| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Original Studies |
Department of Endocrinology and Metabolism, Fukuoka Children’s Hospital, and the Department of Pediatrics, Faculty of Medicine, Kyushu University, Fukuoka, Japan
Address all correspondence and requests for reprints to: Ryuichi Kuromaru, M.D., Department of Pediatrics, Faculty of Medicine, Kyushu University, 3–1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail: kuromaru{at}pediatr.med.kyushu-u.ac.jp
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Atherosclerotic changes start to develop in childhood and progress with age (3). Studies tracking atherogenic risk factors from early childhood suggest that earlier treatment of atherogenic risk factors can delay the development of atherosclerosis (4, 5).
Children with GH deficiency usually present with atherogenic risk factors, such as truncal obesity and hypercholesterolemia (6, 7, 8). The effects of early GH treatment on these risk factors, especially those involving lipid metabolism, remain controversial (8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28). Young adults with childhood-onset GH deficiency were reported to have an increased intima-media thickness of the carotid artery (29). However, little is known about the metabolic sequelae of early sustained GH treatment in GH-deficient children.
We performed a prospective longitudinal study to evaluate the effects of long term GH treatment and its discontinuation on body composition and lipid metabolism in GH-deficient children.
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Ninety-four children with idiopathic GH deficiency (67 boys and
27 girls) were divided into 2 groups: a group receiving GH treatment
(under GH treatment group) and a group that had completed GH treatment.
GH deficiency was diagnosed between 6–14 yr of age on the basis of a
peak GH concentration of less than 10 ng/mL in response to two or more
standard provocation tests with insulin hypoglycemia (0.1 U/kg),
arginine infusion (0.5 g/kg), or L-dopa (10 mg/kg). The
subjects were treated with recombinant human GH in a weekly dose of 0.5
IU/kg (
0.19 mg/kg) by daily sc injection. No subject had associated
malformations, chromosomal abnormalities, or intrauterine growth
retardation. Renal, liver, and thyroid functions were normal during the
study in all subjects.
Protocol
GH treatment was started in 62 (46 boys and 16 girls) of the 94 subjects (under GH treatment group). All were prepubertal (age: boys, 9.7 ± 2.7 yr; girls, 9.6 ± 2.4 yr) at the start of GH treatment. The pretreatment height SD score and growth velocity were -2.81 ± 0.90 and 4.3 ± 1.1 cm/yr in boys and -3.14 ± 0.88 and 4.3 ± 1.4 cm/yr in girls, respectively. They were evaluated before and after 3, 6, 12, 18, 24, and 36 months of GH treatment. During the GH treatment, 17 boys and 8 girls entered puberty at the average age of 13.8 ± 1.3 yr for boys and 11.4 ± 1.1 yr for girls.
The remaining 32 subjects (21 boys and 11 girls) who had already received GH were studied 6 months before discontinuation of GH treatment, at the time of discontinuation of GH treatment, and 3 and 6 months after the discontinuation of GH treatment (completed GH treatment group). GH treatment was discontinued in these subjects when the growth velocity had become less than 2.0 cm/yr or the bone age had reached 17 yr in boys and 15 yr in girls. Reevaluation of the GH status was not performed after discontinuation of GH, because informed consent was not obtainable from the subjects. The mean age at cessation of GH treatment was 17.0 ± 1.1 yr in boys and 15.5 ± 1.2 yr in girls. The duration of GH treatment was 6.1 ± 2.9 yr in boys and 5.2 ± 1.6 yr in girls. In this group, the pretreatment and attained final height as SD scores were -2.93 ± 0.53 and -1.34 ± 0.74 in boys and -2.82 ± 0.68 and -1.38 ± 0.67 in girls, respectively. Twenty-four of 32 subjects had undergone a magnetic resonance imaging study, in which all showed structurally normal or small anterior pituitary glands except for 6 (4 boys and 2 girls) who had had pituitary stalk transection.
On each visit, height, body weight, waist to hip ratio, body composition [body fat (BF) and lean body mass (LBM)], serum lipids [total cholesterol (TC), low density lipoprotein cholesterol (LDLC), high density lipoprotein cholesterol (HDLC), triglycerides (TG), apolipoproteins (Apo), and lipoprotein(a) (Lp(a))] were evaluated in all subjects.
The protocol was approved by the clinical research committee of Fukuoka Children’s Hospital, and informed consent was obtained from all subjects and their parents.
Methods
Height was measured with a Harpenden stadiometer and expressed as the SD score for chronological age, based on recent Japanese growth references (30). Overweight was calculated for each subject as the obesity index, indicating the percent deviation from ideal body weight based on height, age, and sex. Body composition was measured with a bioelectrical impedance analyzer (BIA 101, Spectrum II 287, RJL Systems, Detroit, MI). Preliminary analysis of repeated within-day measurements for percent BF in the same subject did not show a significant difference (P > 0.05), and the correlations of between-day measurements were high (r = 0.80), consistent with the results of other validation studies (31, 32).
Venous blood samples were taken after an overnight fast. TC and TG concentrations were measured with a fully enzymatic method using an automatic analyzer (JCA-RX 20, JEOL, Tokyo, Japan). HDLC concentrations were determined enzymatically after precipitation of LDLC and very low density lipoprotein cholesterol with dextran sulfate and magnesium chloride (HDL-C2, Daiichi Pure Chemicals, Tokyo, Japan). LDLC concentrations were calculated with the Friedewald formula (33). Serum Apo-AI, Apo-AII, Apo-B, Apo-CII, Apo-CIII, and Apo-E were determined by turbidimetric immunoassay using the reagent kits (Apoauto, Daiichi, Tokyo, Japan) (34). The atherogenic index was evaluated as the ratio of TC/HDLC (35) and Apo-B/Apo-AI (36). Lp(a) concentrations were measured with a fully automated latex immunoassay method based on a latex-enhanced turbidimetric immunoassay, using an immunochemical analyzer (501X, A&T Corp., Tokyo, Japan) (37). Insulin-like growth factor I (IGF-I) was detected with a RIA kit (SM-C II Chiron, Uka Medias, Tokyo, Japan). GH was measured in duplicate with a conventional RIA kit (Dinabot, Tokyo, Japan). All intra- and interassay coefficients of variance were less than 2.0%.
Statistical analysis
Results are expressed as the mean ± SD. ANOVAs for repeated measurements were carried out to compare the different time periods studied. If the F value was statistically significant (P < 0.05) on analyses of variance, pairs of time periods were compared by paired t test. Pretreatment levels of TC, HDLC, and Apo were compared with the values for normal, age- and sex-matched Japanese children by Student’s t test (38, 39). P < 0.05 was considered statistically significant.
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Anthropometry and body composition. The mean height and
height SD score significantly improved from 120.9 cm
(-2.81 SD) to 139.0 cm (-1.70 SD) in boys and
from 118.7 cm (-3.14 SD) to 135.9 cm (-1.84
SD) in girls after 36 months of GH treatment (Table 1
). The total body weight increased
linearly in all subjects. Mean obesity index values decreased by 6.1%
(P < 0.01) in boys and by 9.7% (no statistical
significance) in girls during the GH treatment. The waist/hip ratio did
not change appreciably in either sex. BF decreased significantly from
16.5% (4.9 kg) to 11.7% (3.7 kg) in boys and from 16.7% (3.6 kg) to
11.6% (2.7 kg) in girls during the first 6-month period of GH
treatment (P < 0.01; Table 1). Subsequently, BF
remained constant in boys, but increased in girls after 2 yr of
treatment (Fig. 1). LBM increased
significantly in both sexes throughout the treatment period
(P < 0.01).
|
|
).
At the beginning of GH treatment, mean values of TC, TG, LDLC, HDLC,
apolipoproteins, and Lp(a) in both boys and girls were not
statistically different from those in age-matched normal children.
However, 9 boys and 2 girls (18% of the subjects) had TC levels
greater than 200 mg/dL at entry. This incidence was higher than that
expected in normal subjects (5%) (39). TC decreased from 175.5
± 30.0 to 160.9 ± 23.8 mg/dL in boys and from 178.6 ± 33.3
to 167.5 ± 25.6 mg/dL in girls during 3 yr of GH treatment;
however, the decrease was statistically significant only in boys
(P < 0.01). Four subjects (3 boys and 1 girl) had LDLC
levels above 130 mg/dL at entry into the study. The mean LDLC level
decreased markedly from 101.9 ± 30.8 to 77.0 ± 25.3 mg/dL
in boys (P < 0.01) and from 103.5 ± 32.2 to
76.3 ± 28.5 mg/dL in girls (P > 0.05). None of
the subjects had elevated TC or LDLC after 3 yr of GH treatment. HDLC
increased significantly in boys from 57.8 ± 12.7 mg/dL to
65.9 ± 17.4 mg/dL after the first 3 months of GH treatment and
remained elevated thereafter (P < 0.01). In contrast,
HDLC did not change appreciably in girls. Apo-AI increased rapidly
(P < 0.01) and remained stable in boys, whereas it
increased gradually during GH treatment in girls (P >
0.05). The mean TG and Apo-CIII levels in both sexes and the Apo-CII
level in girls increased slightly, but not significantly, during GH
treatment. Apo-AII, Apo-B, and Apo-E levels in both sexes and Apo-CII
in boys did not change appreciably during the study. Lp(a) did not
change significantly in either sex during GH treatment. TC/HDLC and
Apo-B/Apo-AI ratios decreased during GH treatment in both sexes, as
shown in Figs. 2 and 3, but the decline reached statistical
significance only in boys (P < 0.01).
|
|
|
After GH treatment
Anthropometry and body composition. Height continued to
increase at a rate of less than 2.0 cm/yr in boys after the cessation
of GH treatment. There were no significant changes in either sex with
respect to other anthropometric data after discontinuation of GH (Table 1
). BF increased from 9.0% (4.7 kg) to 12.0% (6.3 kg) at 3 months
after the cessation of treatment and remained high thereafter in boys
(P < 0.01; Fig. 1). Girls also had an increase in BF
from 19.1% (7.9 kg) to 21.3% (9.0 kg) at 6 months after the cessation
of treatment, but the increase did not reach statistical significance.
Three months after the discontinuation of GH, LBM decreased from
47.4 ± 3.4 to 46.2 ± 3.2 kg in boys (P <
0.01), whereas there was no significant change in girls (Table 1).
Lipid profiles (Table 2). During the last 6 months of GH
treatment, both TC and LDLC still continued to decrease slightly, but
not statistically. In boys, mean TC and LDLC levels at 6 months after
the discontinuation of GH increased from 150.9 ± 22.7 to
158.6 ± 26.5 mg/dL and from 74.3 ± 24.1 to 83.9 ±
25.6 mg/dL (P < 0.05). These variables did not change
significantly in girls. Other lipoproteins did not change, except for
Lp(a), which decreased significantly from 22.9 ± 20.4 to
18.7 ± 17.6 mg/dL at 6 months after the cessation of GH treatment
only in boys (P < 0.01). The TC/HDLC ratio increased
slightly in boys, but the difference was not significant (Fig. 2). The
Apo-B/Apo-AI ratio decreased in girls at 6 months after discontinuing
GH treatment, with marginal significance (P < 0.05;
Fig. 3).
IGF-I. Six months after the discontinuation of GH, IGF-I decreased during 6 months from 650.8 to 456.3 ng/mL in boys and from 501.4 to 441 ng/mL in girls.
|
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Our subjects had a normal mean TC level at the start of GH treatment,
consistent with the results of several previous studies in children
with GH deficiency (14, 21, 26, 27, 28) but in contrast to the results of
others, which reported increased mean TC levels (8, 17, 18, 19, 20, 25). The
incidence of hypercholesterolemia (TC, >200 mg/dL) at the beginning of
GH treatment in our subjects (18%) was considerably higher than the
incidence in normal Japanese children (5%) (39). Controversy also
remains with regard to the effects of GH replacement therapy on TC.
Some studies found a significant reduction in TC after very short term
treatment (15, 16, 20), whereas others reported no significant
difference from baseline in TC after 4 months to 4 yr of treatment (14, 17, 18, 21, 25, 26, 27, 28). In our subjects, TC decreased by 14.6 mg/dL in
boys and 11.1 mg/dL in girls after 36 months of GH treatment. These
decreases in TC are similar to those found in normal Japanese children
between 9–13 yr of age at our institution (17 mg/dL in boys and 14
mg/dL in girls) as a result of decreases in LDLC and HDLC in boys and a
decrease in LDLC in girls (39). Changes in LDLC and HDLC during GH
treatment, however, differed considerably from those in normal
children.
As for the changes in LDLC, few data are available in children with GH deficiency compared with adults. Frindik et al. showed a high value of LDLC at baseline, with no significant change during GH treatment (21). Our study showed marked decreases in LDLC levels in both sexes (24.9 mg/dL in boys and 27.2 mg/dL in girls) after 3 yr of GH treatment in children with GH deficiency. An age-related decline in LDLC has also been observed in normal Japanese children (39). However, the decline in LDLC in the current study was about 2–3 times greater than that in normal children. The mechanism underlying the drop in LDLC is thought to involve a direct effect of GH on the expression of hepatic LDL receptors, which govern the plasma LDLC concentration (42).
Most studies in GH-deficient children have reported no change (17, 18, 21, 25, 27, 28) or a decrease in HDLC (16, 20) during GH treatment. Only our previous study has shown an initial rise followed by no change in HDLC in boys with GH deficiency (26). In the present study, we also found that HDLC remained high and stable in boys after 3 yr of GH treatment. This high HDLC level is quite interesting in view of the decrease in HDLC in normal Japanese boys entering puberty (39). In girls, the HDLC level remained constant during GH treatment, similar to that in normal Japanese girls, who show no change in HDLC with age (39). HDLC revealed a considerable gender difference in the response to GH treatment in our children with GH deficiency. The TC/HDLC ratio is constant with age among healthy Japanese children (39). In the present study, both boys and girls showed a decrease in the TC/HDLC ratio; however, the changes reached statistical significance only in boys, possibly due to the rapid elevation of HDLC detected only in boys.
GH treatment has been associated with a decrease (15), no change (8, 25, 27), or an increase in Apo-AI (28). In the present study, Apo-AI increased rapidly in boys, parallel to the change in HDLC. Girls also had a slight, but insignificant, increase in Apo-AI despite no change in HDLC. Apo-B did not change during GH treatment in either sex in our study, in agreement with the findings of some studies (25, 27, 28) but in contrast to the results of others that showed a decrease in Apo-B (8, 15). Further investigations are required to explain why LDLD decreased, but Apo-B did not in our study.
We have previously shown no change in Lp(a) levels during 12 months of GH treatment (27, 43). In the present study, the changes in Lp(a) during 36 months of GH treatment also did not reach statistical significance. This is inconsistent with the results of many other trials among adults with GH deficiency (44). It should be noted that Lp(a) appeared to increase transiently during the first year of treatment even in our study. Genetic differences, duration of treatment, or age-specific effects of GH may be responsible for the different results.
After discontinuation of the GH treatment, the percent BF increased rapidly and LBM decreased in boys, consistent with the results of previous studies (10, 45, 46, 47). Percent BF also slightly, but insignificantly, increased in girls after the withdrawal of GH. The physiological increase in the percent BF with age observed in healthy girls at these ages (41) makes it difficult to discuss net effects of GH on percent BF in our girls. The increase in BF (kilograms) may be attributed to an increase in the total body weight, as LBM did not increase in girls after discontinuation of GH.
It is also noteworthy that both TC and LDLC started to increase again after the cessation of GH treatment in both sexes, although a significant increase was noted only in boys. TC/HDLC and Apo-B/Apo-AI ratios also increased in boys after the discontinuation of GH treatment. These reversed alterations in lipid profiles were more striking in boys than in girls in the present study. These results may indicate an increased risk of atherosclerotic development in boys after the cessation of GH treatment.
The decline in Lp(a) in boys after the cessation of GH treatment did not lead us to the straightforward concept mentioned above. There were also considerable discrepancies in the Lp(a) at the 36th month of GH treatment and at the discontinuation of GH. As the subjects in the GH initiation group and those in the GH discontinuation group were different in this study, further investigation of identical subjects are required to evaluate the discrepancies and delineate the effects of GH treatment and its discontinuation on Lp(a).
There are several issues to be clarified in further studies. First, in the current study, the mean values of serum lipids were similar to those in normal children. However, the values could have become worse if untreated (29, 48). None of our subjects had hypercholesterolemia after 3 yr of GH treatment despite the increased prevalence of hypercholesterolemia before GH administration, suggesting that GH treatment prevented the values from worsening. Further long term study is required to prove the protective effects of GH treatment throughout life. Second, this study was underpowered to detect the modest influences of pubertal progress because of the limited number of girls at each pubertal stage, although it may affect both body composition and lipid metabolism (41, 49). Preliminary adjustment for puberty, dividing the subjects into those entering puberty during GH treatment and those who did not, however, revealed no changes in the results (data not shown).
We examined body composition and lipid profiles in boys and girls. Previous studies of adults with GH deficiency concluded that men are more responsive to GH treatment than women (50, 51). In children with GH deficiency, we also detected considerable gender differences in the responses of HDLC, Apo-AI, and ratios of TC/HDLC and Apo-B/Apo-AI during GH treatment and those of TC, LDLC, Apo-B/Apo-AI ratio, and Lp(a) after discontinuing GH treatment. Atherogenic risk factors were improved during GH treatment and worsened after discontinuation in boys, whereas the changes were somewhat equivocal in girls. Gender differences in the response to GH might be due to an effect of gonadal steroids. Further studies concerning gender and pubertal situation are needed to elucidate the influence of GH on atherogenic risk factors, especially in girls.
In conclusion, GH treatment has beneficial effects on body composition and lipid metabolism in both GH-deficient boys and girls with some gender differences. The reversal of these effects after discontinuation of GH treatment again suggests that GH-deficient children should benefit from continued GH treatment even after the completion of linear growth (52).
|
Footnotes |
|---|
Received March 19, 1998.
Revised July 9, 1998.
Accepted July 20, 1998.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  R. N. Dhir, C. Thangavel, and B. H. Shapiro Attenuated Expression of Episodic Growth Hormone-Induced CYP2C11 in Female Rats Associated with Suboptimal Activation of the Jak2/Stat5B and Other Modulating Signaling Pathways Drug Metab. Dispos., November 1, 2007; 35(11): 2102 - 2110. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Thangavel and B. H. Shapiro A Molecular Basis for the Sexually Dimorphic Response to Growth Hormone Endocrinology, June 1, 2007; 148(6): 2894 - 2903. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A Ciresi, M C Amato, A Criscimanna, A Mattina, C Vetro, A Galluzzo, G D'Acquisto, and C Giordano Metabolic parameters and adipokine profile during GH replacement therapy in children with GH deficiency Eur. J. Endocrinol., March 1, 2007; 156(3): 353 - 360. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Veldhuis, J. N. Roemmich, E. J. Richmond, and C. Y. Bowers Somatotropic and Gonadotropic Axes Linkages in Infancy, Childhood, and the Puberty-Adult Transition Endocr. Rev., April 1, 2006; 27(2): 101 - 140. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Salerno, V. Esposito, V. Farina, G. Radetti, A. Umbaldo, D. Capalbo, L. Spinelli, S. Muzzica, G. Lombardi, and A. Colao Improvement of Cardiac Performance and Cardiovascular Risk Factors in Children with GH Deficiency after Two Years of GH Replacement Therapy: An Observational, Open, Prospective, Case-Control Study J. Clin. Endocrinol. Metab., April 1, 2006; 91(4): 1288 - 1295. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Chihara, E. Koledova, A. Shimatsu, Y. Kato, H. Kohno, T. Tanaka, A. Teramoto, P. C Bates, and A. F Attanasio An individualized GH dose regimen for long-term GH treatment in Japanese patients with adult GH deficiency Eur. J. Endocrinol., July 1, 2005; 153(1): 57 - 65. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-C. Leung, G. Johannsson, G. M. Leong, and K. K. Y. Ho Estrogen Regulation of Growth Hormone Action Endocr. Rev., October 1, 2004; 25(5): 693 - 721. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. van Pareren, P. Mulder, M. Houdijk, M. Jansen, M. Reeser, and A. Hokken-Koelega Effect of Discontinuation of Growth Hormone Treatment on Risk Factors for Cardiovascular Disease in Adolescents Born Small for Gestational Age J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 347 - 353. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. K. van Pareren, S. M. P. F. de Muinck Keizer-Schrama, T. Stijnen, T. C. J. Sas, and S. L. S. Drop Effect of Discontinuation of Long-Term Growth Hormone Treatment on Carbohydrate Metabolism and Risk Factors for Cardiovascular Disease in Girls with Turner Syndrome J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5442 - 5448. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. T. Span, G. F. F. M. Pieters, F. G. J. Sweep, A. R. M. M. Hermus, and A. G. H. Smals Gender Differences in rhGH-Induced Changes in Body Composition in GH-Deficient Adults J. Clin. Endocrinol. Metab., September 1, 2001; 86(9): 4161 - 4165. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. M. K. Biller, G. Sesmilo, H. B. A. Baum, D. Hayden, D. Schoenfeld, and A. Klibanski Withdrawal of Long-Term Physiological Growth Hormone (GH) Administration: Differential Effects on Bone Density and Body Composition in Men with Adult-Onset GH Deficiency J. Clin. Endocrinol. Metab., March 1, 2000; 85(3): 970 - 976. [Abstract] [Full Text]
|
|
|
|
|
|
S. S. Damjanovic, M. S. Petakov, D. Micic, J. Marinkovic, C. Dieguez, F. F. Casanueva, and V. Popovic Serum Leptin Levels in Patients with Acromegaly before and after Correction of Hypersomatotropism by Trans-Sphenoidal Surgery J. Clin. Endocrinol. Metab., January 1, 2000; 85(1): 147 - 154. [Abstract] [Full Text]
|
|
|
|
|
|
J. Svensson, J.-O. Jansson, M. Ottosson, G. Johannsson, M.-R. Taskinen, O. Wiklund, and B.-A. Bengtsson Treatment of Obese Subjects with the Oral Growth Hormone Secretagogue MK-677 Affects Serum Concentrations of Several Lipoproteins, But Not Lipoprotein(a) J. Clin. Endocrinol. Metab., June 1, 1999; 84(6): 2028 - 2033. [Abstract] [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
) and girls (•). Bars represent
the SDs. Asterisks denote significant
differences (P < 0.05) vs. values
at the time of initiation (START) or discontinuation (STOP) of GH
treatment.
