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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2008-0707
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 11 4342-4350
Copyright © 2008 by The Endocrine Society

Dose-Dependent Effect of Growth Hormone on Final Height in Children with Short Stature without Growth Hormone Deficiency

Kerstin Albertsson-Wikland, A. Stefan Aronson, Jan Gustafsson, Lars Hagenäs, Sten A. Ivarsson, Björn Jonsson, Berit Kriström, Claude Marcus, Karl Olof Nilsson, E. Martin Ritzén, Torsten Tuvemo, Otto Westphal and Jan Åman

Göteborg Pediatric Growth Research Center (K.A.-W., B.K., O.W.), Department of Pediatrics, Institute of Clinical Sciences, The Sahlgrenska Academy at University of Gothenburg, SE-41685 Gothenburg, Sweden; Department of Pediatrics (A.S.A.), The Central County Hospital of Halmstad, SE-30185 Halmstad, Sweden; Department of Women’s and Children’s Health (J.G., B.J., T.T.), Uppsala University, SE-75185 Uppsala, Sweden; Department of Woman and Child Health (L.H., E.M.R.), Karolinska Institutet, SE-17176 Stockholm, Sweden; Department of Clinical Sciences (S.A.I., K.O.N.), University Hospital Malmö, Lund University, SE-20502 Malmö, Sweden; Department of Clinical Science, Paediatrics (B.K.), Umeå University, SE-90185 Umeå, Sweden; Division of Pediatrics (C.M.), Department for Clinical Science, Intervention and Technology, Karolinska Institutet, SE-14186 Stockholm, Sweden; and Department of Pediatrics (J.A.), Örebro University, SE-70185 Örebro, Sweden

Address all correspondence and requests for reprints to: Kerstin Albertsson-Wikland, Göteborg Pediatric Growth Research Center/Växthuset, The Queen Silvia Children’s Hospital, SE-416 85 Göteborg, Sweden. E-mail: kerstin.albertsson-wikland{at}pediat.gu.se.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: The effect of GH therapy in short non-GH-deficient children, especially those with idiopathic short stature (ISS), has not been clearly established owing to the lack of controlled trials continuing until final height (FH).

Objective: The aim of the study was to investigate the effect on growth to FH of two GH doses given to short children, mainly with ISS, compared with untreated controls.

Design and Setting: A randomized, controlled, long-term multicenter trial was conducted in Sweden.

Intervention: Two doses of GH (Genotropin) were administered, 33 or 67 µg/kg·d; control subjects were untreated.

Subjects: A total of 177 subjects with short stature were enrolled. Of these, 151 were included in the intent to treat (AllITT) population, and 108 in the per protocol (AllPP) population. Analysis of ISS subjects included 126 children in the ITT (ISSITT) population and 68 subjects in the PP (ISSPP) population.

Main Outcome Measures: We measured FH SD score (SDS), difference in SDS to midparenteral height (diff MPHSDS), and gain in heightSDS.

Results: After 5.9 ± 1.1 yr on GH therapy, the FHSDS in the AllPP population treated with GH vs. controls was –1.5 ± 0.81 (33 µg/kg·d, –1.7 ± 0.70; and 67 µg/kg·d, –1.4 ± 0.86; P < 0.032), vs. –2.4 ± 0.85 (P < 0.001); the diff MPHSDS was –0.2 ± 1.0 vs. –1.0 ± 0.74 (P < 0.001); and the gain in heightSDS was 1.3 ± 0.78 vs. 0.2 ± 0.69 (P < 0.001). GH therapy was safe and had no impact on time to onset of puberty. A dose-response relationship identified after 1 yr remained to FH for all growth outcome variables in all four populations.

Conclusion: GH treatment significantly increased FH in ISS children in a dose-dependent manner, with a mean gain of 1.3 SDS (8 cm) and a broad range of response from no gain to 3 SDS compared to a mean gain of 0.2 SDS in the untreated controls.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
GH has been used therapeutically in humans since the 1950s (1). Children with short stature of various etiologies were treated soon thereafter, but owing to a supply shortage, the use of GH was restricted to children with very low GH secretion (2, 3). When biosynthetic GH became available in the late 1980s (4), the cutoff level defining GH deficiency (GHD) changed (5, 6, 7, 8). Databases were initiated to monitor the safety and efficacy of GH treatment in children, and these data support the good safety profile of biosynthetic GH that has been seen in clinical trials (9, 10). However, there was limited information on the effect of GH for non-GHD short children with idiopathic short stature (ISS) (11, 12, 13). Therefore, to investigate the GH effect in short non-GHD children especially, randomized, controlled trials were initiated in both the United States (14) and Sweden in children born either slightly small for gestational age (SGA) or appropriate for gestational age (AGA). The results of some of these trials have been published; however, some lack randomized control groups, whereas others have a limited number of subjects who were followed to final height (FH) (14, 15, 16).

The aim of the present study was to investigate in a long-term trial the effects of GH therapy on FH in short non-GHD children as compared with randomized, untreated controls. Secondary aims of the study were to determine whether there was a dose-response relationship, to evaluate whether GH therapy induced earlier onset of puberty, and to evaluate if and how the variation in FH could be explained.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Ethics

The study was approved by the Ethical Committees of Sweden at Göteborg, Lund, Linköping, Uppsala, Huddinge, Umeå, and Karolinska Institutet. Informed consent was obtained from all the children and their parents.

Subjects

Inclusion Short children, defined as height below –2 SD score (SDS) according to the Swedish population-based reference (17), whose chronological age was 8–13 yr for girls and 10–15 yr for boys, with a corresponding bone age no more than 11 yr in girls and no more than 13 yr in boys according to Tanner-Whitehouse, were included.

Exclusion Children were excluded if they had GHD, defined as GHmax value at two GH stimulation tests below 10 µg/liter (20 mU/liter); had a bone age retardation of at least 3 yr; or had significant chronic diseases, skeletal dysplasia, or chromosome aberrations. Children born at a gestational age less than 35 wk or with extreme intrauterine growth retardation were also excluded.

Study populations In total, 177 short children were enrolled into the study, of whom three did not participate; therefore, 174 children constituted the safety population. Of the patients enrolled, 26 were not included for the efficacy analysis, primarily owing to protocol inclusion/exclusion violations in the GH-treated group (n = 14) and the use of treatment regimens such as GH or testosterone that were violations of the protocol in the controls (n = 12). The remaining 151 children constituted the all subject intent to treat (AllITT) population, of which 108 adhered to the protocol, the all subject per protocol (AllPP) population, the primary efficacy population for the analyses.

When the study was initiated, there was no distinction between children with ISS and those born SGA. As knowledge about differences between these two groups became known, we then classified children as ISS or SGA based on current clinical guidelines (18, 19). The growth responses of subjects with ISS were further evaluated. Thus, after exclusion of 48 subjects [45 with SGA (20, 21), three without available birth weight or length data], our analysis included 126 children with ISS in the ISS intent to treat (ISSITT) population and 68 subjects in the ISS per protocol (ISSPP) population. The baseline characteristics of the various populations are described in Table 1Go.


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  		TABLE 1. Subject characteristics at birth, at study start, and at FH of the all subjects and ISS populations

 
Methods

Study design Eligible children were enrolled into this randomized, controlled, dose-response study at seven university hospitals in Sweden between 1988 and 1999. Children were evaluated during a 12-month prestudy period, and those who remained prepubertal were randomized to no treatment (controls, n = 47) or to one of two doses of GH (Genotropin; Pfizer Inc., New York, NY): 33 µg/kg·d (0.1 U/kg·d), n = 49; or 67 µg/kg·d (0.2 U/kg·d), n = 50.

The 31 children who entered puberty during the prestudy year were randomized to either 67 µg/kg·d of GH (n = 16) or an untreated control group (n = 15).

Children were followed at least once a year at a university hospital for efficacy and safety measurements, which included bone age determination, lab tests, auxology, and puberty staging. Children were also clinically evaluated for dose adjustments every third month at their local children’s hospital. They were followed until they reached FH, which was defined as the height when growth velocity was less than 1 cm/yr (the height end point value used for analyses of FH). However, according to this definition of FH, GH treatment was stopped prematurely in 64 children. All children had passed their peak height velocity; 34 had a growth rate between 1 and 2 cm/yr, 16 had a growth rate between 2 and 3 cm/yr, and 14 had a growth rate of more than 3 cm/yr at the time they stopped GH treatment.

Prestudy assessments During the year before randomization, standing and sitting heights were measured using a stadiometer every third month, and the mean of three measurements was recorded. GH provocation tests and a spontaneous 24-h GH secretion profile were performed (22); methods for assaying GH and IGF-I concentrations were previously reported (6, 23, 24). Bone age was evaluated according to Tanner-Whitehouse by one radiologist in a blinded manner (Table 1Go).

Growth outcome variables Three outcome variables were used for evaluation of response to GH treatment: 1) FH as measured in centimeters and SDS using the reference population born in 1974 (17); 2) gain in heightSDS, which was calculated using FHSDS minus heightSDS at baseline using the childhood component of the growth reference (25); and 3) FHSDS minus midparental height (MPH) SDS, referred to as diff MPHSDS. MPHSDS was calculated as follows: (father’s height SDS + mother’s height SDS)/1.61 (26). Body mass index SDS was calculated vs. the new Swedish reference (27).

Statistical analyses

The statistical analyses were performed using the standard statistical package SPSS, version 15.0 (SPSS Inc., Chicago, IL). Results are expressed as mean ± SD unless otherwise specified. Analyses were performed using nonparametric tests of Wilcoxon type. Safety analyses included all 173 children in the safety population.

For analyses, the AllPP population of 108 children was used as the primary efficacy population. Analyses were also performed in subjects with ISS (ISSPP, n = 68). Furthermore, growth response in children with MPHSDS below –2 SDS, i.e. with familial short stature (FSS), was compared with growth in non-FSS children (18, 19). Stepwise multiple forward regression analyses were performed for the analysis of factors that significantly explained the variance in growth response and FH. In all analyses, low and high GH doses were included as dummy variables. Only variables entering the regressions at levels below the significance level 0.05 were used.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
FH outcome

All subject populations In the AllPP population, GH-treated children (n = 77) reached a significantly taller FH compared with untreated controls (n = 31), for both males and females (Table 2Go). FHSDS, gain in heightSDS during treatment, and diff MPHSDS also improved significantly in GH-treated subjects compared with untreated controls (Figs. 1Go and 2Go). When the effects of GH treatment on growth outcomes in females and males were evaluated separately, the effects in females were less pronounced; the response in males was significant for all variables at the P < 0.001 level (FHSDS –1.6, diff MPHSDS –0.35, and gain in heightSDS 1.0), whereas this was not the case for all comparisons in females [FHSDS –2.1 (P < 0.002), diff MPHSDS –0.45 (P < 0.034), and gain in heightSDS 0.71 (P < 0.001)]. The results in the AllITT population were similar to those found in the AllPP population (Table 2Go).


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  		TABLE 2. Outcome results at FH of the four populations

 

Figure 1
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  		FIG. 1. Primary outcome. FHSDS of the AllPP population (n = 108) of the three randomized groups: untreated (n = 31), GH 33 µg/kg·d (n = 32), and GH 67 µg/kg·d (n = 45). Box and whisker plot shows median, interquartile range (IRQ), and values within ± 1.5 IRQ of baseline and FHSDS. The dotted line represents the mean MPHSDS of the study population. Open boxes, Height at study start; filled boxes, FH.

 

Figure 2
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  		FIG. 2. Final outcome of the individuals of the AllPP population, expressed as FHSDS (top panel), diff MPHSDS (middle panel), and gain in heightSDS from study start to FH (bottom panel). Dotted lines represent MPHSDS of the entire population in top panel and 95% confidence interval for MPH, i.e. ± 1.64 SD, in bottom panel.

 
ISS populations

In the ISSPP population (n = 68), GH treatment resulted in significant improvements in FH for both girls and boys compared with untreated control subjects, including FHSDS, diff MPHSDS, and gain in heightSDS (Table 2Go). In fact, when growth parameters of the 24 SGA children in the AllPP population were compared with the ISSPP population, there were no significant differences in growth responses (data not shown). A significant gain in height with GH therapy was also observed in the ISSITT population, which was similar to that seen in the ISSPP population. The 45 SGA children (in the AllITT population) exhibited a significant growth response to GH therapy similar to the children in the ISSITT population (data not shown).

Dose response

All subject populations In the AllPP population, a dose-response relationship was evident when comparing the FHSDS obtained in those receiving the higher dose (67 µg/kg·d) of GH vs. the lower dose (33 µg/kg·d): –1.4 ± 0.86 SDS vs. –1.7 ± 0.70 SDS; P < 0.032. A significant dose-response relationship was also observed in the AllITT population for FHSDS (P < 0.008), diff MPHSDS (P < 0.005), and gain in heightSDS (P < 0.007) (Table 2Go).

ISS populations In both the ISSPP and ISSITT populations, significant dose-response relationships were found for diff MPHSDS (P < 0.05) (Table 2Go).

Prepubertal growth

Sixty-two children from the AllPP population were in the study for at least 1 yr before the onset of puberty. The mean gain in {Delta} heightSDS after 1 yr on treatment compared with baseline was 0.53 ± 0.20 in the 33 µg/kg·d group (n = 17), 0.76 ± 0.22 SDS in the 67 µg/kg·d group (n = 27), and –0.01 ± 0.27 in the untreated controls (n = 18). Children in both GH-treated groups had significantly greater prepubertal growth than the untreated controls (P < 0.001), and there was a significant difference between the two GH dose groups (P < 0.001). During the pretreatment year, the change in heightSDS was 0.01 SDS in the low dose, –0.01 in the high dose, and 0.07 in the untreated controls. If the same growth velocity was assumed when evaluating the changes in heightSDS during the first year of treatment with GH (0.52 in the low dose, 0.77 in the high dose, and –0.076 in the controls), the changes remained significant within the treated group (P < 0.001). A GH dose-dependent growth response was found (P < 0.004).

Time from study start to onset of puberty

In the AllPP population, GH treatment had no effect on time until puberty onset, which started 22.6 ± 9.81 months after the study start in the GH-treated children and 22.2 ± 8.3 months in the untreated controls. Gain in height from onset of puberty to FH was significantly greater in both the 33 and 67 µg/kg·d GH-treated groups (0.95 ± 0.79 SDS and 1.10 ± 0.94 SDS, respectively) vs. the untreated controls (0.48 ± 0.70 SDS; P < 0.02 and P < 0.006, respectively). There was no significant difference between the two GH-treated groups.

FSS vs. non-FSS

Of the 108 children in the AllPP population, there were 21 with FSS of whom 13 were GH-treated. The non-FSS individuals grew significantly better than those with FSS; the difference between FSS and non-FSS in FHSDS was 1.0 in the untreated controls (P < 0.019) and 0.7 (P < 0.011) in the GH-treated individuals; the difference in gain in heightSDS was 0.7 (P < 0.034) in the controls and 0.4 (P < 0.041) in the GH group; and the difference in diff MPHSDS was 0.7 (P < 0.020) in controls and 1.0 (P < 0.001) in GH-treated children. The FH of FSS children was closer to their parents’ height than non-FSS children. The 36 non-FSS children treated with high-dose GH showed the highest growth response: the FHSDS was –1.18, gain in heightSDS was 1.53, and diff MPHSDS was –0.20. The corresponding values of the AllITT population are presented in Table 2Go.

Multivariate analyses

With the use of multivariate analyses in the AllPP population, the factors explaining the variance in growth outcomes were: 1) at birth and infancy—length at birth, height difference to the parents, infancy growth, high/low GH dose; and 2) at baseline—bone age delay, heightSDS, and IGF-ISDS. These variables explained 58% of the variation in FHSDS, 47% of the variation in gain in heightSDS, and 50% of the variation in diff MPHSDS. Table 3Go illustrates the order of entrance and the regression coefficients for the predictors of growth response. The high dose always entered the regression before the low dose independent of the study population, indicating a dose-dependent growth response.


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  		TABLE 3. Regression coefficients, adjusted R2 signs, and order of entrance of the significant predictors in the multiple forward regression analyses are given for all four populations

 
In the AllITT population relative to the AllPP population, the variables explained approximately 10% more of the variability in FHSDS, gain in heightSDS, and diff MPHSDS being 60, 68, and 61%, respectively (Table 3Go). The corresponding figures of the ISSPP and ISSITT populations are presented in Table 3Go.

Safety

The safety population consisted of 112 subjects treated with GH and 61 controls. No serious adverse events were attributed to GH therapy. Six children were withdrawn from the study owing to adverse events: four in the low-dose GH-treated group, and two controls. Dissociative identity disorder, pituitary cyst, mood swings, and irritability were the adverse events leading to discontinuation of GH therapy in the treated groups; in the untreated control group, discontinuations were due to a road traffic accident and a brain tumor. There was no effect found on thyroid or liver function during this long-term study. Fasting glucose and insulin levels increased in a dose-dependent fashion; however, no individual had persistently elevated glucose and insulin levels. During GH treatment, 29 subjects had an elevated glucose and insulin level that was subsequently normal on the following assessment.

IGF-I levels remained within ± 3 SDS throughout the study in all but 21 children (20 on GH and one untreated control). During the first year of GH treatment, 14 children (seven on each GH dose) had one instance of an IGF-I level between 3 and 3.5 SDS. In six children (five high-dose GH and 1 low-dose GH), two to four subsequent IGF-I levels were above +3 SDS during the first and second years of GH therapy, whereas it remained high in only one child during the third year. Thereafter, all levels were below +3 SDS in all children while on GH treatment. Figure 3Go illustrates the mean levels of IGFSDS and ratio IGF-I/IGFBP3binding protein-3 (IGF-I/IGFBP3) SDS for the three groups.


Figure 3
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  		FIG. 3. Mean levels and 95% confidence intervals of AllITT population for IGFSDS (left) and ratio IGF-I/BP3 SDS (right) at baseline, 3 months, 1 yr, and the mean value of the individual mean between 1 yr and GH stop for the three different randomization groups. On GH 33 µg/kg·d, the ratio IGF/BP3 increased from –0.52 ± 0.93 to a mean level of 0.01 ± 1.5, whereas on GH 67 µg/kg·d the corresponding figures were from –0.99 ± 0.94 to 0.57 ± 0.8. IGF-I levels in the low-dose GH group increased from –0.66 ± 1.11 to 0.63 ± 1.10, and for the high-dose GH group, levels increased from –0.94 ± 1.2 to 1.11 ± 1.08. In the untreated controls, the corresponding data for IGF/BP3 SDS ratio was from –0.88 ± 0.83 to –0.70 ± 1.24, and for IGF-I SDS from –0.78 ± 0.96 to –0.77 ± 1.06.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This randomized, controlled trial in non-GHD children with short stature and ISS demonstrated that GH treatment for a mean of 5.9 ± 1.1 yr, given from near start of puberty, significantly increased the FH of subjects to a height close to that of their parents. The GH effect was dose-dependent, and the children with parents of normal heights responded best, their mean FH being –1.2 SDS and only 0.2 SDS below MPH after a gain of 1.5 SDS (approximately 9 cm). The FH in untreated controls was –2.4 SDS, and –1.0 SDS from their parents after a gain of only 0.2 SDS from the start of the study. Notably, one third of individuals receiving the high GH dose and one fifth of those receiving the low dose reached a FH above –1 SDS compared with none of the controls.

Since the study commenced in 1988, other long-term studies evaluating the growth effect of GH treatment in children with ISS have been reported (14, 15, 16). However, our study provides more conclusive results in that it is the only randomized, controlled study using two doses of daily GH with a start in prepubertal children who were followed to FH. Importantly, 88% of the prepubertal children enrolled in the study were part of the primary PP population of this study; 65% of children receiving the low dose, 90% of children receiving the high dose, and 66% of untreated control children were followed to the study endpoint of FH. It can be argued that those with the lowest growth response were those who decided to stop prematurely. If so, the dose effect may be somewhat overestimated. Placebo-controlled studies would have been superior to the present design with an untreated control group. However, placebo-treated subjects tend to show an even higher dropout rate; the only such GH trial reports as much as 90% dropouts (14).

In agreement with previous studies in GHD (28) and in ISS (16), we found that the higher the daily GH dose, the better the growth response, corresponding to the correlation between height and GH secretion in healthy children (22). In addition, a daily injection compared with a three times weekly administration schedule affects outcomes (29), although the spontaneous GH secretion is blunted owing to a negative feedback mechanism after each GH injection (30). Both the doses and the frequency of injections used contribute to the better growth in the present study compared with previous studies (14, 15, 16).

During puberty, the GH secretion rate more than doubles in boys and quadruples in girls compared with before puberty (22, 31). Consequently, giving boys and girls the same numerical GH dose during puberty will lead to a biologically lower dose in girls. In fact, the boys in the present study grew more than girls during puberty on GH treatment, although both girls and boys significantly responded to GH therapy.

Children with short stature are diagnosed with ISS when all known causes of short stature are excluded (18, 19). It is presumed that within subgroups of children with ISS, there are different causes for their short stature including genetic disorders of the GH axis (32). Until more knowledge is gained on GH responsiveness, prediction models for growth response, based on estimations of the heterogeneity in GH sensitivity, can be clinically used to assess the individual responsiveness to GH therapy (33, 34, 35, 36). The dose of GH in our study was chosen for each child based only on a strict randomization procedure and not on his or her own responsiveness to GH, which may account for the broad variation in the response to GH therapy, i.e. from no gain up to 3 SDS (18 cm), similar to findings in other studies (14, 15, 16). This variation may have been less if a dose estimated from the best available prediction model had been applied, rather than a fixed dose per kilogram of body weight (34). We recently demonstrated a reduction in the growth response variation using a prediction model for selection of the individual GH dose (33, 37).

There are many variables known to affect the growth response to GH treatment. In the present study, the results of the multivariate analyses showed that already at an early age, low and/or high GH dose, birth length, diff MPHSDS, and early growth during the first years of life (38) were significantly correlated to growth response, confirming the results of other studies (14, 15, 16). The greater the height difference between the child and his or her parent, the better the response will be to GH (14, 15). In other words, children from parents of normal height (non-FSS) respond better than those from short parents (FSS). Similarly, bone age delay has been shown to be an important predictor of response to GH treatment (14, 16). In our study, there were no entry criteria regarding diff MPHSDS; therefore, the genetic potential of the child’s predicted height was not accounted for. Relative to other studies, the children of our study were taller. They were below –2 SDS vs. the population born in the mid-1970s, but in other trials, the height criteria for study entry were shorter and related to older reference values. Despite these variables, there was an even better growth outcomes in the individuals of our study relative to those of other studies (14, 15, 16).

Children born SGA were not excluded from the GH trials in children with ISS initiated in the 1980s (12, 14, 15), as was the case for the present study. In a population of short prepubertal children, approximately 30% of children would have been born SGA (20). We found that size at birth, as a continuum, is an important predictor of the variation in response. However, children born SGA responded at the same magnitude as those born AGA, suggesting a low value of the arbitrarily chosen statistical cutoff level of –2 SDS for the definition of SGA as an indicator of different GH responsiveness (20, 34).

In conclusion, GH treatment that commenced as late as near the start of puberty in children with short stature and with ISS resulted in a dose-dependent increase in FH of approximately 1 SDS more than the control group randomized to no treatment. GH therapy was safe and had no impact on the time until onset of puberty. This long-term, randomized, controlled trial is unique in that so many individuals were followed to FH. Although there was variation in the growth response owing to individual GH responsiveness, most individuals receiving the high-dose GH regimen reached normal adult height. However, the demonstration of a significant height gain in the GH-treated individuals compared with the nontreated group does not mean that such treatment is recommended for all children with ISS. On the contrary, it should be recommended to those predicted to have a good growth response (33, 34), and only after thorough discussions with the subjects and parents to determine, on a case-by-case basis, those who suffer substantially from their short stature, thus justifying this long-term therapy.


   Acknowledgments
 
The authors are thankful for the participation of all the children and their families, for great care of the study population over the years by our Swedish pediatric colleagues, for our own excellent pediatric nurses, and for the staff members at Göteborg Pediatric Growth Research Center for their long-term commitment to the study, not least of all Carola Pfeiffer Mosesson and Eva Mölleborn. The authors also thank Susan Sutch (Envision Pharma) for valuable editing of the manuscript.


   Footnotes
 
This study was initiated in 1988 as a Kabi-sponsored study but was changed to an investigator-sponsored study in the 1990s. An unrestricted research grant as well as a free supply of drug was kindly provided by Pharmacia/Pfizer. The study was also supported by grants from Swedish Research Council (7905) the Swedish Foundation for Pediatric GH Research, and the Foundation Växthuset for Children.

Pfizer had no influence on the collection, analysis, and interpretation of the data or in the writing of this manuscript.

Disclosure Information: Research grants were received by K.A.-W., J.G., E.M.R., T.T., and O.W. Stock options were held by A.S.A., J.G., and J.Å. Consulting fees were obtained by J.G., L.H., B.J., B.K., E.M.R., T.T., and J.Å. Lecture fees were received by J.G., L.H., E.M.R., T.T., O.W., and J.Å. S.A.I., C.M., and K.O.N. have nothing to declare.

First Published Online August 26, 2008

Abbreviations: AGA, Appropriate for gestational age; diff MPHSDS, difference in SDS to MPH; FH, final height; FSS, familial short stature; GHD, GH deficiency; IGFBP-3, IGF binding protein-3; ISS, idiopathic short stature; ITT, intent to treat; MPH, midparental height; PP, per protocol; SDS, SD score; SGA, small for gestational age.

Received March 31, 2008.

Accepted August 15, 2008.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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B. Kristrom, A. S. Aronson, J. Dahlgren, J. Gustafsson, M. Halldin, S. A. Ivarsson, N.-O. Nilsson, J. Svensson, T. Tuvemo, and K. Albertsson-Wikland
Growth Hormone (GH) Dosing during Catch-Up Growth Guided by Individual Responsiveness Decreases Growth Response Variability in Prepubertal Children with GH Deficiency or Idiopathic Short Stature
J. Clin. Endocrinol. Metab., February 1, 2009; 94(2): 483 - 490.
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