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Adult Height in Growth Hormone (GH)-Deficient Children Treated with Biosynthetic GH

Department of Pediatrics, State University of New York (S.L.B.), Stony Brook, New York 11794-8111; Genentech, Inc. (J.B., J.K., A.J.), South San Francisco, California 94080-4990; the Department of Pediatrics, Children’s Hospital of Pittsburgh (T.F.), Pittsburgh, Pennsylvania 15213-2583; and the Department of Pediatrics, Oregon Health Sciences University (S.L.), Portland, Oregon 97201-3011

Address all correspondence and requests for reprints to: Dr. Sandra L. Blethen, Genentech, Inc., 460 Point San Bruno Boulevard, South San Francisco, California 94080-4990.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Near-adult height (AH) was determined in 121 children (72 males and 49 females) with GH deficiency (GHD) who were prepubertal when they began treatment with recombinant DNA-derived preparations of human GH. AH as a SD score was -0.7 ± 1.2 (mean ± SD), significantly greater than the pretreatment height SD score (-3.1 ± 1.2), the predicted AH SD score (-2.2 ± 1.2; Bayley-Pinneau method), and the height SD score at the start of puberty (-1.9 ± 1.3). In contrast to studies of GH treatment outcome, which used pituitary-derived GH (pit-GH) in lower doses, we found that males did not have a higher AH SD score than females, spontaneous puberty did not diminish AH, and AH was significantly greater than that predicted at the start of GH treatment. In a multiple regression equation, the statistically significant variables (all P < 0.0001) related to AH (r² = 0.70) were the following: duration of treatment with GH, sex (males were taller than females, as expected for the normal population), age (younger children had a greater AH) and height at the start of GH, and growth rate during first year of GH. For the AH SD score (r² = 0.47), pretreatment predicted AH, duration of GH, and bone age delay were significant (P < 0.0002) explanatory variables. Bone age delay (chronological age - bone age) had a negative impact on the AH SD score. Target height, etiology of GHD, previous treatment with pituitary GH, and the presence or absence of spontaneous puberty did not significantly improve the prediction of AH. Early diagnosis of GHD and continuous treatment with larger doses of GH to near AH should improve the outcome in children with short stature due to GHD.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
IMPROVED ADULT height (AH) is a major goal in the treatment of children with short stature due to GH deficiency (GHD). When the only source of human GH was cadaver pituitaries, treatment efforts were limited by GH supply. Treatment outcomes in terms of AH were not very satisfactory, with 50% or more of patients failing to attain heights above the third percentile (1, 2, 3, 4, 5, 6, 7, 8). The introduction of GH prepared by recombinant DNA techniques has allowed children to receive continuous treatment with larger doses of GH until near AH is attained. In this paper, we report our experience with 121 children treated using 2 preparations of GH until near AH.

	Subjects and Methods

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Subjects

The studies began in 1981. Adult height was available for 121 subjects who were prepubertal at enrollment (age, 4.2–17.2 yr). There were 49 females and 72 males. Eighty-four were treated with methionyl-GH (somatrem for injection, Protropin^TM (Genentech Inc., South San Francisco, CA), and 37 were treated with GH with the same amino acid sequence as human pituitary GH (somatropin for injection, Nutropin^TM (Genentech Inc., South San Francisco, CA). All received a dose of 0.3 mg/kg·wk. Initially, GH was given three times a week; after 1987, subjects were randomly assigned to receive that same total weekly GH dose either daily or three times a week. Doses were adjusted yearly as the subjects’ weight increased. The diagnosis of GHD was based on a failure to increase serum GH to more than 9.9 µg/L after two pharmacological stimuli (insulin, arginine, L-dopa, glucagon, and clonidine were the stimuli used). GH levels were determined by RIA at each participating institution.

Children were excluded from the study if they had an abnormal karyotype, had evidence of a systemic disease that could have contributed to their growth failure, or had received treatment for a malignancy during the previous 12 months. Initially, children were examined every 3 months, but after 1991, children taking Protropin were examined every 6 months. Height, weight, and pubertal status were noted at each visit. Children were discontinued from the study for repeated failure to keep scheduled visits or for missing more than 15% of their scheduled injections.

Statistical methods

Near AH was defined on the basis of a growth rate of 2.0 cm/yr or less over an interval of at least 6 months and age. Both chronological age (CA) and bone age (BA) had to be at least 14 yr for females and 16 yr for males. If BA was not assessed at the last recorded visit, then the time from the last BA to the last visit (mean, 19 months) was added to the last BA to derive an estimated BA. All BA determinations were performed at the Fels Institute (Yellow Springs, OH).

Height at the start of puberty was defined as height at the first visit when a patient was described as having at least Tanner stage 2 breast development (females) or a testicular volume of 3 cc or more (males). For subjects with gonadotropin deficiency, height at the start of puberty was taken as the height at the visit at which gonadal steroid replacement was started.

Pediatric heights standardized for age and sex and adult heights standardized for sex were derived from published data for North American children and adults (9). Predicted AH (PAH) was determined by the method of Bayley-Pinneau (10) for the 100 children with BA of 6 yr or more on study enrollment. For the 21 subjects with BA between 3–6 yr, PAH was determined using a revision of the Bayley-Pinneau method developed by Khamis and Roche (personal communication).

All values are reported as the mean ± SD. Within-patient changes from baseline to AH were tested using the paired t test. Differences between sexes before and during GH treatment were evaluated using either the t test or Fisher’s exact test as appropriate.

Multiple linear regression was used to determine which explanatory variables were related to the change in height from the start of GH treatment in these studies to AH. Variables considered included baseline characteristics at the start of recombinant GH treatment [age, BA, age minus BA, BA SD score, height, height SD score, PAH, PAH SD score, whether the patient had received pituitary GH, the duration of pituitary GH treatment, maximum stimulated GH levels, sex, etiology of GHD, midparental target height (MPTH) in centimeters, and SD score] and treatment characteristics (growth rate during first year of GH treatment, duration of GH therapy during these studies, total duration of GH therapy, including previous GH treatment, and whether puberty was spontaneous or induced with exogenous sex steroids.)

	Results

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The demographic characteristics of the children at the time that they began treatment with recombinant GH are shown in Table 1. AH outcome is summarized in Table 2. One hundred and six (87.6%) of the children treated in these protocols reached an AH within 2 SD of the normal mean for American adults. The 13-cm difference in AH between males and females (Table 2) is comparable to that between males and females in the general population. Therefore, data for males and females were converted to SD score and analyzed together. When AH was expressed as an SD score, there was no difference (by t test, P = 0.8) in outcome between males and females. The etiology of GHD and the presence or absence of spontaneous (as opposed to induced) puberty did not affect outcome in our patients.

AH SD score was positively correlated with PAH SD score at the start of protocol, duration of GH treatment, and growth rate during the first year of GH treatment; BA delay was negatively correlated with the AH SD score. The regression equation was AH SD score = -1.6 + 0.6 (PAH SD score at the start of treatment) + 0.2 (yr on GH) + 0.2 (growth rate during the first year) - 0.2 (BA delay), with r² = 0.47. Variables are listed in order of their contribution to r²; each was highly significant (P < 0.0002), and there were no interactions.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
There are only a few studies reporting AH, and many lack statistical power because of the small number of subjects. Our study is the largest reporting results with recombinant GH and is second only to that of Hibi et al. (7) in total number of patients. While it is difficult to compare our results to those of older studies of GH treatment outcome because of variations in the potencies of different preparations of pituitary GH, differences in treatment regimens, and treatment interruptions, some generalizations are possible. 1) The AH SD score reported here was greater than that in previous studies tht used GH in lower doses (range, 0.06–0.19 mg/kg·week). 2) There was a statistically significant improvement in AH over PAH at the start of treatment. In previous studies, untreated children with GHD did not reach their predicted heights (11), and the Bayley-Pinneau method of AH prediction corresponded well to the height reached after GH treatment (4). Our finding of a significant increase in AH over pretreatment PAH may be due to our use of larger doses of GH given without treatment interruption. 3) In contrast to earlier studies (12, 13), we did not find that spontaneous puberty or female sex adversely affected the AH SD score. The height SD score improved significantly during puberty from -1.9 ± 1.3 to -0.7 ± 1.2. Recent studies using GH in doses between 0.15–0.19 mg/kg·week given daily (14, 15) continue to show that patients with gonadotropin deficiency are taller than those with spontaneous puberty. As the log mean GH dose during puberty was an important predictor of AH in one study (14), we believe that the higher doses of GH that we used may have contributed to our results. 4) We did not find that including MPTH improved the predictive power of our regression equation. Although MPTH was not a statistically significant predictor of AH, it is reflected in the height SD score at the start of GH treatment, which was an important predictive variable in our study. 5) Although maximum stimulated GH and more frequent GH injections were significant predictors of first year growth rate (16), they were not predictive of AH or the AH SD score.

Conclusion

Our most important observation is the effect of CA at the start of GH treatment on AH. Although the benefits of early treatment seem intuitive, not all previous studies found a correlation between AH and the age at which GH treatment was begun. The direct effect of age on AH may be due to longer duration of therapy and smaller height deficit at the beginning of treatment. This would be expected because children with untreated GHD grow more slowly than normal children, and thus, their height SD scores decrease the longer they are untreated. Of the variables that affect AH, age when treatment starts and duration of GH are the only ones that can be modified. It is, therefore, very important that growth problems in children be identified and evaluated as early as possible.

	Acknowledgments

 
Other physician members of the Genentech Growth Study Group are Gilbert August, Jennifer Bell, Dennis Bier, Robert Blizzard, David R. Brown, Steven Chernausek, Joseph Gertner, Ronald Gotlin, Raymond Hintz, Abbey Hollander, Nancy Hopwood, Selna Kaplan, John Kirkland, Rebecca Kirkland, Barbara Lippe, Margaret MacGillivray, Thomas Moshang, Wayne Moore, John Parks, Leslie Plotnick, Alan Rogol, Paul Saenger, Louis E. Underwood, and David T. Wyatt. Other Genentech employees who participated in the study were Kenneth Attie, James Frane, Andrew Perlman, and Barry Sherman.

Received August 26, 1996.

Revised October 14, 1996.

Accepted October 21, 1996.

	References

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