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Original Studies |
International Pediatric Growth Research Center, Department of Pediatrics, University of Umea (B.K.) and University of Goteborg (B.K., S.R., K.A.-W.), and Research Center for Endocrinology and Metabolism, Department of Medicine, University of Goteborg (B.C., L.M.S.C.), 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 Gothenburg, Sweden. E-mail: berit.kristrom{at}pediatri.umu.se
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Abstract |
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The first year mean increase in height SD score was 0.79 (SD, 0.34), with a broad range (0.08–2.27). Serum leptin concentrations were significantly reduced after 1, 3, and 12 months of GH treatment compared with levels at the start of treatment. The growth response correlated with the serum leptin concentration at the start of treatment (r = 0.49; P < 0.0001) and with the change in serum leptin concentration after both 1 month (r = -0.41; P < 0.01) and 3 months (r = -0.60; P < 0.0001) of treatment. When multiple stepwise regression analysis was applied to the auxological and biochemical variables that correlated (P < 0.10) with the first year growth response to GH treatment, the 3-month change in serum leptin concentration was the single most important variable for explaining the variance in individual growth responses. We conclude that leptin levels at the start of GH treatment as well as short term changes in leptin levels in response to GH treatment are valuable markers of the long term growth response.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In addition to its effect on longitudinal bone growth, GH has profound metabolic effects. GH treatment stimulates lipolysis and decreases body fat mass in both humans and rodents (10, 11, 12). Children with insufficient GH secretory capacity have an increased body fat content, which is reduced by GH treatment, particularly in severely GH-deficient children. The serum leptin concentration reflects body fat mass (13, 14, 15), and a reduction in body fat mass in response to GH treatment is accompanied by a reduction in serum leptin levels (11).
In the present study we have analyzed serum leptin concentrations in a group of short prepubertal children with a maximum GH secretory capacity ranging from very low to high, i.e. both short and/or slowly growing children judged as GH-deficient (GHD) and idiopathic short statured (ISS) children are included. The aim of the study was to evaluate whether serum leptin is useful as a metabolic marker for the growth response to GH treatment.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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A group of 150 short, healthy, prepubertal, Swedish children (21
girls and 129 boys) with a broad range of GHmax during a
provocation test (3–104 mU/L) was treated with daily injections of GH
(0.1 IU/kg) and followed for at least 1 yr. Of these 150 children, 86
had isolated idiopathic GH insufficiency, defined as a
GHmax during an AITT below 32 mU/L using the WHO
international reference preparation (IRP) 80/505 (corresponding to <20
mU/L using the WHO IRP 66/217) (16), and 64 were short but did not have
GH insufficiency, defined as a GHmax during an AITT above
32 mU/L (or 20 mU/L), and were included in national clinical trials of
GH treatment. All children were well nourished and had normal thyroid,
liver, and kidney functions. Coeliac disease was excluded, and the
children were free from chronic disease and dysmorphic syndromes. For
all of the children in the study, gestational age at birth was more
than 30 weeks, and their birth weight and birth length were more than
-2.5 SD score for gestational age (17). 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, and the GHmax was estimated (9). A blood sample was obtained for determination of leptin, IGF-I, and IGF-binding protein-3 (IGFBP-3) concentrations.
Treatment follow-up. All children underwent the same regimen of daily GH treatment (0.1 IU/kg BW). Blood samples were taken at the start of treatment and after 10 and/or 30 days, 3 months, and 1 yr of treatment. The samples were usually taken between 1400–1800 h, i.e. about 24 h after the last GH injection and when the leptin levels are relatively stable, taking the diurnal variation into account (18).
The study was approved by the ethical committees of the Medical Faculties of the Universities of Goteborg, Lund, Uppsala, Linkoping, and Umea, and the Karolinska Institute (Stockholm, Sweden). Informed consent was obtained from the parents of each child and from the child if old enough.
Auxology. Information on gestational age at birth, birth
weight, and birth length were collected from the Medical Birth
Registry. The growth of the children was recorded at healthcare units
from birth to inclusion in the study, i.e. 1 yr before the
start of GH treatment. Thereafter, height was measured at pediatric
endocrine units in Swedish childrens hospitals. Height parameters were
transformed into SD score for sex and age using the
childhood component of the infancy, childhood, and puberty
growth model of Karlberg (19), and weight parameters were transformed
into SD scores according to the method of Karlberg et
al. (20). Weight for height was transformed according to the
method of Karlberg and Albertsson-Wikland to provide an expression of
body composition that is independent of both chronological age and
height (WHSD SCORE SD score; weight
SD score - ß x height SD score) (21, 22). Parental heights were expressed as SD scores (20). The
auxological variables included in the statistical analysis are listed
in Table 2.
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Leptin. Serum leptin concentrations were measured in duplicate by RIA (Linco Research, St. Charles, MO). The assay has a range of 0.22–100 µg/L. The intraassay coefficients of variation were 7.0% at 2.4 µg/L and 4.9% at 14.0 µg/L. The corresponding interassay coefficients of variation were 9.6% and 6.7%. All samples were analyzed using the same assay batch. The leptin levels are related to pubertal stage (23), but in a reference group of exclusively prepubertal healthy children (aged 5.7–12.9 yr; height SD score range, -2.5 to 2.5), leptin levels were not age related (14). The actual estimated serum concentrations (instead of SD scores) were therefore included in the analysis.
GH. Generally the Pharmacia (Uppsala, Sweden) standard WHO IRP 80/505 was used. If another method or an earlier WHO IRP was used, the concentration was transformed into comparable levels (1, 24, 25).
IGF-I. IGFBP-blocked RIA without extraction and in the presence of an approximately 250-fold excess of IGF-II (Mediagnost, Tubingen, Germany) (1, 26).
IGFBP-3: RIA (1, 26) IGF-I and IGFBP-3 were converted into SD scores (27). The ratio of IGF-I SD score/IGFBP-3 SD score was calculated for each sample.
Statistical methods
To test the significance of changes over time, Fisher’s nonparametric permutation test for paired observations was used (28). Correlations were tested using Pitman’s nonparametric permutation test (28). Pearson’s correlation coefficients were used only for descriptive purposes.
A multiple stepwise linear regression analysis was applied to variables associated (P < 0.10) with the growth response to GH treatment to identify variables explaining the variance in the growth response.
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Results |
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The mean gain in height SD score during the first year of GH treatment was (SD, range) 0.79 (0.34, 0.08–2.27; P < 0.0001 compared with the pretreatment year change in height SD score). The mean height SD score at the start of GH treatment was -2.72 (0.68, -6.00 to -1.12), and after 1 yr of treatment it was -1.93 (0.70, -4.49 to -0.09). The growth response can also be expressed as the change in intrafamilial height deficit (the difference in height SD score between the individual child at the start of treatment and the midparental height SD score, diffSD score); the mean value at the start of GH treatment was -1.90 (1.01, -6.16 to 0.08), and after 1 yr of treatment it was -1.08 (0.90, -4.65 to 1.21).
Leptin levels
Serum leptin levels before the start of GH treatment are shown in
Fig. 1 and Table 1
. Compared with the
serum leptin level at baseline, mean leptin concentrations were
significantly reduced at 10 and/or 30 days, (mean, -0.49 µg/L;
SD, 1.01; range, -4.35 to 1.73; n = 113;
P < 0.0001), at 3 months (mean, -0.72;
SD, 1.27; range, -7.19 to 3.57; n = 92;
P < 0.0001), and at 1 yr after the start of GH
treatment (mean, -0.66; SD, 1.38; range, -6.15 to 3.46;
n = 119; P < 0.0001; Fig. 2).
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Univariate analysis. Individual serum leptin concentrations at
the start of GH treatment correlated with the first year growth
response to GH treatment for the whole group (r = 0.49;
P < 0.0001; Fig. 3). If the study group was divided
into two groups, GHD and ISS, based on the GHmax level, the
correlation persisted (GHD: r = 0.48; P < 0.001;
n = 105; ISS: r = 0.48; P < 0.001; n =
42). The leptin concentration at 10 and/or 30 days of treatment had a
lower correlation with the growth response, whereas the correlation was
lost at 3 months (data not shown). However, the short term changes in
serum leptin between baseline and 10 and/or 30 days and between
baseline and 3 months of GH treatment correlated significantly with the
first year growth response (P < 0.0001; Fig. 3 and Table 3), and the correlation persisted if the
children were grouped based on GHmax level (GHD group:
r = -0.60; P < 0.0001; ISS group: r =
-0.64; P < 0.0001).
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Neither the leptin values at the start of treatment nor the short term
changes in serum leptin levels after the start of treatment showed any
correlation with body mass index (data not shown) or
WHSD SCORE SD score (Fig. 4, left panel) or pretreatment
year growth rate (data not shown). There were also no correlations
between baseline leptin levels or short term leptin changes after the
start of GH treatment and the IGF-I SD score (Fig. 4, right panel), the IGFBP-3 SD score, or the
GHmax AITT at the start of GH treatment (data not
shown).
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analysis 1a). If the GHmax AITT was excluded, 54% of the
variance was explained by the remaining four variables (analysis
1b).
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Short term changes after the start of GH treatment: In an additional analysis, incorporating changes in serum leptin, IGF-I SD score, and IGFBP-3 SD score between baseline and 1 and 3 months, respectively, values from 66 children were available. In this analysis 58% of the variance in the first year growth response could be explained. The variables were selected in the following order: the 3-month changes in leptin concentration, the ratio of IGF-I SD score/IGFBP-3 SD score, age, height SD score at 1 yr of age, and length SD score at birth (analysis 2a).
An analysis was also performed in which leptin values were excluded. The single most important variable to explain the growth response was change in weight SD score from 1 yr of age to the start of GH treatment. However, during the stepwise multivariate analysis, this variable was excluded, and 43% of the variance in the growth response could be explained using age, height SD score at 1 yr before the start of treatment, IGF-I SD score at baseline, and length SD score at birth (analysis 2b). Thus, including baseline and short term changes in serum leptin, the variance in the growth response that could be explained increased by 15%, from 43% to 58%. Among the pretreatment variables, the IGF-I SD score was the single most informative variable, closely followed by the serum leptin level. However, the short term changes in leptin levels were even more informative when included, which makes serum leptin the most important single variable with which to explain the growth response to GH treatment.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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There are several indications that the GH and leptin systems are connected. An interaction between leptin and spontaneous GH secretion has been shown in male rats; a physiological level of leptin in the cerebroventricular fluid was necessary to maintain normal spontaneous GH secretion, indicating that leptin is an important neuroendocrine factor involved in the regulation of GH secretion (31). Fasting and a reduced leptin level had the same effect on GH secretion, but supraphysiological levels of leptin did not change the amount of GH secreted in the rats (31). Furthermore, both leptin and the leptin receptor are expressed in bone and cartilage in the mouse fetus (32). Leptin may therefore act as a paracrine growth factor to influence bone growth in the fetus. Interestingly, there is a strong correlation between serum leptin levels and bone mass and bone surface area in humans (33).
The strong correlation between changes in serum leptin levels and the growth response to GH probably does not exist under all conditions. For example, if energy restriction is pronounced, growth velocity is reduced despite high GH levels. In this situation the metabolic and growth-promoting effects of GH on peripheral tissue are separated; there is a marked lipolytic effect of GH, whereas there is a resistance to the growth-promoting effect of GH. The mechanisms by which GH produces the different effects are poorly understood. However, in the present study we included children with a GH secretory capacity ranging from very low to high. Dividing the study group into GHD and ISS children did not change the result regarding leptin correlating to the growth response to GH treatment. This indicates that leptin may be a valuable marker in short children treated with GH. It is also possible that leptin is a metabolic signal, which directly or indirectly contributes to the growth-promoting effect of GH. The level of leptin is positively correlated with the concentration of GH-binding protein in healthy children, and there is covariation between the short term changes in leptin and GH-binding protein (34). Thus, leptin may affect GH sensitivity, possibly by regulating expression of the GH receptor gene.
Among the pretreatment variables, serum leptin levels contributed significantly to explain the growth response to GH treatment, and only the IGF-I SD score at the start of treatment was more informative. Baseline serum leptin concentrations were positively related to the growth response to GH treatment, in agreement with our finding in short children born small for gestational age (14). This is also consistent with previous studies demonstrating a positive correlation between body mass index and the growth response to GH treatment in children with GH deficiency (35).
We have previously reported that pretreatment information, i.e. the growth pattern of the child before 2 yr of age, together with IGF-I SD score and GHmax at AITT, explains 46% of the variance in the growth response to GH (1). The magnitude of the growth response explained could be improved if short term changes in the IGF-I SD score after the start of GH treatment were added to the analysis. We now report that by adding baseline serum leptin concentrations, the same level of explanation (58%) is achieved with the use of information available before the initiation of GH treatment. It should be noted that even if the goal is prediction of the individual growth response, we here present markers that correlate with the growth response as well as the explained variance for the growth response in the group of children. However, the fact that the leptin concentration correlates with the growth response to GH treatment justifies its future use in prediction models.
In conclusion, GH treatment reduces serum leptin levels in prepubertal short children. This metabolic effect of GH correlates negatively with the growth-promoting effect of exogenous GH. In addition, inclusion of baseline leptin levels together with other pretreatment variables improves the explanation of variance in the growth response to GH treatment.
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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 January 21, 1998.
Revised April 10, 1998.
Accepted May 11, 1998.
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References |
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,
Girls; 
, boys. The shaded area represents leptin
levels from a reference group of 109 healthy prepubertal children with
a height SD score range from -2.5 to 2.5 (
