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Original Studies |
Department of Pediatrics, University of Umea (B.K.), Umea; and University of Goteborg (B.K., C.J., S.R., K.A.-W.), Goteborg, Sweden
Address all correspondence and requests for reprints to: Dr. Berit Kriström, University of Goteborg, Department of Pediatrics, International Pediatric Growth Research Center, Sahlgrenska University Hospital East, S-416 85 Goteburg, Sweden. E-mail: Berit.Kristrom{at}pediatri.umu.se
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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With the diagnostic criteria used worldwide today, children with very low pituitary GH secretory capacity can be identified. Various GH provocation tests have been used in an attempt to identify predictors of the growth response to GH treatment (10, 11, 12) or in diagnosing GHD, sometimes together with biochemical parameters, such as basal levels of IGF-I and IGF-binding protein-3 (IGFBP-3) (1, 13) or their short term changes during GH treatment (14).
The aim of this study was to evaluate an alternative diagnostic approach to possible GH treatment of a short child without using a cut-off serum level of GH during the stimulation test as the crucial value. The relationship between the 1- and 2-yr growth responses to GH treatment and the basal levels of both IGF-I and IGFBP-3 and their short term changes was evaluated in a group of prepubertal short children with different GH secretory capacities, estimated by a stimulation test, together with auxology variables.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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A group of 193 short healthy prepubertal Swedish children (30 girls and 163 boys) with a broad range of GHmax in response to an arginine-insulin tolerance test (AITT; 0–104 mU/L) were treated daily with GH (0.1 IU/kg) and followed during treatment for 1 yr (n = 193) or 2 yr (n = 128). The patients were either children with isolated idiopathic GHD, defined as having GHmax below 32 mU/L using the WHO International Reference Preparation (IRP) 80/505 (or <20 mU/L using the WHO IRP 66/217), reported to the Swedish National Registry for GH treatment (n = 117) or short children without GHD, defined as having a GHmax above 32 mU/L, included in national clinical trials with GH treatment (n = 76).
All children were well nourished and had normal thyroid, liver, and
kidney functions. Children with coeliac disease were excluded, and the
children were free from chronic disease and dysmorphic syndromes. All
children had a gestational age (GA) at birth of more than 30 weeks, and
their birth weights and birth lengths were -2.5 SD score
or more for gestational age (15). The characteristics of the patients
are given in Table 1
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Pretreatment investigations. The endocrine investigation was performed during the pretreatment year. The children underwent an AITT according to the protocol described previously, and the GHmax was used for the analysis (12).
Treatment follow-up. All children underwent the same regimen of daily GH treatment (0.1 IU/kg). Blood samples were taken at the start of treatment and after 10 and/or 30 days, 3 months, 1 yr, and 2 yr of treatment for analysis of serum concentrations of IGF-I and IGFBP-3. The samples were mostly taken between 1400–1800 h, i.e. nearly 24 h after the latest GH injection. Measurements of IGF-I and IGFBP-3 were used only when the child was healthy; any known ongoing infection meant that the blood samples were excluded from the analysis for the prediction models. Serum samples were kept frozen until measurement of GH, IGF-I, and IGFBP-3.
The studies were approved by the ethical committees of the Medical Faculties of the Universities of Goteborg, Lund, Uppsala, Linkoping, and Umea and the Karolinska Institute in Stockholm. Informed consent was obtained from the parents of each child and from the child, if old enough.
Auxology
Information on GA, birth weight, and birth length was collected from the obstetric report on the mothers kept at the Medical Birth Registry. The growth of the children was recorded at health care units from birth to inclusion in the study, i.e. 1 yr before the start of GH treatment. Thereafter, height was measured using a Harpenden stadiometer at the pediatric units. Height parameters were transformed into SD score, corrected for sex and age using the childhood component of the infancy-childhood-puberty (ICP) growth model of Karlberg (16), weight parameters according to Karlberg et al. (17), and weight for height SD score (WHSD score SD score), i.e. weight SD score-ß x height SD score, according to the method of Karlberg and Albertsson-Wikland (18, 19). Midparental height was expressed as the SD score compared with Swedish reference values (17). The difference between the height SD score of each child at the start of treatment and the midparental height expressed as the SD score (diffSD score) was calculated.
Hormone analysis
GH. Measurements of GH during the AITT were performed in different laboratories (n = 86) using a polyclonal antibody-based immunoradiometric assay (Pharmacia & Upjohn, Uppsala, Sweden) with WHO IRP 80/505 as the standard. During 1991 and 1992, the laboratories in Sweden switched from WHO IRP 66/217 to WHO IRP 80/505, which meant that a conversion factor of 1.55 had to be used to compare the results of GH levels (n = 107) (19, 20).
IGF-I. Concentrations of IGF-I were measured by an IGFBP-blocked RIA without extraction and in the presence of an approximately 250-fold excess of IGF-II (Mediagnost, Tubingen, Germany) (21). The intraassay coefficients of variation were 8.1%, 4.4%, and 4.5% at concentrations of 55, 219, and 479 µg/L, respectively, and the interassay coefficients of variation were 10.4%, 7.7%, and 5.3% at concentrations of 55, 219, and 479 µg/L, respectively.
IGFBP-3. Concentrations of IGFBP-3 were determined using a previously reported RIA method (21). The intraassay coefficients of variation were 6.2%, 5.6%, and 4.6% at concentrations of 1964, 2927, and 4799 µg/L, respectively, and the interassay coefficients of variation were 6.8%, 9.2%, and 6.9% at concentrations of 1964, 2927, and 4799 µg/L, respectively.
As serum concentrations of IGF-I and IGFBP-3 are age dependent (22), the values were converted into SD score using a prepubertal reference, obtained in our laboratory from healthy children of normal (±2 SD) stature (23).
The following variables were included in the correlation analysis to the growth response: sex; GA; age at onset of the childhood component in the ICP model; weight, length, WHSD score SD score at birth and at 1 and 2 yr of age, and 1 yr before and at the start of GH treatment; together with the change in height, weight, and WHSD score SD score between birth and 1 yr and between birth and 2 yr of age. Also included were the yearly change in height, weight, and WHSD score SD score from 1 yr of age to the start of treatment and from 2 yr of age to the start of treatment together with the same auxological changes during the pretreatment year. The auxological information from birth to 2 yr of age was referred to as early growth. Maternal and paternal height SD scores as well as midparental height SD score were included in the analysis together with the diffSD score and the difference in height SD score between the child at the start of treatment and maternal and paternal height SD scores separately.
Included in the statistical analyses were the individual basal levels of IGF-I and IGFBP-3, expressed as the SD score, and levels at 10 and/or 30 days (at either time or the mean) and 3 months together with the individual differences between the level at 10 and/or 30 days or 3 months and the level at the start of treatment. Also included was the ratio of IGF-I SD score/IGFBP-3 SD score for each child and the change from the start of treatment to 10 and/or 30 days and to 3 months. The GH values were log transformed before statistical analysis.
Bone age estimations are not included in the analysis due to missing information from a number of patients.
Statistical analyses
For testing changes over time, Fisher’s nonparametric permutation test for paired observations was used; for comparison between groups, Fisher’s nonparametric permutation test was used. Correlations were tested using Pitman’s nonparametric permutation test (24). Pearson’s correlation coefficients were used only for descriptive purposes. Exclusively variables correlated (P < 0.10) with the growth response were entered into a multiple stepwise forward linear regression analysis.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The serum concentrations of IGF-I in individual children at the
start of GH treatment and after 1 and 2 yr of treatment compared with
the age-related prepubertal reference values are shown in Fig. 1 (top panel). After 1 and 3
months of treatment, the mean IGF-I SD score for the group
did not differ from the reference group and did not change
significantly during the following 2 yr (Table 1
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, the change from the start to 10 and/or
30 days of GH treatment was 1.26 (0.90, -0.82 to 4.69; n = 152;
P < 0.0001), that from the start to 3 months of
treatment was 1.47 (0.89, -0.90 to 5.16; n = 142;
P < 0.0001), that from the start to 1 yr was 1.71
(1.13, -0.98 to 6.01; n = 161; P < 0.0001), and
that from the start to 2 yr was 1.66 (1.19, -1.32 to 5.03; n =
95; P < 0.0001). For those 83 children measured at
both 1 and 2 yr of treatment, there was no significant difference in
the individual IGF-I SD score between these two points
[0.07 (0.92, -3.26 to 2.13; n = 83; P =
NS].
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The serum concentrations of IGFBP-3 in individual children at the
start of GH treatment and after 1 and 2 yr of treatment compared with
reference values are shown in Fig. 1 (bottom panel). For
IGF-I, the mean IGFBP-3 SD score of the group was in the
normal range after 1 month of treatment and did not change
significantly during the following 2 yr (Table 1).
The mean increase in individual serum concentrations of IGFBP-3,
expressed as the SD score (SD, range), from the
start to 10 and/or 30 days of GH treatment was 1.10 (0.83, -0.95 to
4.17; n = 151; P < 0.0001), that from the start
to 3 months was 1.08 (0.87, -1.40 to 3.95; n = 142;
P < 0.0001), that from the start to 1 yr was 1.26
(1.05, -1.25 to 5.59; n = 160; P < 0.0001), and
that from the start to 2 yr was 1.46 (1.20, -1.19 to 4.44; n =
94; P < 0.0001). For those 83 children measured at
both 1 and 2 yr of treatment, there was a significant increase from the
first to the second year in individual IGFBP-3 SD score
[mean, 0.22 (0.85, -2.05 to 2.20); P < 0.05; Fig. 2].
Growth response
The mean increase in height SD score (SD,
range) during the first year of GH treatment was 0.80 (0.34, 0.08 to
2.27; P < 0.0001 compared with the pretreatment year
change in height SD score) and during the second year was
0.46 (0.25, -0.11 to 1.51; P < 0.0001 compared with
the pretreatment year change in height SD score). After 2
yrs of treatment, the mean total height gain was 1.26 SD
score (0.53, 0.42 to 3.14; P < 0.0001 compared with
the pretreatment year). There was considerable interindividual
variation in the response, even though none of the children was known
to be noncompliant (Fig. 3, top
panel).
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, middle panel).
The growth response can also be expressed as the diminishing distance
to the individual midparental height, expressed as the SD
score. This mean difference (SD, range), was -1.95 (1.07,
-6.16 to 0.46) at the start of treatment, -1.08 (0.90, -4.65 to
1.21) after 1 yr of treatment, and -0.70 (0.90, -4.22 to 1.05) after
2 yr of treatment. During these 2 yr of treatment, the children were
showing catch-up growth and were approaching their appropriate target
height (Fig. 3, bottom panel).
Correlation of the growth response to GH treatment
Univariate analysis.
The variables that correlated
(P < 0.10, by Pitman’s permutation test) to the
growth response after 1 or 2 yr of GH treatment are presented together
with the correlation coefficients in Table 2. The correlation to IGF-I and IGFBP-3
variables are shown in Fig. 4 and to
other variables selected in the multivariate analysis in Fig. 5. Note the broad range in
GHmax during the AITT as well as the continuum in the
growth response.
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Multivariate analysis.
In the initial linear regression
analysis, the commonly used variables when diagnosing GHD were
included: parental heights, pretreatment growth pattern, age, and
GHmax at AITT. The GHmax at AITT was the first
selected variable, followed, in order of selection, by
diffSD score, attained weight SD score at 1 yr
of age, and age at the start of treatment (analysis 1, Table 3); these variables accounted for 41% of
the variance in the growth response.
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In the third analysis, both the GHmax from the AITT
together with the IGF-I SD score and the IGFBP-3
SD score were included (analysis 3a). This resulted in a
small increase in the level of variance that could be explained (46%).
The highest level of explanation of the variance (58%) was obtained
when the GHmax from the AITT and the IGF-I SD
score at the start of treatment together with short term changes in the
IGF-I SD score after the start of GH treatment were
combined (analysis 3b). When only the variables most often available in
a clinical setting at the start of treatment were included,
i.e. auxology during the pretreatment year, parental
heights, IGF-I SD score, and IGFBP-3 SD score,
but not GH values or the auxological information from before 3 yr of
age (here described as early growth), the following order of selection
was obtained, predicting the 2 yr growth response: IGF-I SD
score at the start, age at the start, midparental height SD
score, and change in WHSD score SD
score during the pretreatment year; these variables explained 39% of
the variance (analysis 4a). Adding the short term changes (both 10
and/or 30 days and 0–3 months) in the IGF-I SD score and
the IGFBP-3 SD score, the 0–3 months change in IGF-I
SD score was selected, and the variance that now could be
explained was 43% (analysis 4b). The estimated regression algorithms
for the yearly 2-yr growth response, based on the different variables
used in each model, are shown in Table 3.
The regression algorithms for the 1-yr growth response were also calculated. Using almost the same variables, 0% (analysis 4a) to 12% (analysis 3b) less of the variance could be explained.
Using the different regression algorithms presented in Table 3, a 95%
prediction interval was calculated, using the mean values,
±1SD, and ±2SD for the included variables
(reminding the reader that the amplitude of the prediction interval is
wider than the amplitude of the 95% confidence interval of the
algorithm). The values obtained are presented in Table 3, right
column. An illustration of the pretreatment growth and the
prediction interval of the 2-yr growth response for one boy, with
growth response about the mean of the group, is shown in Fig. 6.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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According to these results, there is the possibility of using either the GHmax at AITT or the IGF-I SD score at the start of treatment to predict the growth response, but the explanation level is still limited. Both means of investigation have their disadvantages; GHmax at AITT may be falsely low because of refractoriness of the somatotrophs at the time of provocation (25, 26), beside its clinical disadvantage, and IGF-I is markedly dependent not only on GH but also on nutritional factors. We found that the transformation of IGF-I and IGFBP-3 into the SD score, relevant for age and pubertal stage, was very important, as the level of explanation was much lower when absolute values were used (data not shown).
In our patient group, both IGF-I- and IGFBP-3-values were available at each occasion that blood was sampled. The values were strongly correlated with each other, and like results in earlier studies, where IGFBP-3 has been shown to be a reliable reflector of the GH secretion (13, 27), this was also found in this study group, with the IGFBP-3 SD score having a higher correlation coefficient to GHmax at AITT than the IGF-I SD score. However, regarding the growth response to GH treatment, although IGF-I and IGFBP-3 levels at the start of treatment were each negatively correlated with the 1- and 2-yr growth responses, in this study the IGF-I value was selected as the most informative variable of the two. In a more heterogeneous group of children or in a clinical setting, it can be wise to measure both the IGF-I SD score and the IGFBP-3 SD score, because of the stability over time of the latter. If the levels are discordant, additional evaluation may be indicated.
The serum IGF-I concentrations for the whole group were low at the start of GH treatment, but were within the reference range after 1 and 2 yr of treatment in most children. This indicates that the dose of GH given was not too high for most of the children, as we did not find high IGF-I concentrations during treatment. However, the reference ranges of IGF-I and IGFBP-3 are wide, and some children in our study attained high values during treatment, whereas others still had low values. This variability illustrates the need for using individual GH treatment regimens that take account of the variability in individual sensitivity of the GH/IGF-I axis, as reflected by individual IGF-I levels. The variability in the growth response in the present heterogeneous group of short children was expected and reflects the individual differences in tissue responsiveness to GH. Because all children were treated with the same GH regimen, we did not have to consider the effects of different GH doses and injection frequencies, which have been shown to be important contributory factors to the growth response to GH treatment (28, 29). Ranke and Guilbaud (30) and Blethen et al. (10) have shown that the dose and frequency of injections are important predictors of growth in children with GHD and certainly in children with idiopathic short stature (31). Some of the short children in our study group were probably partially GH resistant (32, 33), although we were unable to assess GH-binding protein levels in a sufficient number of children to include this variable in the analysis. However, Attie et al. (34) showed that in prepubertal children, the growth response to GH treatment did not differ between groups with low or normal GH-binding protein levels.
We conclude that this group of short prepubertal children with a wide range of GH status has reduced serum concentrations of IGF-I and IGFBP-3 compared with those in healthy children of normal height. Treatment with GH (0.1 IU/kg·day) normalized the levels of IGF-I and IGFBP-3 for most, but not all, children. There was a broad range in the growth response to GH treatment, which could be best explained by chronological age (the younger the better) and diffSD score (the higher the better). These variables together with the IGF-I SD score at the start of treatment and the GHmax at AITT (the lower the better for both) accounted for about 41–46% of the variability in the 2-yr growth response. The IGF-I SD score and AITT GHmax were interchangeable in the prediction model, as were GHmax at AITT and short term changes in IGF-I SD score during treatment. Although both IGF-I and IGFBP-3 were highly correlated, and both correlated with the growth response, IGF-I was the more informative in explaining the variation in growth response.
Thus, there are two alternatives, to use either the GHmax at AITT or the IGF-I SD score, when predicting the 2-yr growth response before possible GH treatment of a short child. With all of the variables used now, as much as 58% of the variance in the growth response could be explained. This is, to our knowledge, the highest level of explanation presented to date for a study group such as this. However, when using our estimated regression algorithms to construct the prediction intervals, the range in yearly growth response is still wide (about ±0.4 SD) even given the now available combinations of tests and baseline variables. In clinical work, when selecting children for GH treatment, it is valuable to know the calculated estimate of the predictive value of different combinations of variables, although it is low. Thus, the search for better indicators of the individual growth responsiveness to GH treatment should continue.
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Acknowledgments |
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Footnotes |
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2 The Swedish Study Group for Growth Hormone Treatment consists of
Kerstin Albertsson-Wikland, Jan Alm, Stefan Aronsson, Jan
Gustafsson, Lars Hagenäs, Anders Häger, Sten Ivarsson,
Berit Kriström, Claude Marcus, Christian Moëll, Karl Olof
Nilsson, Martin Ritzén, Torsten Tuvemo, Ulf Westgren, Otto
Westphal, and Jan Åman.
Received February 10, 1997.
Revised May 20, 1997.
Accepted June 2, 1997.
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, girls; 
, boys) plotted against reference values
(shaded area) from healthy prepubertal children of
normal stature (±2 SD). Values from the start of GH
treatment (left) and after 1 yr (middle)
and 2 yr (right) of treatment are shown.
