From the Section of Pediatric Endocrinology and Diabetology, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, Indiana
| ABSTRACT |
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Key Words: growth puberty
Abbreviations: SERM, selective estrogen receptor modulator PAH, predicted adult height TV, testicular volume
BA, change in bone age
CA, change in chronologic age SDS, SD score
For children with significant short stature, the preservation of growth potential is an important goal. This is particularly true of adolescents presenting late to the pediatric endocrine clinic, who are often well into puberty by the time that pharmacologic intervention is considered.
Historically, long-acting gonadotropin-releasing hormone analogs have been used in pubertal growth hormone deficient and nongrowth hormone deficient patients as a way of delaying epiphyseal fusion and increasing adult height.1 However, new discoveries highlighting the importance of estrogen in mediating closure of the growth plates has led to the evaluation of novel alternative therapies aimed at decreasing estrogen synthesis or blocking estrogen effects. These therapies have included the use of antiestrogens in the form of aromatase inhibitors and selective estrogen receptor modulators (SERMs) such as tamoxifen. In this study we retrospectively evaluated the effect of tamoxifen on the rate of skeletal maturation and predicted adult height (PAH) in pubertal boys with limited growth potential. To our knowledge, no reports of the use of tamoxifen for this purpose currently exist.
| METHODS |
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4-mL testicular volume (TV) at the initiation of tamoxifen therapy. Availability of bone-age radiographs to calculate the rate of skeletal maturation was also an inclusion criterion. The rate of skeletal maturation was defined as change in bone age (
BA) divided by change in chronologic age (
CA). Bone-age radiographs were read independently, using the standards of Greulich and Pyle,2 by 2 pediatric endocrinologists who were unaware of the subjects' age or treatment status. If the bone-age reading was between 2 standards, the average of those 2 standards was used. These interpretations then were averaged with those of the treating physicians, and the PAH was calculated by using the Bayley-Pinneau method.3 The use of tamoxifen was off-label, and the dose was chosen on the basis of previous studies in children4 and individual physician preference. In general, patients were started on tamoxifen if their PAH was below the midparental height or there was a concern regarding loss of height potential as a result of pubertal status or pubertal tempo. The retrospective chart review was approved by the institutional review boards of Indiana University (Indianapolis, IN) and St Joseph Regional Medical Center (South Bend, IN).
Data were analyzed by using the Statview program for MacIntosh computers (Abacus Concepts Inc, Berkeley, CA).
BA/
CA and PAH were compared before and during tamoxifen therapy by using the paired Student's t test. A P value of <.05 was considered statistically significant.
| RESULTS |
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Hepatic transaminases were routinely recorded for 6 of the 7 patients. In all cases, the alanine aminotransferase, aspartate aminotransferase, and gamma glutamyl transferase remained normal. No adverse effects of therapy were apparent. One patient complained of blurred vision after the initiation of tamoxifen. Tamoxifen was discontinued, and ophthalmologic examination revealed no abnormalities. After reinitiation of tamoxifen the patient had no recurrence of visual symptoms.
| DISCUSSION |
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Although tamoxifen is only approved for use in children with McCune-Albright syndrome, it has been used in a variety of childhood disorders including nasopharyngeal fibromas,8 pubertal gynecomastia,9,10 and a variety of tumors including gliomas.11 In these populations, adverse effects have been rare, and tamoxifen seems to have an excellent safety profile overall.
With our patients, the rationale for treatment was based on a concern that continued pubertal progression would result in a deterioration of height potential to well below the genetic target (midparental height). Oral administration and the ability to allow puberty to continue at a physiologically appropriate time make tamoxifen an attractive option for delaying skeletal maturation and preserving height potential.
It is important to recognize that 6 of the 7 patients in this study were also on growth hormone therapy, yet the average growth velocity was low for pubertal boys. Whether tamoxifen attenuated the growth rate in our patients or whether tamoxifen alone would affect growth velocity during puberty remains unknown. Because none of the subjects had reached final adult height, it is impossible to know if the increase in PAH will translate into a clinically significant increase in final height. It is also difficult to determine the effects of growth hormone therapy alone on increasing the PAH. Because of the retrospective nature of the study, the length of time in which the patients received tamoxifen or growth hormone alone is variable, making specific analysis of the pure effect of tamoxifen on PAH difficult to assess. However, one would not expect growth hormone therapy alone to decrease the rate of skeletal maturation, thus suggesting that the increase in PAH was at least, in part, a result of tamoxifen use.
| CONCLUSIONS |
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| FOOTNOTES |
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Reprint requests to (N.C.K.), Pediatric Endocrinology, Riley Hospital for Children, Room 5960, 702 Barnhill Dr, Indianapolis, IN 46202. E-mail: nkreher{at}iupui.edu
No conflict of interest declared.
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D. B. Allen Growth Hormone Therapy for Short Stature: Is the Benefit Worth the Burden? Pediatrics, July 1, 2006; 118(1): 343 - 348. [Full Text] [PDF] |
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