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CLINICAL REVIEW |
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 Children’s Hospital, Fort Wayne, Indiana 46804; and Department of Pediatric Endocrinology (B.D.), St. John’s 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.
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Abstract |
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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.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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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 µg/liter and 1419 µg/liter (normal 17–248), respectively. Serum prolactin was 265 µg/liter (normal 1–23), 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 µg/liter, which decreased to 2.7 µg/liter after 50 g of oral glucose, IGF-I 390 µg/liter (74–202), and prolactin of 230 µg/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 patient’s GH (8.2 µg/liter), IGF-I (1243 µg/liter), and annualized growth velocity (10.3 cm/yr) remained elevated (Fig. 1A
). At the age of 5 yr 6 months, pegvisomant 10 mg sc daily was added.
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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 µg/liter, IGF-I was 1963 µg/liter (normal 110–395), and his prolactin was less than 1 µg/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 µg/liter, IGF-I was 2023 µg/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 µg/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).
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Results |
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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. 1
). 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 µg/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 6–12 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 µg/liter, his plasma IGF-1 was 490 µg/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.
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Discussion |
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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 Laron’s 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. 2B). 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.
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Footnotes |
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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, SD score.
Received October 11, 2007.
Accepted May 14, 2008.
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References |
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