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Endocrine Care |
Department of Pediatrics (J.M.W., L.T.M.R-.M.), Leiden University Medical Center, Leiden, The Netherlands; and Department of Educational Administration and Management (L.T.M.R.-M.), Faculty of Educational Science and Technology, University of Twente, Enschede, The Netherlands
Address all correspondence and requests for reprints to: Dr. J. M. Wit, Department of Pediatrics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail: JMWit{at}lumc.nl
Abstract
Recombinant human GH therapy to children with idiopathic short stature (ISS) increases growth velocity, but its effect on final height (FH) is still uncertain. The aim of this study was to investigate the effect of recombinant human GH on FH of patients with ISS who were treated according to two protocols in comparison to untreated historical controls. In study 1 (n = 24), all patients were treated with 14 IU (4.6 mg)/m2 body surface·wk in the first year; thereafter the dosage was doubled if the growth response was insufficient. In study 2 (n = 34), patients were randomized into three arms: 18 IU (6 mg)/m2·wk; 27 IU (9 mg)/m2·wk; and 18 IU/m2·wk in the first year, followed by 27 IU/m2·wk thereafter. Observed or estimated FH was available for 53 patients. Thirty-four untreated controls from the same centers were available for comparison. Mean FH SD score in GH-treated children was -2.1, vs. -2.4 in controls (-2.4) (NS), but height SD score gain (1.3 vs. 0.7) and the difference between FH and predicted adult height (4.0 vs. 0.8 cm) were significantly greater. The growth response on an initial dosage of 27 IU/m2·wk (6.9 cm) was significantly better than on other regimens (2.8 cm). We conclude that a GH dosage of 27 IU (9 mg)/m2·wk to prepubertal children with ISS leads to a mean FH gain of approximately 7 cm, whereas regimens starting on lower dosages are less efficacious.
SINCE THE MID 1980s, several clinical trials have been carried out to investigate the effect of recombinant human GH (rhGH) in short children without classical GH deficiency or other detectable conditions, commonly referred to as idiopathic short stature (ISS) (1). ISS is in essence a diagnosis of exclusion and can be considered as a heterogeneous mixture of conditions associated with genes involved in height and in tempo of growth, as well as with intrauterine conditions, possibly partially acting at different levels of the GH/IGF-I axis (2). Although, per definition, GH secretion is assumed to be normal in the sense of a normal GH peak after a standard provocation test, subtle disorders of spontaneous GH secretion may be involved in some children labeled as ISS. On the other hand, in some cases a partial GH insensitivity may be responsible (2, 3, 4, 5).
There is general consensus that rhGH treatment in children with ISS leads to an increased growth rate in the first years of treatment, but conflicting data have been reported on the effect on final height (FH) (for review, see references 6, 7, 8, 9). In summary, the majority of studies reported before 1997, all uncontrolled, indicated only a modest increment of FH of 3–5 cm (7, 10, 11, 12, 13, 14, 15, 16). More recently, in a small controlled study (17) and two larger studies with historical controls (18, 19), FH gain appeared to be approximately 7 cm.
There are a number of possible reasons why the results of the various studies are so variable. Firstly, ISS is a heterogeneous condition covering the full range of children with a typical familial short stature (FSS), characterized by a height SD score close to target height (TH) SD score, to children with nonfamilial short stature (non-FSS), and in both subgroups puberty onset can be delayed or not (1). The natural history of the various subgroups, in terms of FH and its relationship with TH and initial height SD score, is quite different (16). The proportion of FSS and non-FSS may have varied considerably between studies.
Secondly, a wide variety of dosages has been prescribed, ranging from 0.5–2.1 IU (0.17–0.7 mg)/kg body weight·wk (which corresponds with 4.7–21 mg/m2·wk if body surface is close to 1 m2). From a comparison of various studies, a dose-response relationship of the first year’s response and FH gain is apparent (9), but the dose dependency of FH gain has never been studied directly.
Thirdly, a large placebo-controlled study has never been reported. So far, only data from a small controlled study (including 10 treated girls and 8 untreated control girls) (17) and a few larger studies with historical controls from endocrine clinics or population studies have been published (13, 15, 18, 19). In such study designs, differences between treated and untreated children in terms of year of birth or selection method may cause a significant bias.
Fourthly, in many reports results were published on an incomplete, relatively old subsample of all patients included in the trials by leaving out patients who had not yet reached FH. This can cause bias because the older the child is at the start of treatment, the worse is his gain in FH (20). So, it is important to evaluate the effects of rhGH on FH in all children who once started this treatment.
The aims of this study were to investigate the effects of rhGH on FH of all patients with ISS who were included in two Dutch trials starting between 1986 and 1988 in comparison with a large group of untreated controls from the same centers to evaluate whether there was a dose-response relationship and to assess which baseline variables predict the response to rhGH.
Subjects and Methods
GH-treated subjects
In The Netherlands, 58 children diagnosed as ISS in pediatric clinics started with rhGH therapy during the late 1980s on the basis of two different study protocols. Twenty-four patients included in study 1 were treated for more than 1 yr with rhGH (Genotropin, Pharmacia, Stockholm, Sweden) seven times per week in a dose of 14 IU/m2·wk. If their height velocity (HV) was insufficient in the first year or became insufficient in the following years (n = 16), the rhGH dosage was doubled to 28 IU/m2·wk. At the time of the initiation of the study, this dose was equivalent to 0.5 IU (0.17 mg) and 1 IU (0.33 mg)/kg body weight·wk. For further details, see our earlier papers (13, 21, 22). The 34 patients of study 2 were treated with rhGH (Humatrope, Eli Lilly \|[amp ]\| Co., Indianapolis, IN) 6 times per week and randomized into 3 groups: 1) 18 IU (6 mg)/m2·wk (n = 11); 2) 27 IU (9 mg)/m2·wk (n = 9); and 3) 18 IU/m2·wk during the first year and 27 IU/m2·wk thereafter (n = 14). At the start of treatment, these dosages were equivalent to 0.64 IU/kg (0.21 mg/kg) or 0.96 IU/kg (0.32 mg/kg)·wk. This study was part of a large international clinical trial on which we reported 4 yr of data (23). Because the individual dosages were calculated on the basis of body surface and because of the nonlinear relationship between body surface and body weight, the dosages per kilogram of body weight gradually decreased to 0.13 and 0.27 mg/kg·wk in study 1 and 0.17 and 0.26 mg/kg·wk in study 2 at discontinuation of treatment.
The inclusion criteria were similar for studies 1 and 2: age, more than 5 yr; bone age, less than 11 yr (study 1), or 12 yr for males (study 2) and 10 yr for females, according to the Tanner-Whitehouse 2 method (24); height, less than -2.5 SD score for Dutch references (25) (study 1), or less than -2 SD for British references (26) (study 2); prepubertal state, breast less than 2 or genitals less than 2 (27, 28); stimulated GH peak, more than 15 mU/liter (study 1) or more than 20 mU/liter (study 2) (at that time, 1 mU/liter was equivalent to 0.5 ng/liter); no organic cause of growth failure or dysmorphic syndrome. A low birth weight or length was not used as an exclusion criterion.
During treatment, the children were seen every 3 months at the clinic, including a set of four height measurements of which the mean was used for analysis. Bone age radiography and laboratory tests were repeated every 6 months in the first 2 yr and thereafter once a year.
Both studies were accepted by all medical ethical committees involved, and informed consent was obtained from all children and their parents.
Five subjects were lost to follow-up, and their FH could not be measured or estimated. They were excluded from the analysis. One of these withdrew from rhGH treatment after 5.5 yr (bone age, 13.0 yr) because of an epiphyseolysis of his right femur and because he was satisfied with his attained height.
FH, defined as HV less than 0.5 cm/yr, was attained by 49 subjects. In two subjects whose HV was between 0.5–1.0 cm/yr, FH was estimated on the basis of their individual growth curves. Another two subjects were still receiving rhGH treatment, but they were approaching FH because their HVs were 2.1 and 3.0 cm/yr and their bone ages (29) were 17.0 yr (male) and 15.0 yr (female), respectively (29). Their predicted adult height (PAH), according to Bayley and Pinneau (30), was used as their estimated FH. Thus, FH or estimated FH data were available in 53 subjects (36 males, 17 females). This is 91% of the subjects who once started rhGH treatment. These subjects were included in the intention-to-treat analysis.
The children were retrospectively subclassified as FSS (n = 5), non-FSS (n = 36) [according to the international consensus reported by Ranke (1)], or intrauterine growth retardation (IUGR) with persisting short stature (n = 12) (defined by a birth weight SD score less than -2 (31)]. The mean age at start of therapy was 10.5 yr, ranging from 5.4–15.2 yr. The duration of rhGH treatment was on average 5.9 yr, ranging from 0.2–11.7 yr. The treatment period of children in study 1 was as long as that of children in study 2.
According to the study protocols, rhGH treatment had to be continued until height gain was less than 1 cm over a period of 6 months. Thirty-eight subjects (72%) completed the study protocol without detectable protocol violation. The remaining children discontinued treatment after a mean of 3.8 (SD 2.4) yr, mainly because of lack of motivation. The 38 patients strictly treated according to the protocol were included in a per-protocol analysis to evaluate the validity of results from the intention-to-treat analysis and to study the optimal possible growth response to a dosage of rhGH ranging from 14–28 IU/m2·wk in children with ISS.
Control subjects
The rhGH-treated subjects were compared with a retrospective control group of 64 patients (33 males, 31 females). Like the treated children, control subjects were diagnosed as ISS in a prepubertal state, but they were never treated for their shortness or asked to participate in a trial on rhGH treatment. This was mainly related to the fact that most of them had already reached adolescence at the time biosynthetic GH became available. Their mean year of birth was 1971 (3.4), 6.2 yr earlier than the mean year of birth of the treated group. Of the 64 FH measurements, 44 (64%) were measured at home after extensive instruction. In an earlier study (32), we showed that with this method mean reported height was not significantly different from height measured in the clinic. For each child, an imaginary start of study was determined. At this start of study, the child had to be prepubertal, and his/her age was within 1 yr from the mean age at start of treatment in the treated group. The children usually visited the pediatric clinic once a year. If no bone age (29) reading at start was available, a bone age reading within 3 yr from this time point was used and transformed to bone age (BA) at start as follows: BA start = (BA visit/Age visit)·Age start.
Methods
Five outcome parameters were used for evaluation of the response to rhGH treatment; for each parameter, the SD score was based on Dutch references for the general population (25). The parameters were: 1) FH SD score; 2) FH SD score minus height SD score for chronological age (CA) at baseline; 3) FH SD score minus height SD score for BA (29) at baseline; 4) FH minus PAH, according to Bayley and Pinneau (30); and 5) FH minus TH. TH was calculated as the average of father and mother’s height plus 6 cm for boys or minus 6 cm for girls, plus 3 cm to account for the average secular trend in The Netherlands (13).
Statistical analysis
Results are described by mean and SD, unless indicated otherwise. Between groups, comparison was analyzed using t tests and ANOVA. By means of bivariate analysis, the following predictors for the response to rhGH were evaluated: gender, diagnostic subgroup, and dosage of rhGH. In a stepwise multiple regression analysis, these response predictors were extended with some baseline predictors: age, height SD score, bone age delay, and GH peak after provocation. The significance level was set at 0.05.
Results
Intention-to-treat analysis
Baseline characteristics and FH results of the treated and control subjects are presented in Table 1
. There were no significant differences in the baseline characteristics, except for height SD score at start, with children in study 1 being significantly shorter than those in study 2 and controls. The children in study 1 attained an average FH that was significantly lower than that of the children in study 2 [-2.4 (1.0) SD score vs. -1.8 (0.8) SD score, respectively; P = 0.04]. Also, FH minus PAH and FH SD score minus baseline height SD score for BA were significantly lower for the subjects of study 1 compared with study 2 [1.9 (6.0) cm vs. 5.5 (5.1) cm; P = 0.04; and -1.2 (1.2) vs. -0.3 (1.0) SD score; P < 0.01, respectively). However, the gain in FH compared with baseline height SD score and to FH minus TH were similar for the subjects of both studies [1.2 (0.9) vs. 1.3 (0.9) SD score, and -8.3 (6.9) vs. -7.4 (7.2) cm, respectively].
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Bivariate analysis of predictors for growth response. There was no gender difference in response to rhGH treatment. For example, in treated boys the difference between FH and PAH was 3.8 (6.0) cm; in treated girls, this was 4.4 (5.0) cm. Also, the other outcome parameters (FH SD score, FH minus TH, and total height SD score gain) were similar.
Children with non-FSS benefited significantly from rhGH treatment (Table 2). The differences in the five outcome parameters between treated and untreated children with non-FSS were significantly different, except for FH SD score. In the children with FSS or IUGR, both considerably smaller in number than non-FSS, the response to rhGH was slightly less, and the observed differences between treated and control subjects in these subgroups did not reach statistical significance.
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, the outcome parameters are presented for the three dosage regimens group. The five response parameters of the children treated with 18–27 IU/m2·wk were similar to those of children treated with 18 IU/m2·wk. However, the response of children treated with 27 IU/m2·wk was significantly better than that of children treated with 18–27 IU/m2·wk or 18 IU/m2·wk. This holds true for all outcome determinants. Ninety percent of the children receiving 27 IU/m2·wk reached an adult height that was greater than predicted, compared with 69% with the lower (starting) dosage (NS). The diagnostic subgroups were evenly distributed over the study groups (Pearson’s 
2 test; P = 0.73). The duration of rhGH treatment was not correlated to any of the outcome parameters.
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. In all models, high-dose GH therapy came out as the first or second predictor, and low-dose GH therapy as the third or fourth. In addition, each outcome parameter was also dependent on clinical characteristics at onset of therapy. FH SD score was dependent on initial height SD score and bone age delay (shown graphically in Fig. 1, A and B) and gender (girls better than boys). FH minus PAH was not significantly related to height SD score at start (Fig. 2A), but in this scattergram the superior efficacy of the high-dose GH therapy is clearly demonstrated. In the prediction model of FH minus PAH, bone age delay at start was the most important predictor; the more delayed bone age was, the less was the height gain compared with PAH (Fig. 2B). However, height gain of the treated and untreated differed most when bone age delay was greatest. The mean estimated FH gain from this model compared with controls was 6.9 (SE 1.4) cm on a dosage of 27 IU/m2·wk and 2.8 (SE 1.0) cm on the other dosages. In none of the models did the GH peak in a provocation test come out as a significant predictor.
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The growth of 38 children (21 from study 1, 17 from study 2) who perfectly completed the study protocol (per-protocol children) was compared with that of the treated children who stopped rhGH treatment too early. The baseline characteristics (gender, diagnosis, age, height SD score, height SD score for BA, and BA delay at start) of both groups were similar (data not shown).
FH of the per-protocol children was 167.7 (6.8) cm in boys and 156.0 (5.8) cm in girls. This was similar to FH of the boys and girls excluded from this part of the analysis. The same applied to all other outcome parameters (data not shown).
The per-protocol children from study 2 were selected to investigate the optimal possible response to the dosage rhGH in children with ISS. As in the intention-to-treat analysis, the growth response of children treated with 27 IU/m2·wk was better than that of the other groups (18 and 18–27). A dosage of 27 IU/m2·wk resulted in a FH SD score of -1.3 (0.7) SD score, a gain in FH SD score compared with baseline height SD score of 1.7 (0.8), and compared with baseline height SD score for BA of 0.3 (0.8). For this group of children, FH minus PAH was 8.8 (4.2) cm, and FH minus TH was -4.3 (5.0) cm.
Discussion
We have shown that the average gain in FH of rhGH-treated children with ISS is dependent on the dosage regimen. On regimens starting with a dosage that is considered a substitution dosage for GH-deficient children in many countries [14–18 IU/m2·wk, equivalent to 0.50–0.64 IU (0.17–0.21 mg)/kg·wk], either maintained during the full treatment period or increased to 27–28 IU/m2·wk (0.33 mg/kg·wk) after one or more years, the estimated FH gain is only small (3 cm). In contrast, a dosage of 27 IU/m2·wk, which corresponds to 0.96 IU (0.32 mg)/kg·wk at the start of treatment, resulted in a substantial mean height gain of 7 cm, compared with controls. This dosage effect was similar for all outcome parameters. Our results in the high-dosage group are very similar to the findings in the British-controlled study in girls with ISS (7.5 cm) (17) on a dosage of 30 IU/m2·wk and the American study (19) (9.2 cm for boys, 5.7 cm for girls in comparison to untreated short controls, 5.0 and 5.9 cm more than the initial prediction) on a dosage of 0.3 mg/kg·wk. The height gain obtained in the study of Buchlis et al. (18) (3 cm for boys, 6.8 cm for girls) on the same dosage was somewhat less, possibly because the average age at start was considerably higher (11.9 yr).
These results indicate that there is a discrepancy between the effect of a dosage regimen of 14–18 IU/m2·wk in the first years of treatment and on FH. In the first years, this dosage invariably leads to a definite increase of HV, suggesting that the administration of 14–18 IU/m2·wk leads to a higher GH exposure in comparison to the pretreatment state. Although the height increase on this dosage in the first 4 yr of therapy is very close to the effect of a higher dosage (23), we have now shown that there is a clear difference between both dosage regimens in terms of FH gain.
Another noteworthy result of our study is that a regimen that starts at a relatively low dosage in the first year (when the growth response is usually quite good) and then continues on a higher dosage (aimed at preventing the weaning effect in the following years) is not more efficacious than the lower dosage continued over the full period and is clearly less efficacious than a high dosage administered right from the start. This suggests that the major impact of rhGH therapy on FH occurs in the first year.
The effect of GH on FH was not different between sexes in four of five outcome measures, in contrast to the suggestion of a slightly better effect in boys in one study (19). There was an indication that the subgroup of children with non-FSS and IUGR responded slightly better than children with FSS. Although IUGR is excluded in the most recent definition of ISS (1), we decided not to exclude these children from the present analysis, because the dividing line between ISS and IUGR of unknown origin is only arbitrary. We have shown previously that in the whole group of children with ISS the distribution of birth weight is shifted to the left (9).
A more important predictive power can be attributed to bone age delay. When bone age delay is relatively great, the effect of GH therapy is relatively good. One should note, however, that if the response to GH therapy is expressed as the difference between FH and PAH, bone age delay correlates negatively with the response, both in treated children and controls (Fig. 2B
). This figure also shows that, whereas the average difference between FH and PAH in controls is small (indicating a good average accuracy), there is a wide range around the mean (indicating a low precision). Similar results were obtained previously (33). The distance between both regression lines, indicating the effect of GH therapy, is greater with a larger bone age delay. In the recent American study (19), no significant correlations were found between FH gain (defined as FH SD score minus PAH SD score) and any auxological, clinical, or biochemical variable.
With respect to possible biochemical predictors, we were only able to study the GH peak after provocation. Its correlation coefficients with the five outcome parameters were between -0.25 and 0, but its contribution to these outcome parameters in a multiple regression analysis was not statistically significant. In our earlier study (13), the correlation between the GH peak and FH minus PAH was -0.58 (P = 0.02). We were unable to investigate the predictive power of serum IGF-I and IGFBP-3. So far, the data on the predictive power of serum IGF-I and IGFBP-3 for the short-term growth response is still equivocal (34, 35, 36, 37) and totally unclear for FH gain.
To prevent any selection bias, we performed an intention-to-treat analysis as well as a per-protocol analysis. The results were not different, suggesting that our results can be generalized for children who enter such protocols and for whom FH data are available. One should note, however, that originally in these clinical trials several children were included who could not be analyzed in terms of FH. In study 1, initially consisting of 30 children, 2 children did not want to start GH therapy after their initial 1-yr observation period, and we considered them as controls; 2 children were actually treated according to protocol of study 2, and another 2 children did not fulfil all inclusion criteria but still started rhGH therapy (1 child was diagnosed with hypochondroplasia, and 1 child was adopted from a foreign country). So, 24 children started with rhGH therapy according to the protocol of study 1. During treatment, one patient was lost to follow-up and his (near) FH remained unknown. The number of patients included in the FH analysis of study 1 was therefore 23. In study 2, five of an original group of 35 children could not be analyzed (14%).
Another methodological issue concerns the question of which outcome measure is most suitable to assess the effect on FH, particularly important if studies are not designed as randomized clinical trials. From our results, it is clear that when FH SD score as such is used, initial height SD score and bone age delay at start should be assessed as covariates. Our earlier studies on the natural history of growth in ISS (16) and the present study have shown that children with non-FSS tend to end up with a somewhat lower adult height SD score than children with FSS. The difference between FH SD score and initial height SD score (height SD score gain) is quite different between FSS and non-FSS subgroups and dependent on bone age delay. FH SD score minus the PAH at baseline in controls is strongly dependent on bone age delay, is imprecise, and can only be used if bone age is greater than 6 yr. Finally, FH minus TH of untreated children with ISS is much lower in non-FSS and IUGR than in FSS. Under these circumstances, it may be best to assess various outcome parameters in treated and untreated children.
It is still a matter of debate whether the arguments in favor of rhGH therapy in ISS outweigh those against (38, 39). Basically, there are three arguments in favor. The first is that rhGH therapy generally increases HV in childhood, leading to less height deficit in childhood and adolescence in almost all children and to an approximately 7 cm higher adult height on a supraphysiological dosage. The second is the assumption that short stature may lead to psychosocial stress in childhood and adolescence (40), which may be at least partially relieved by bringing height closer to the mean for age. Thirdly, GH administration can be seen as rewarding for the child and the parents because they have the feeling that something is done to address their problem; for the clinician, it may be more satisfactory to treat than to observe.
However, there are also several arguments against the widespread use of GH therapy in ISS. Firstly, even with a high rhGH dosage, the average effect on FH is modest, and in almost all cases FH is still below or in the lower half of the normal distribution of the population and lower than TH. In addition, the response appears very variable and cannot be predicted with an acceptable accuracy. Secondly, most studies on quality of life in short children and adults have failed to demonstrate a significant negative effect of shortness (41, 42, 43, 44, 45, 46), although many pediatric endocrinologists in the United States perceive that a short child is disadvantaged (47). During therapy, no significant changes were observed in a controlled trial (48). Thirdly, rhGH treatment signifies a long period of daily injections and regular clinic visits, which brings about medicalization of a child who should be considered healthy. Theoretically, unwanted long-term sequelae of the elevated serum GH and IGF-I levels might occur, as epidemiological associations have been found between serum IGF-I levels and the prevalence of various types of cancer (49). In general, however, psychological and somatic side effects of rhGH treatment seem to be limited (50). Finally, large-scale use of rhGH therapy for ISS at the present price (approximately $300,000 for a 7-yr treatment of a child from 10 yr onward) would consume an important part of the health budget and thereby has a considerable opportunity cost, leaving less money available for other purposes with possibly a higher priority rating. In addition, there is still controversy about the ethics of administering GH to short but otherwise healthy children (47, 51, 52).
In conclusion, the effect of a dosage of 0.17–0.21 mg/kg·wk, even if this would be increased by 50–100% after one or a few years, on FH of children with ISS is limited to approximately 3 cm and can therefore not be recommended. A dosage of 27 IU/m2·wk (0.33 mg/kg·wk) has an average effect of 7 cm on FH, and more if bone age is considerably delayed. Treatment can be considered in individual cases with severe short stature, particularly if bone age is delayed, if there are other symptoms and signs indicating that a low GH secretion might be the rate-limiting factor for growth (53) and if the child appears to suffer considerably due to his/her shortness. In view of the incomplete and inconclusive data about all pros and cons of rhGH treatment to children with ISS, rhGH treatment for ISS cannot be advised in general.
Acknowledgments
Thanks are due to all pediatric endocrinologists involved in this study, to Mrs. E. de Beus and Mrs. S. de Vries for administrative support, and to Pharmacia (Stockholm, Sweden) and Eli Lilly \|[amp ]\| Co. (Erlwood, United Kingdom) for financial support.
Footnotes
1 The members of the Dutch Growth Hormone Advisory Group who participated in this study are: S. M. P. F. de Muinck Keizer-Schrama (Sophia Children’s Hospital, Erasmus University, Rotterdam), B. J. Otten (Nijmegen University Medical Center), W. Oostdijk (Leiden University Medical Center), M. Jansen (Wilhelmina Children’s Hospital, Utrecht University), C. Rouwé (Beatrix Children’s Hospital, Groningen), J. J. J. Waelkens (Catherina Hospital, Eindhoven), H. A. Delemarre-Van de Waal (Free University Medical Center, Amsterdam), T. Vulsma (Academic Medical Center, Amsterdam), M. Reeser (Juliana Children’s Hospital, The Hague), and J. Gosen (Rijnland Hospital, Leiderdorp). 
Abbreviations: BA, Bone age; CA, chronological age; FH, final height; FSS, familial short stature; HV, height velocity; ISS, idiopathic short stature; IUGR, intrauterine growth retardation; PAH, predicted adult height; rhGH, recombinant human GH; TH, target height.
Received July 3, 2001.
Accepted November 1, 2001.
References
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