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Human Growth Hormone Treatment of Short-Stature Children Born Small for Gestational Age: Effect on Muscle and Adipose Tissue Mass during a 3-Year Treatment Period and after 1 Year’s Withdrawal

Pediatric Endocrinology and Diabetes Unit (J.L., A.F.-P., P.C.), Radiology Department (C.G., M.H.), INSERM U457, Hôpital Robert Debré, 75019 Paris, France.

Address all correspondence and requests for reprints to: Juliane Leger, M.D., Pediatric Endocrinology and Diabetes Unit, Hôpital Robert Debré, 48, Bd Sérurier, 75019 Paris, France.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In addition to its growth promoting effect, GH has profound metabolic effects that have not always been evaluated in longitudinal studies. We have recently shown that the effect of GH on body composition can be evaluated by magnetic resonance imaging measurement of adipose and muscle tissue cross-sectional (cs) areas in the thigh.

The aim of this study was to evaluate the long-term effects of human GH (hGH) (0.2 IU/kg·day) on muscle and adipose tissue mass during a 3-yr treatment period and after 1 year’s withdrawal in short SGA (small for gestational age) children. Measurement of muscle and fat tissue mass by magnetic resonance imaging of the thighs was used to study the metabolic effect of hGH in 14 prepubertal short children born SGA. Results were compared with those of a control group of 7 normal children followed longitudinally.

An increase of muscle tissue cs area was observed during the 3 yr of hGH treatment, an increase which was significantly different during the first 2 yr of treatment from that seen in controls (+31.2 ± 2.6% and +18.1 ± 1.8% during the 1st and 2nd year, respectively, vs. +9.1 ± 2.6% change during 1 yr in controls). After a significant decrease in adipose tissue cs area during the first year of therapy (^-16.4 ± 3.4% vs. baseline values), an increase in adipose tissue cs area occurred during the second and third years. At the end of the third year, the muscle tissue cs area change was significantly greater in SGA-treated children, as compared with controls (+71.6 ± 4.6% vs. 22.1 ± 4.6%; P < 0.001), whereas the adipose tissue cs area change was similar in the two groups (+12.6 ± 9.5% vs. +19.9 ± 4.2%).

After hGH withdrawal, the effects were opposite after 3 months, as compared with those observed after the first 3 months of hGH administration, whereas no additional significant change was seen after 1 yr off treatment, indicating the maintenance of muscle and adipose tissue mass.

In conclusion, hGH administered to SGA children is effective in improving growth velocity and has long-term effects on muscle and adipose tissue mass. These effects may lead to speculation about the sensitivity of these tissues to GH. The physiological consequences of such effects must be evaluated.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
GH HAS profound effects on carbohydrate, lipid, and protein metabolism (1). GH replacement therapy in several controlled short-term trials has shown effects on body composition, such as decreased fat mass and increased lean body mass (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12). We have previously demonstrated that, in children with or without GH deficiency, human GH (hGH) therapy during the first year of treatment induces rapid and important variations in muscle and adipose tissue mass, and that magnetic resonance imaging (MRI) can be used to study these metabolic actions of GH (13).

Studies of postnatal growth in infants born small for gestational age (SGA) or with intrauterine growth retardation (IUGR) have shown that they generally effect a postnatal catch-up growth during the first 2 yr of life (14, 15). Nevertheless, a significantly reduced mean final height has been reported, implying short final stature in 10–15% of cases (16, 17). Although hGH administration has been reported to increase height velocity in short children born SGA (18, 19, 20), the long-term metabolic action of hGH has not been evaluated in these subjects.

The aim of this study was to evaluate whether a long-term hGH treatment, lasting 3 yr, followed by 1 year’s withdrawal, induces significant changes in muscle and adipose tissue mass in a group of short children born SGA.

	Subjects and Methods

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Fourteen prepubertal children born SGA (eight boys and six girls), 6.1 ± 1.9 yr old (from 3–8.7 yr) participated in the study. The mean (SD) height at the start of GH treatment was -3.6 ± 0.8 SD score (SDS) (from -4.8 to -2.7). SGA subjects were defined as showing a birth weight below the 3rd percentile, according to the French Leroy’s growth curve standards (21). Their mean (±SD) birth weight was -2.3 ± 0.7 SDS and their mean (±SD) birth length was -2.6 ± 1 SDS. Both the length and weight of nine children (64%) were below the 3rd percentile at birth. Five children were born pre term, before 37 weeks of gestation. Children with chromosomal disorders, malformations, or unknown syndromes were excluded. A standard arginine-insulin tolerance test was performed (22), and all SGA children had normal peak GH secretion above 20 mU/L (10 µg/L). Thyroid, kidney, liver functions, and glucose tolerance were normal.

Recombinant hGH was given by daily sc injection at a dose of 0.2 IU/kg (0.07 mg/kg) (Saizen, Serono, Milan, Italy; Genotropin, Pharmacia & Upjohn, Inc., Stockolm, Sweden) during 3 yr.

Muscle and adipose tissue mass were measured before and 3, 6, 12, 24, and 36 months after the onset and 3, 6, and 12 months after the withdrawal of hGH treatment.

Height and weight were measured during each period studied and expressed as the SDS for sex and chronological age (23). Body mass index [BMI: weight (kilograms)/height (meter squared)] was expressed in SDS for sex and chronological age (24). All 14 patients completed the hGH treatment study period and 10 of these 14 subjects were studied after hGH withdrawal.

Seven healthy prepubertal children of normal stature (mean ± SD height = 0.1 ± 1.1 SDS), born with appropriate birth weight for gestational age, 6.7 ± 1.8 yr old (from 4–9.7 yr), not receiving hGH treatment, were included as the control group and followed longitudinally every 3 months for 1 yr and at 2 and 3 yr.

The results of the first year of the study have been previously reported (13).

Muscle and adipose tissue mass were estimated by measuring the muscle and sc fat on the cross-sectional (cs) area of the thigh, by MRI. A detailed description of the methods has been previously provided (13).

The study was approved by the faculty ethics committee and was explained to each subject and parent who signed a written consent.

Statistical analysis

Results were expressed as means ± SEM, unless otherwise stated. At each studied period, results were also expressed as the percent change (means ± SEM) in adipose and muscle tissue cs areas of the baseline studied value. Because the subjects were studied during two different experimental situations, the results were also analyzed separately to study the effect of hGH treatment and its withdrawal. ANOVA for repeated measurements was carried out to compare the different time periods studied. When the overall F value was significant (P < 0.05), pairs of time periods were compared using the Wilcoxon signed-rank test. The Mann-Whitney U test was performed for comparisons between groups. Relationships between variables were evaluated using simple regression analysis.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Height and BMI

The clinical characteristics of the patients born SGA, having completed 3 yr of hGH treatment, followed by 1 yr of hGH withdrawal, are shown in Table 1. All patients remained prepubertal during the study. The height velocity increased significantly during hGH treatment (F = 42; P = <0.0001), with a progressive waning effect of hGH during the 2nd and 3rd yr of treatment. For the 3 yr of hGH treatment, the mean (± SD) gain in height SDS (0–3 yr) was +2.6 ± 0.6 SDS, and the children reached a mean (± SD) height of -1.2 ± 0.6 SDS, at the end of this period. After discontinuation of hGH therapy, a dramatic decrease in mean growth velocity occurred (P = 0.005).

Muscle and adipose tissue cs area

During hGH administration. As expected in normally growing children, the muscle and adipose tissue cs areas increased progressively in the control group. The change was significantly different from baseline values (P = 0.03) after 1 yr of observation (for muscle and adipose tissue cs areas, +9.1 ± 2.6% and +7.2 ± 2.2%, respectively) (Table 2). The muscle/adipose tissue cs area ratio did not change.

During the first year of hGH treatment, a rapid (1–3 months) and significant increase of muscle (P < 0.0001) and decrease of adipose (P = 0.003) tissue cs areas were observed (for muscle and adipose tissue cs areas, +31.2 ± 2.6% and -16.4 ± 3.4%, respectively). As a consequence, the muscle/adipose tissue cs area ratio increased significantly during that time. At the end of the first year of the study, the change was significantly different from that seen in the control group (Table 2).

During the second year of hGH treatment, a gradual increase in both muscle (P = 0.002) and adipose (P = 0.003) tissue cs areas occurred (for muscle and adipose tissue cs areas, +18.1 ± 1.8% and +24.4 ± 7.7%, respectively, for treated group).

During the third year of hGH treatment, no specific changes in tissue mass were observed, as compared with controls (Table 2) (for muscle and adipose tissue cs areas, +8.9 ± 1.6% and +7.6 ± 6.3%, respectively).

No relationship was found either between these changes and height velocity or between the baseline values of adipose tissue cs areas and the growth response to treatment.

After hGH withdrawal. As shown in Table 2, 3 months after hGH withdrawal, the effects were opposite, as compared with those seen during the first 3 months of hGH treatment. A tendency to decrease in muscle (-4.4 ± 2.0%; P = 0.07) and a significant increase in adipose tissue (+17.8 ± 6.1%; P = 0.02) led to a significant decrease (P = 0.01) in the muscle/adipose tissue cs area ratio soon after discontinuation of hGH therapy. No significant change was observed after 1 yr of hGH withdrawal (for muscle and adipose tissue cs areas, -0.1 ± 0.1% and +0.3 ± 0.2%, respectively), and this result was significantly different from that of the control group.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We have shown that 3 yr of hGH treatment in short children born SGA increased muscle tissue mass and, after a transient decrease, an increase in adipose tissue mass leading to a progression similar to that seen in controls over the same 3 yr observation period. Although a significant increase in adipose tissue and a tendency to decrease in muscle tissue mass were observed within 3 months of hGH withdrawal, the maintenance of muscle and adipose tissue mass was demonstrated over the 1-yr withdrawal period.

This study shows, for the first time, the long-term effects of rhGH administration on muscle and adipose tissue mass in non-GH-deficient short children.

The effects of GH on lipid, protein, and body composition have previously been well described during the first months of GH administration. The specific consequences of its metabolic actions include decreased fat, increased fat-free mass, sodium retention, and increase in muscle strength. The catabolic effect of GH on adipose tissue is accompanied by an anabolic effect on protein metabolism in children and adults with (2, 3, 4, 5, 6) or without (7, 8, 9, 10, 11, 12) GH deficiency. We have previously demonstrated in short children, with or without GH deficiency, that these effects can be observed within the first 3 months of GH treatment and that the quantitative changes in muscle and adipose tissue can be evaluated with MRI by measurement of a cs area of the thigh (13).

In children with GH deficiency, the GH therapy is substitutive; whereas in SGA children, it is pharmacological. In most protocols, the hGH dosage for children born SGA is approximately twice that used for replacement treatment, and it is often administered for 2 or 3 yr (18, 19, 20). We have previously shown that, during the first year of hGH treatment, these body composition changes were more rapid and intense in SGA, as compared with those of GH-deficient children (13). Therefore, it is possible that the effect of hGH administration on muscle and adipose tissues could also be dose-dependent. This has not been studied in the present work, because a single dosage has been used in our population of children born SGA.

Because the body composition of subjects born SGA has generally been studied in newborn infants (25, 26, 27, 28) or in adolescents at the end of puberty (29), there is a lack of data concerning childhood. A simple anthropometric method, i.e. measurement of adiposity, using the BMI, has shown that children born with IUGR, in general, were light rather than short at 2 yr of age, with a mean BMI at -0.8 ± 1 SDS (30). The short SGA children evaluated in this study were thin, with a mean BMI of -1.4 ± 0.9 SDS at the time of hGH administration. Moreover, as previously shown (13), the BMI SDS values were significantly and positively correlated with thigh muscle and adipose surface tissues measured by MRI for all subjects, which confirms the accuracy of the method used. Further studies are needed to determine whether the reduced fat mass in short children born SGA is an indicator of the reduced adipose tissue stores or simply a consequence of low nutritional status.

This study has shown a significant adipose tissue mass reduction during the first year of hGH treatment, which is in accordance with the well-documented adipose tissue lipolysis induced by hGH administration (31). Interestingly, however, this change occurred with no significant alteration in BMI SDS. This may be because of the fact that GH treatment may affect the adipose tissue in various fat depots differently (32).

During the second year of treatment, significant increases in both adipose tissue mass and BMI SDS occurred, whereas no significant change occurred during the third year of treatment.

Data concerning the effects of long-term (2–4 yr) hGH treatment on body composition are limited, this having been studied only in GH-deficient adults (33, 34, 35, 36). The beneficial effects of GH on muscle tissue mass, although maintained in the long term, have been found to be greater during the first year of hGH administration. However, the maximal body fat reduction was observed after 6 months of treatment, with no further decrease thereafter; although the anabolic effects of hGH, illustrated by the increase in body cell mass, do not reach a steady state after 6 months but continue to increase over a 2-yr administration period (33, 34, 35, 36).

Our results in short SGA children without GH deficiency are in agreement with the previous reports in GH-deficient adults, in that we demonstrated an increase in muscle mass during the first 2 yr of treatment, which was most pronounced during the first months of GH administration. No change in tissue mass occurred during the third year of treatment, as compared with controls.

After hGH discontinuation, and as shown in adult patients with GH deficiency (37, 38, 39), withdrawal led to effects opposite to those seen during the induction of hGH treatment. hGH withdrawal also led to a reduced growth rate in all patients within the first year, as has previously been shown in short children without GH deficiency, born SGA or not (40, 41).

An association between low birth weight and insulin resistance has been described in middle-aged adults (42, 43). More recent work has demonstrated indications of insulin resistance at 20 yr of age in subjects born with SGA (17), and impaired insulin sensitivity at the age of 8.5 yr has been shown in a group of short children born SGA (44). Fat and muscle tissues are the major responders to insulin.

It is known that GH treatment alone may constitute a risk factor for insulin resistance (45). Normal glucose tolerance (as tested by an oral glucose tolerance test), with increased plasma insulin levels, has been described during GH administration in short children born SGA (18, 19, 20). These results are in accordance with studies on glucose metabolism in short-stature children without GH deficiency or IUGR and for which hyperinsulinemia induced by GH administration was reversible after the end of treatment (46). Whether the effect of GH on muscle and adipose tissue will influence insulin sensitivity later in life in subjects born SGA requires further studies.

The long-term effects of GH administration on fat and muscle tissue mass have not been previously described and may lead to speculation about the sensitivity of these tissues to GH. Their physiological consequences have to be evaluated. This is part of the long-term safety studies which must be undertaken in non-GH-deficient children treated with GH.

Received March 25, 1998.

Revised June 12, 1998.

Accepted June 22, 1998.

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