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Departments of Pediatrics (R.C., S.R., J.M.L.), Nuclear Medicine (F.B.d.C.), Biochemistry A (O.D.), Biochemistry B (E.M.), and Rheumatology (M.A.), University Hospital, 49000 Angers, France
Address all correspondence and requests for reprints to: Dr. Régis Coutant, Department of Pediatrics, University Hospital, 4 rue Larrey, 49000 Angers, France. E-mail: recoutant{at}chu-angers.fr
Abstract
Serum IGF-I levels in GH-treated subjects demonstrate a wide range
of responsiveness to GH. However, the factors influencing GH
sensitivity are not well known. The aim of this work was 1) to test
whether body composition (determined by dual energy x-ray
absorptiometry) or factors related to body composition (fasting blood
glucose, FFA, C-peptide, leptin, and insulin sensitivity determined by
an insulin tolerance test) influence GH sensitivity; and 2) to study
the effect of sex steroid priming on GH sensitivity. We measured serum
IGF-I at baseline and 24 h after a single administration of GH (2
mg/m2) in 60 healthy prepubertal and early pubertal
children (height, -2.1 ± 1.0 SD score). GH
sensitivity, as estimated by the increase in serum IGF-I after GH
administration (difference between stimulated and baseline serum
IGF-I = 
IGF-I), was also determined after a short-term
administration of oral ethinyl E2 in girls and im T in boys.
The serum IGF-I concentration was 297 ± 114 µg/liter at
baseline and increased to 429 ± 160 µg/liter, corresponding to
a 46 ± 29% increase over the baseline value
(P < 0.0001, stimulated vs.
baseline serum IGF-I). IGF-I was not different between gender or
pubertal stage. There were positive correlations (P
< 0.001) between IGF-I and adiposity (total body fat, r =
0.62; trunk fat, r = 0.62), fasting leptin (r = 0.64), and
C-peptide (r = 0.54), and a negative correlation with fasting FFA
(r = -0.33; P < 0.05) even after adjustment
for age, gender, and pubertal stage. These factors remained significant
independent predictors of the absolute as well as the percent increase
in serum IGF-I in multiple regression analyses. Priming with T and
ethinyl E2 had a similar stimulating effect on the serum GH peak in
response to the insulin tolerance test. In boys, serum baseline IGF-I
increased by 60%, and IGF-I was similar after vs.
before T administration. By contrast, in girls, serum baseline IGF-I
was similar, and IGF-I was 60% less after vs.
before ethinyl E2 administration.
This study indicates that 1) GH sensitivity is determined by fat mass, serum fasting leptin, C-peptide, and FFA; and 2) oral ethinyl E2 and im T have divergent effects on the IGF-I response to a single administration of GH.
MOST OF THE anabolic actions of GH are thought to be mediated by IGF-I (1), and changes in serum IGF-I in response to GH treatment have been correlated to the growth rate in GH-treated short children with GH deficiency (GHD) and idiopathic short stature (2). Serum IGF-I levels measured in GH-treated subjects have demonstrated a wide range of individual responsiveness to GH, probably dependent on a variety of factors (2, 3, 4, 5). However, the metabolic or hormonal factors influencing IGF-I production in response to GH are not well known. The recent consensus guidelines from the GH Research Society underlined the need for further work to establish the role of the IGF-I response to GH for the diagnosis and treatment of GHD in childhood (6).
Several physiological or pathological conditions suggest potential determinants of GH sensitivity. During chronic undernutrition, GH secretion is high, and IGF-I is low, and relative insensitivity to GH administration, which is reversible after refeeding, has been demonstrated (7). Conversely, chronic overnutrition and obesity result in low GH secretion and normal-high serum IGF-I levels, suggesting either overnutrition-induced (GH-independent) IGF-I production and/or increased GH sensitivity (7, 8). Overall, these data indicate that body composition or metabolic-hormonal factors related to body composition may alter GH sensitivity. In addition, the effects of gender and sex hormone replacement therapy on GH sensitivity have been highlighted in adults with GHD. These studies have shown that women are less responsive to higher GH doses than men (3, 4, 5, 9, 10), thus providing evidence of a different effect of androgens and estrogens on GH sensitivity. Finally, in most GH-treated subjects, changes in serum IGF-I levels have been described after several months or years of GH treatment, whereas short-term changes have not been studied.
The aim of this work was to investigate the relationships between the
IGF-I response to a single administration of GH, total and regional
body composition, and factors related to body composition (leptin,
C-peptide, insulin sensitivity, blood glucose, and FFA) in peripubertal
children. In addition, we determined whether sex steroid priming
influenced the IGF-I response to GH. Last, we measured leptin response
to GH administration in these children. We report the serum IGF-I,
IGF-binding protein-3 (IGFBP-3), and leptin concentrations at baseline
and 24 h after a single administration of GH (2
mg/m2) in 60 healthy peripubertal children (35
boys and 25 girls) with short stature or decreasing growth velocity
before the pubertal growth spurt. Body composition was determined using
dual energy x-ray absorptiometry. In a subgroup of 41 children (25 boys
and 16 girls), GH sensitivity, as estimated by the difference between
stimulated and baseline serum IGF-I ( IGF-I), was also measured
after short-term administration of sex steroids (oral ethinyl E2 in
girls, im T heptylate in boys).
Subjects and Methods
Subjects
We studied 60 children, aged 9.75–16.5 yr (25 girls and 35 boys). These children were primarily referred for assessment of GH secretion using an insulin tolerance test (ITT) because of short stature and/or decreasing growth velocity. Children were at Tanner stage I (17 girls and 24 boys) or stage II (8 girls and 11 boys) before the acceleration of growth rate: serum T levels were below 0.50 ng/ml in the boys, and serum E2 was below 10 pg/ml in the girls (11, 12). The SD scores of height, growth velocity, and body mass index (BMI) for age and sex were calculated (13, 14). GHD was ruled out (GH peak to the ITT or the arginine-insulin test >20 mIU/liter). The children were all in good health. None of them had gonadotropin deficiency, hypothyroidism, chromosomal abnormalities, dysmorphic syndromes, skeletal dysplasia, chronic illness, or any endocrine or metabolic disease. None was taking medication. Protocols were approved by our institutional review board. All subjects and families gave their informed consent.
Study design
The first day a standardized ITT was performed in the children after a physiological overnight fast. After placement of a catheter in a peripheral vein, regular insulin was injected at a dose of 0.1 U/kg, iv, at 0800 h. Blood samples were collected at 0, 15, 30, 45, 60, and 120 min for GH measurements. Blood was also collected for measurements of glucose at 0, 3, 7, 10, 15, 30, and 60 min. The second day, each subject received recombinant human GH (Genotonorm, Pharmacia & Upjohn, Inc., Stockholm, Sweden) at a dose of 2 mg/m2 at 0800 h after a physiological overnight fast. Treatment was administered by sc abdominal injection. Blood was sampled 0 and 24 h after injection for measurement of leptin, IGF-I, and IGFBP-3. We checked that their values at baseline were not influenced by the ITT; they were not different at time zero between d 1 and 2. Blood was also obtained for basal (fasting) measurements of C-peptide and FFA concentrations. Subjects were permitted a normal oral diet; they consumed three major meals and one snack.
The GH response to ITT and the IGF-I response to GH were also examined after sex steroid administration in a subgroup of 41 children (25 boys and 16 girls) who volunteered for the exploration. Boys received a single injection of T heptylate (100 mg, im) and were reassessed 7 d later. Girls received ethinyl E2 (50 µg/d, orally) for 3 d before retesting. The rationale for the use of these sex steroid priming protocols was that they are known to strongly stimulate GH secretion (15, 16).
Body composition
Body composition was investigated by dual energy x-ray absorptiometry using a QDR 4500A densitometer (Hologic, Inc., Waltham, MA). Whole body scans were performed, and body compartments were analyzed using software from Hologic, Inc. (version V8.24a:3).
Insulin sensitivity index
The insulin sensitivity index was calculated from the glucose concentrations during the ITT (17). The rate of constant glucose disappearance was calculated from the formula 0.693/t1/2. The plasma glucose t1/2 was calculated from the slope of the least square analysis of the plasma glucose concentrations from 3–15 min after iv insulin injection.
Hormone assays
Serum leptin was measured by a specific RIA (Mediagnost, Tubingen, Germany). Sensitivity was 0.04 µg/liter, and the intra- and interassay coefficients of variation were 5% and 7.6%, respectively. Serum GH was measured by immunoradiometric assay (IRMA; Immunotech/Beckman Coulter, Inc., Villepinte, France). Sensitivity was 0.05 µg/liter, and the intra- and interassay coefficients of variation were 1.5% and 14.03%, respectively. The GH results are expressed in International Reference Preparation 66/217 units, for which 2 mU = 1 µg. Serum total IGF-I measurements were performed by IRMA after acid-ethanol extraction, and serum IGFBP-3 measurements were made by IRMA (Immunotech/Beckman Coulter, Inc.). The intra- and interassay coefficients of variation were 5.7% and 8.6% for IGF-I, and 4.8% and 6.4% for IGFBP-3, respectively. Serum C-peptide was measured by RIA (Schering AG CIS-Bio International, Gif sur Yvette, France). The intra- and interassay coefficients of variation were 6.5% and 11.2%, respectively. T and E2 were measured by RIA (Immunotech/Beckman Coulter, Inc. and Schering AG CIS-Bio International). The intra- and interassay coefficients of variation were 8.6% and 10.6% for T, and 5.4% and 12.8% for E2, respectively. Plasma glucose was measured with a Hitachi 917 analyzer (Roche, Meylan, France). Plasma FFA were measured using enzymatic methods (Wako Chemical, Richmond, VA) on a Cobas Mira analyzer (Roche).
Statistical methods
We first tested the normality of the distribution of the studied
variables using the Komolgorov-Smirnov test. Given the non-Gaussian
distribution of body composition data, serum leptin, C-peptide, and GH
in the study population, these variables were
log10 transformed to normalize their
distribution. We then used the Komolgorov-Smirnov test again to verify
that the log10-transformed variables followed a
Gaussian distribution. The results are presented as the geometric means
(-1; +1 tolerance factor), corresponding to the reverse transformation
of the mean ± SD of the
log10-transformed variables. All other data are
expressed as the mean ± SD. Parametric tests were
then used. Paired and unpaired t tests were used for
comparison of subjects. Simple regression analyses were performed, with
IGF-I (stimulated IGF-I - baseline IGF-I) and GH peak in
response to ITT as dependent variables. Clinical variables (age,
gender, pubertal stage, and body composition) and biological variables
(serum fasting glucose, C-peptide, leptin, FFA, and insulin sensitivity
index) were used as independent variables. To determine the best
combination of predictors of the IGF-I response to GH administration,
backward multiple regression analyses were performed, using significant
variables in simple regression analysis as well as their interactions.
Given the colinearity of leptin and fat mass, both variables could not
be entered concurrently in one multiple regression analysis: instead,
two models were constructed, one using leptin (but not fat mass), and
the other using fat mass (but not leptin). GH peak was defined as the
maximal GH value in response to ITT. Significance was defined as
P < 0.05. All analyses were two-tailed and performed
with the SPSS 9.0.1 statistical package (SPSS, Inc.,
Chicago, IL).
Results
IGF-I and leptin responses to GH
The clinical and biological characteristics of the children are
presented in Tables 1
and 2. The serum
IGF-I concentration was 297 ± 114
µg/liter at baseline and increased to 429 ± 160 µg/liter in
response to a single injection of GH, corresponding to a 46.0 ±
28.7% increase over the baseline value (P < 0.0001,
baseline vs. stimulated IGF-I concentration). The serum
IGFBP-3 concentration was 2933 ± 633 µg/liter at baseline and
increased to 3139 ± 620 µg/liter, corresponding to a 9 ±
16% increase over the baseline value (P < 0.0001,
baseline vs. stimulated IGFBP-3 concentration). Serum leptin
was 5.4 (2.1; 13.9) µg/liter at baseline, and increased to 6.7
(2.6; 17.6) µg/liter (P < 0.0001, baseline
vs. stimulated leptin concentration).
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IGF-I; r = 0.30; P <
0.05) and did not correlate with the serum GH peak in response to
ITT.
There was no difference in IGF-I between gender or pubertal stage
(Tanner stage I vs. early stage II).
IGF-I response to GH and body composition
A positive correlation was found between IGF-I and BMI (r
= 0.53; P < 0.001), BMI SD score
(r = 0.48; P < 0.001), total body fat (r =
0.62; P < 0.0001), trunk fat (r = 0.62;
P < 0.0001), nontrunk fat, (r = 0.60;
P < 0.0001), and percent fat (r = 0.57;
P < 0.001; Fig. 1).
IGF-I was also correlated with lean body mass variables (lean body mass
and trunk lean mass), with lower correlation coefficients. All
correlations persisted after adjustment for age, gender, and pubertal
stage.
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As IGF-I was strongly correlated to body fat data, we sought
to determine whether metabolic and hormonal factors related to fat mass
were also predictors of the IGF-I response to GH administration. A
positive correlation was found with fasting blood glucose (r =
0.28; P < 0.05), fasting C-peptide (r = 0.54;
P < 0.0001), and fasting leptin (r = 0.64;
P < 0.0001; Fig. 1
), a negative correlation was found
with fasting FFA (r = -0.33; P < 0.05), and no
correlation was found with the insulin sensitivity index.
Independent predictors of IGF-I response to GH: multivariate analyses
In addition to body composition variables and metabolic-hormonal
factors that were correlated with the IGF-I response to GH, we found
significant simple correlations between IGF-I and age, growth rate
SD score, and serum GH peak to ITT. To select the best
combination of independent predictors of the IGF-I response to GH, we
entered all the variables that were significantly related to IGF-I
in simple regression analyses into backward multiple regression
analyses (Table 3). As fat mass and
fasting leptin were colinear, they could not be entered concurrently in
one regression analysis; two models were thus constructed: one using
fat mass (but not fasting leptin), and the other using fasting leptin
(but not fat mass). In the first model, fasting FFA, fasting C-peptide,
and trunk fat mass were independent predictors of the IGF-I response
(multiple r = 0.75; P < 0.0001). In the second
model, fasting FFA, fasting C-peptide, and fasting leptin were
independent predictors of the IGF-I response (multiple r = 0.73;
P < 0.0001; Table 3). These variables remained
significant independent predictors of the IGF-I response to GH when
expressed as a percent change in serum IGF-I (not shown).
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Several variables that were positively related to the IGF-I
response to GH showed an inverse relationship with the GH peak in
response to ITT. BMI SD score (r = -0.30;
P < 0.05), total fat (r = -0.27;
P < 0.05), trunk fat (-0.29; P <
0.05), percent body fat (r = -0.31; P < 0.05),
and serum fasting leptin (r = -0.31; P < 0.05)
were negatively correlated to GH peak to ITT. Finally, the IGF-I
response to GH was negatively correlated to GH peak in response to ITT
(r = -0.26; P < 0.05; Fig. 1).
IGF-I response to GH: effect of gender and administration of gonadal steroids
A subgroup of 41 children (25 boys and 16 girls) was also examined
after sex steroid administration. Their clinical and biological
characteristics were not different from those of the whole cohort of
children (Tables 1 and 2). There was no difference in baseline serum
IGF-I and IGF-I response to GH between gender before sex steroid
administration (Fig. 2). In boys,
baseline serum IGF-I was 60% higher after vs. before im
administration of T (P < 0.0001; Fig. 2). However, the
absolute increase in serum IGF-I after GH administration ( IGF-I)
was unchanged (116 ± 93 vs. 137 ± 70 µg/liter,
after vs. before im T administration; P >
0.05). By contrast, in girls, baseline serum IGF-I was similar after
vs. before administration of oral ethinyl E2, whereas the
absolute increase in serum IGF-I after GH administration was 60% less
(62 ± 63 vs. 143 ± 77 µg/liter;
P < 0.01; Fig. 2). Conversely, the GH peak in response
to ITT increased from 16.5 (11.2; 24.4) to 28.7 (16.6; 49.5) mU/liter
(P < 0.0001) after sex steroid administration, with no
difference between boys and girls.
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This study evidenced several factors associated with GH sensitivity in healthy peripubertal children. The serum IGF-I response 24 h after a single GH administration was positively correlated with body fat. Among the metabolic and hormonal factors related to fat mass, serum fasting leptin, C-peptide, and FFA were significant predictors of GH sensitivity. In contrast, both fat mass and serum leptin were inversely related to GH peak to ITT. As a result, the IGF-I response to GH was inversely related to the GH peak in response to ITT. Short-term administration of oral ethinyl E2 or im T had divergent effects on GH sensitivity. In boys, serum baseline IGF-I increased, and the absolute change in serum IGF-I after GH administration was similar after vs. before T administration. In girls, serum baseline IGF-I was similar, and the absolute change in serum IGF-I after GH administration was less after vs. before ethinyl E2 administration. In contrast, both treatments had similar stimulating effects on the GH response to ITT. Last, we showed that a single GH administration in healthy peripubertal children increased the leptin concentration.
This study found that adiposity was a major positive determinant of GH sensitivity. The relationship between adiposity and GH sensitivity has been previously suggested from studies of the serum IGF-I concentrations after GH treatment in adults with GH deficiency; higher levels were found in obese than in lean patients (5). Positive correlations were also found between serum IGF-I and body mass index in treated GHD children (18). The serum GH-binding protein (GH-BP) concentration, which is thought to mirror cell surface GH receptor density, has been associated with obesity and abdominal fat mass (19). However, the divergence between serum GH-BP and IGF-I levels raised questions of whether it accurately reflects hepatic GH receptor function and suggested that adipose tissue may be a significant source of GH-BP (20, 21). Our results in healthy nonobese children provide evidence that fat mass is truly associated with GH sensitivity, i.e. the ability to produce IGF-I in response to GH. This may explain in part the association between growth velocity and weight described in GH-treated children with GHD (22). Regarding regional fat distribution, we found that trunk fat was the strongest predictor of the IGF-I response to GH. We did not determine the respective importance of visceral and sc fat; future research is needed to better clarify this point.
Several metabolic and hormonal factors may mediate the association between fat mass and GH sensitivity. The IGF-I response to GH was positively determined by serum fasting leptin and C-peptide, was negatively determined by fasting FFA, and was not determined by insulin sensitivity. The relationship between the IGF-I response to GH and serum leptin is consistent with the known correlation between serum GH-BP and leptin in healthy nonobese children and adults (23, 24). Similarly, the growth-promoting effect of GH treatment in short prepubertal children has been found to correlate positively with leptin levels at the start of GH treatment, supporting an association between leptin and GH sensitivity (25, 26). In animal studies, a link between changes in serum leptin and GH-induced IGF-I secretion has been shown in agonadal monkeys (27). Along the same lines, ip administration of recombinant leptin to juvenile fasting rats stimulated IGF-I-gene expression in hepatic extracts (28). Overall, these data may suggest a role for leptin in the control of GH sensitivity. Alternatively, the increase in serum IGF-I and leptin after GH administration may result from an increased production in adipose tissue. In animal studies, GH administration has been found to induce a 4-fold increase in IGF-I and leptin mRNA in adipose tissue, with a high correlation between both mRNA concentrations (29, 30). Although serum IGF-I is believed to originate mainly from hepatocytes (31), further studies are needed to determine the contribution of the adipose tissue in circulating IGF-I levels.
Insulin (determined by fasting C-peptide), but not insulin sensitivity (determined by the glucose response to ITT), was an independent positive predictor of GH sensitivity in this work. In humans, insulin treatment (32), and, more efficiently, intraportal insulin delivery (33), corrected the low serum IGF-I found in diabetic subjects. In the hepatoma cell line, insulin up-regulated total and intracellular GH receptors in a concentration-dependent manner (34). In the rat, insulin treatment increased GH binding to the liver (35). All of these findings provide strong evidence that insulin is essential for GH-induced hepatic IGF-I production.
In this study fasting FFA was a negative predictor of GH sensitivity, independent of fasting leptin, fasting C-peptide, and fat mass. Although several pathological conditions, such as anorexia nervosa (36) and critical illness (37), associate high fasting plasma FFA with high GH-low IGF-I concentrations, the relationship between FFA and GH sensitivity has not been previously studied in humans. Further work is needed to determine whether this statistical association reflects a physiological interaction.
Factors positively related to GH sensitivity, such as fat mass and serum fasting leptin, were inversely correlated to GH peak to ITT in the present study. Moreover, GH sensitivity was inversely related to GH peak in response to ITT. The negative associations between GH secretion and fat mass have been known for a long time, even in nonobese subjects (38, 39, 40, 41). A negative association between serum leptin and GH secretion has been recently described in children, with correlation coefficients similar to those of this study (41, 42), and also in postmenopausal women (43) and elderly subjects (44). Our data suggest that the positive effect of fat mass and leptin on GH sensitivity may be counterbalanced by its negative effect on GH secretion.
We showed that the GH peak in response to ITT, baseline serum IGF-I, and the increase in serum IGF-I after GH administration were similar between genders in children during prepuberty and at the onset of puberty. After sex steroid administration, the GH peak in response to ITT almost doubled, with no difference between im T and oral ethinyl E2. After a single administration of im T in boys, baseline serum IGF-I increased by about 60%, whereas the absolute increase in serum IGF-I after GH administration remained unchanged compared with the values found before T administration. By contrast, after short-term administration of oral ethinyl E2 in girls, baseline serum IGF-I remained unchanged, whereas the absolute increase in serum IGF-I after GH administration was about 60% less compared with the values found before ethinyl E2 administration. These data suggest that the stimulation of GH production by im T was directly responsible for the increase in baseline IGF-I, with no change in GH sensitivity, whereas the stimulating effect of oral ethinyl E2 on GH production was counteracted by its inhibiting effect on GH sensitivity, leading to an unchanged serum baseline IGF-I. The sex steroid priming protocols we used have been shown to strongly stimulate GH secretion (15, 16). The measurement of the GH response to ITT and the IGF-I response to GH administration on 2 consecutive d allowed us to study the relationships between the two responses. However, whether the interval between sex steroid administration and hormone measurements was optimal for the evaluation of GH sensitivity remains to be determined. We cannot exclude the possibility that different results may have been obtained with different time intervals from sex steroid administration. If established, our findings suggest that oral estrogen administration to induce pubertal development should be cautiously undertaken in GH-treated short girls, as it may hamper IGF-I production. The negative effect of oral estrogen on GH sensitivity has been described in adults with GHD (3, 4, 5, 9, 10) and in postmenopausal women (45, 46), after several weeks or years of replacement therapy. We found that this effect was already present in healthy peripubertal girls after a very short-term administration (3 d) of oral estrogen. It may be linked to the route as well as the dose of estrogen administration, as GH sensitivity was lower with oral than with transdermal estrogens (46, 47, 48). In our study the oral estrogen dose was equivalent to that used for oral estrogen replacement therapy. However, in subjects with GHD, eugonadal women also required higher GH doses than eugonadal men (48), suggesting a physiological difference for the effects of sex steroids on GH sensitivity. We did not find any difference in GH sensitivity between Tanner stage I and early stage II in girls and boys. However, we did not investigate children with more advanced pubertal stage: further characterization of the evolution of GH sensitivity during puberty is needed.
In pharmacodynamic studies, serum IGF-I concentrations have been found to increase 3 h after a single sc administration of rhGH and to reach a plateau within approximately 18–24 h (46, 49, 50). Here, we showed a mean 46% increase in serum IGF-I over the baseline value 24 h after the administration of recombinant human GH (2 mg/m2), and we considered that this increase was an acceptable estimation of GH sensitivity. However, the individual pharmacodynamics of GH and IGF-I may vary, and frequent sampling over 3–72 h could have provided a more accurate estimate of GH sensitivity. In addition, repeated rhGH administration has been found to alter body composition and insulin and FFA concentrations (51). It is therefore likely that GH sensitivity may evolve during GH treatment, and the IGF-I response 24 h after a single GH administration may not be an adequate indicator of GH sensitivity during prolonged GH treatment.
We observed a stimulating effect of a single administration of GH on serum leptin concentration in healthy children. This is in line with the increase in serum leptin found 24 h after GH administration in GH-deficient elderly subjects (52). This acute effect contrasts with the decrease in serum leptin described after chronic administration of GH as a result of the concurrent reduction in fat mass (25, 26). Whether the acute stimulation of serum leptin after GH administration reflects a direct effect of GH or is indirectly mediated by changes in insulin or IGF-I secretion remains to be studied.
In conclusion, this study in peripubertal children indicates several factors associated with GH sensitivity, namely, fat mass (more specifically trunk fat mass), fasting leptin, fasting C-peptide, fasting FFA, and sex steroid administration. Some of these factors, i.e. insulin secretion or FFA production, may be the target of therapies; future studies will determine whether such therapies are able to change GH sensitivity.
Acknowledgments
We thank Yannick Simon, who performed the dual energy x-ray absorptiometry, and Anne Liger, Claire Baril, and Martine Chiffoleau, who provided care for the subjects who participated in the study.
Footnotes
This work was supported by a grant from Programme Hospitalier de Recherche Clinique 1998 (PHRC 1998, Ministère de la Santé).
Abbreviations: BMI, Body mass index; GH-BP, GH-binding protein;
GHD, GH deficiency; IGF-I, difference between stimulated and
baseline serum IGF-I; IGFBP, IGF-binding protein; IRMA,
immunoradiometric assay; ITT, insulin tolerance test.
Received April 9, 2001.
Accepted August 29, 2001.
References
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  N. Bouhours-Nouet, F. Gatelais, F. Boux de Casson, S. Rouleau, and R. Coutant The Insulin-Like Growth Factor-I Response to Growth Hormone Is Increased in Prepubertal Children with Obesity and Tall Stature J. Clin. Endocrinol. Metab., February 1, 2007; 92(2): 629 - 635. [Abstract] [Full Text] [PDF]
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