme hipofisis dengan Hormon Pertumbuhan Receptor Antagonis Pegvisomant

Naila 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

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 Metode Persyaratan 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), masingmasing. 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 GHmensekresi 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

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

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).

). 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 sampai pertimbangan 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

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 <540), dan kecepatan pertumbuhannya adalah 9,4 cm / tahun (pada atau> 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

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 serupa pada 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.

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 anakanak. Titrasi dosis pegvisomant memungkinkan perkembangan pertumbuhan somatik pada tingkat normal. Perhatian harus dilakukan ketika menggunakan pegvisomant dan tindak 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 (

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 Referensi 1. Eugster EA, Pescovitz OH, gigantisme J1999. Clin Endocrinol Metab 84:4379-4384. [PubMed] 2. Zampieri P, Scanarini M, N Sicolo, Andrioli G, Mingrino S1983 The acromegaly sindrom gigantisme. Laporan empat kasus pembedahan. Surg Neurol 20:498-503. [PubMed] 3. Cozzi R, Montini M, Attanasio R, Albizzi M, Lasio G, Lodrini S, Doneda P, Cortesi L, Pagani G2006 pengobatan primer acromegaly dengan octreotide LAR: a (sampai sembilan tahun) studi prospektif jangka panjang kemanjurannya dalam pengendalian aktivitas penyakit dan penyusutan tumor. J Clin Endocrinol Metab 91:1397-1403. [PubMed] 4. Pelatih PJ, Drake WM, Katznelson L, Freda PU, Herman-Bonert V, van der Lely AJ, Dimaraki EV, Stewart PM, Teman KE, Vance ML, Besser GM, Scarlett JA, Thorner MO, Parkinson C, Klibanski A, Powell JS, Barkan AL, Sheppard MC, Malsonado M, Rose DR, DR Clemmons, Johannsson G, Bengtsson BA, Stavrou S, Kleinberg DL, Cook DM, Phillips LS, Bidlingmaier M, Strasburger CJ, Hackett S, Zib K, Bennett WF, davis RJ2000 Pengobatan Akromegali dengan pertumbuhan hormon-reseptor antagonis pegvisomant. N Engl J Med 342:1171-1177. [PubMed]

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17. Trainer PJ2003 Pelajaran dari 6 tahun terapi antagonis reseptor GH untuk acromegaly. J Endocrinol Investasi 26:44-52. [PubMed] 18. Colao A, Pivonello R, Auriemma RS, De Martino MC, Bidlingmaier M, Briganti F, Tortora F, P Burman, Kourides IA, Strasburger CJ, Lombardi G2006 Efikasi pengobatan 12 bulan dengan antagonis reseptor GH pegvisomant pada pasien dengan akromegali resisten untuk jangka panjang, somatostatin dosis tinggi pengobatan analog: efek IGF-1 tingkat, massa tumor, hipertensi dan glukosa toleransi. Eur J Endocrinol 154:467-477. [PubMed]