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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-0981
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 4 1288-1295
Copyright © 2006 by The Endocrine Society

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

Mariacarolina Salerno, Valentina Esposito, Vincenzo Farina, Giorgio Radetti, Angela Umbaldo, Donatella Capalbo, Letizia Spinelli, Stefania Muzzica, Gaetano Lombardi and Annamaria Colao

Departments of Pediatrics (M.S., V.E., V.F., A.U., D.C., S.M.), Internal Medicine I (L.S.), and Molecular and Clinical Endocrinology and Oncology (G.L, A.C.), University "Federico II" of Naples, 80131 Naples, Italy; and Department of Pediatrics (G.R.), Regional Hospital of Bolzano, 39100 Bolzano, Italy

Address all correspondence and requests for reprints to: Mariacarolina Salerno, M.D., Ph.D., Department of Pediatrics, Federico II University of Naples, Via S. Pansini 5, 80131 Naples, Italy. E-mail: salerno{at}unina.it.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: GH deficiency (GHD) in adults is associated with a cluster of cardiovascular risk factors that may contribute to an increased mortality for cardiovascular disease.

Objective: The aim of this study was to evaluate the effect of GHD and GH replacement therapy on cardiac performance, lipid profile, and insulin resistance in children.

Design: This was a 2-yr case-control prospective study.

Patients: Thirty children with GHD aged 9.3 ± 0.5 yr and 30 healthy matched controls were studied.

Intervention: Children were studied before and after 1 and 2 yr of GH replacement (GHD children) or no treatment (controls).

Main Outcome Measures: Lipid profile, serum insulin levels, homeostasis model of assessment (HOMA) index, and left ventricular (LV) mass and function by echocardiography were the main outcome measures.

Results: At study entry, the LV mass index was significantly lower in GHD children (50.2 ± 1.7) than in controls (60.3 ± 2.5 g/m2; P < 0.002), whereas LV systolic and diastolic function, lipid profile, insulin levels, and HOMA index were similar. In GHD children LV mass index significantly increased (66.3 ± 2.4 g/m2; P < 0.0001) after 1 yr of GH replacement and remained stable thereafter. LV systolic and diastolic function did not change during treatment. After 2 yr of GH replacement, total cholesterol (P < 0.007) and the atherogenic index (P < 0.0001) significantly decreased, whereas fasting insulin levels (P < 0.001) and HOMA index (P < 0.0001) significantly increased compared with both pretreatment and control values.

Conclusions: GHD in children is associated with a reduced cardiac size but with a normal cardiac function, lipid profile, and insulin sensitivity. Two years of GH replacement normalizes cardiac morphology, improves lipid profile, and slightly impairs insulin sensitivity.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
THE PRIMARY GOAL of GH replacement in children is to promote linear growth and to normalize final height to within or above the genetic target. GH has, however, other important physiological functions that influence several key metabolic processes, body composition, muscle strength, and bone mineral density. It is now established that adults with GH deficiency (GHD) may develop a cluster of cardiovascular risk factors, including unfavorable lipid profile, increased body fat, premature atherosclerosis, decreased fibrinolytic activity, increased peripheral insulin resistance (1, 2), as well as reduced cardiac performance (3, 4), all of which may contribute to a reduced life expectancy with an increased mortality for cardiovascular disease (CVD) (5).

In adolescents with severe GHD, there is increasing evidence that suggests that the discontinuation of GH replacement therapy at completion of linear growth may result in adverse effects on body composition, lipid profile, bone mineral density, cardiac morphology, and performance. However, there is still debate as to whether these abnormalities may predispose these patients to increased cardiovascular morbidity (6, 7, 8, 9). The possibility that these changes may be a result of reversal of supraphysiological serum IGF-I due to the high GH doses used in some cases (6) should also be considered.

In contrast, relatively few studies have investigated whether or not children with GHD have metabolic and cardiac abnormalities that may place them at a higher risk of CVD at an early age. In the majority of these studies, lipoproteins in children with GHD are normal at baseline, but a beneficial effect of GH on lipid profile is observed during treatment (10, 11, 12, 13, 14). In addition, GH therapy reduces plasma homocysteine levels, which are increased in children with GHD (14, 15). Elevated plasma homocysteine levels are considered to be independent risk factors for CVD.

Only a few studies have investigated the effect of GHD and GH replacement therapy on cardiac performance in children with GHD (16, 17, 18). GHD in children was associated with reduced cardiac mass, which increased after 1 yr of GH replacement therapy (17, 18). Conversely, neither GHD nor GH replacement was associated with alteration of cardiac function in children (17, 18).

The existing evidence indicates that atherosclerotic CVD begins in childhood (19, 20). In children, obesity occurs with other risk factors for CVD, such as increased blood pressure, adverse changes in serum lipoproteins, and hyperinsulinemia, leading to acceleration of atherosclerotic lesion; therefore, the primary prevention of atherosclerotic CVD should begin in childhood.

The aim of this observational, open, prospective, case-control study was to investigate the cardiovascular risk of GHD in prepubertal children. Therefore, cardiac mass and function, lipid profile, and degree of insulin resistance were evaluated in children with GHD before and after 1 and 2 yr of GH replacement therapy and in age-, sex-, pubertal status-, body surface area-, and body mass index (BMI)-matched controls before and 1 and 2 yr of observation. Moreover, to investigate whether the severity of GHD was also correlated with the degree of cardiac and metabolic impairment, children were divided in two groups on the basis of GH response at stimulation tests.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

Thirty prepubertal children with GHD (18 boys and 12 girls) aged 9.3 ± 0.5 yr (range, 6.0–11.5 yr) were enrolled in the study. GHD was diagnosed according to clinical and auxological criteria (21) and by peak GH concentrations <10 µg/liter after two stimulation tests (mean peak GH after clonidine, 4.5 ± 0.5 µg/liter; after arginine, 3.5 ± 0.4 µg/liter). Twenty-seven children had isolated GHD; three had multiple pituitary hormone deficiency, and these children were receiving stable replacement with L-thyroxin, hydrocortisone, and 1-desamino-8-D-arginine vasopressin as necessary, before GHD was investigated. Magnetic resonance imaging of the hypothalamus-pituitary region documented pituitary hypoplasia in nine patients, ectopic posterior pituitary with stalk hypoplasia in five, empty sella in four, pituitary cyst in two, and craniopharyngioma in one. Before entry in the study, none of the patients received GH replacement. Previous or current CVD, respiratory, renal, or endocrine disease, or family history of CVD were exclusion criteria for entering the study.

Patients’ profile at study entry is summarized in Table 1Go. Height and target height (sex-corrected midparental height) were expressed as SD score (SDS) according to the standards of Tanner (22).


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  		TABLE 1. Clinical characteristics of the patients and controls at study entry

 
Controls

Thirty healthy children (18 boys), age, sex, pubertal status, body surface area, BMI, socioeconomic status, and geographic area matched with the patients, were enrolled in the study as controls. As for the patients, previous or current CVD respiratory, renal, or endocrine disease, or history of CVD were exclusion criteria.

Study protocol

At study entry, all subjects underwent measurement of height, weight, heart rate, systolic (SBP) and diastolic (DBP) blood pressure, serum IGF-I, total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglycerides, glucose and insulin levels, and echocardiography. We calculated the atherogenic index (AI) as the ratio of total/HDL cholesterol, considered as an index of severe cardiovascular risk (23). Low-density lipoprotein (LDL)-cholesterol was calculated using the Friedewald formula (24). Insulin resistance was evaluated by the homeostasis model assessment (HOMA) score, by applying the formula of Matthews et al. (25) [fasting serum insulin (microunits per milliliter) x fasting plasma glucose (millimoles per liter)/22.5].

In children with GHD, the evaluation of these parameters was also repeated after 1 and 2 yr of GH replacement therapy, whereas in controls evaluation was repeated after 1 and 2 yr of follow-up. Children with GHD were treated with a 30 µg/kg·d dose of GH (21).

To investigate whether the severity of GHD was correlated with the degree of cardiac impairment, children were divided in two groups on the basis of GH peak after stimulation tests. The group with severe GHD (n = 13) was characterized by a GH peak less than 5 µg/liter at both stimulation tests (range, 0.3–4.9 µg/liter); the group with partial GHD (n = 17) was characterized by a GH peak concentration above 5 µg/liter at one or both stimulation tests (range, 5.0- 9.5 µg/liter). Informed parental consent to participate in the study was obtained for both patients and controls.

Echocardiography

M-mode, two-dimensional, and pulsed Doppler echocardiographic studies were performed with ultrasound systems (Sonos 2000; Agilent Technologies, Andover, MS) using a 3.5-mHz transducer, during at least three consecutive cardiac cycles. The records were made by two investigators (L.S. and V.F.) blind in respect to the patients’ status. All patients were studied in the left lateral recumbent position after a 10 min resting period according to the recommendations of the American Society of Echocardiography (26). The following measurements were recorded: interventricular septum thickness (IST), left ventricular (LV) posterior wall thickness (LVPWT), and LV end-systolic (LVESD) and end-diastolic (LVEDD) diameter; LV end-diastolic volume (LVEDV) and end-systolic volume (LVESV) were calculated according to the Simpson algorithm (27). The LV ejection fraction (LVEF) was calculated using the following formula: LVEF% = (LVEDV – LVESV)/LVEDV x 100. The fractional shortening (FS) percentage was calculated using the following formula: FS% = (LVEDD – LVESD)/LVEDD x 100. The LV mass (LVM) was calculated by using Devereux’s formula according to Penn’s convention with the regression-corrected cube formula LVM = 1.04[(ISV + LVEDD + PWT)3 – (LVEDD)3] – 13.8 g, and expressed by LVM index (LVMi) after correction for BSA. Doppler studies provided indexes of ventricular filling that were derived from the mitral flow velocity curves, i.e. maximal early diastolic flow velocity (E in centimeters per second), maximal late diastolic flow velocity (A in centimeters per second), and the ratio between E and A curves (E/A, normal value >1); the isovolumetric relaxation time (IRT), which represents the interval between the end of aortic valve closure and the onset of mitral valve opening, was also evaluated.

Assays

Serum GH levels were measured by immunoradiometric assay using commercially available kits (HGH-CTK-IRMA; Sorin, Saluggia, Italy). The sensitivity of the assay was 0.2 µg/liter. The intraassay and interassay coefficients of variation were 4.5 and 7.9%, respectively. Plasma IGF-I was measured using two-site immunoradiometric assay kit (Diagnostics System Laboratories, Webster, TX). Values were expressed as SDS according to the normative data provided by the manufacturer. The IGF-I intraassay and interassay coefficients of variation were 3.4 and 8.2% respectively.

Statistical analysis

All data are reported as mean ± SEM unless otherwise specified. The statistical analysis was performed by a package from SPSS (Chicago, IL). All of the variables evaluated in our study have been screened for normality before statistical analysis; skewness and kurtosis have been estimated for all variables, and in no case did these parameters suggest a major deviation from normality, because a Kolmogorov-Smirnov test of normality did not show significant deviation from normality.

Comparisons between patients and controls, patients with severe and those with partial GHD, and between males and females with GHD were performed by paired or unpaired Student’s t test as appropriate.

To evaluate differences between repeated measurements before and during GH treatment in GHD patients and over time taking into account the correlation from within subject’s data, a generalized linear model for repeated-measures ANOVA was adopted. The F test provides the estimate of the differences over time and treatment with respect to baseline. Linear component over time has also been estimated. This method does incorporate dependency within an experimental unit and compare contrasts among groups, not raw values.

Pearson’s correlation coefficient was calculated to test the relationship between variables. Significance was set at 5%.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Clinical, hormonal, and cardiovascular parameters in controls and in GHD patients at baseline and during GH replacement therapy are reported in Table 2Go. At study entry, height and serum IGF-I, as expected, were significantly lower in GHD subjects than in healthy children (P < 0.0001). During years 1 and 2 of GH therapy, both height (P < 0.0001) and serum IGF-I (P < 0.0001) significantly increased, becoming similar to the control group.


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  		TABLE 2. Clinical, hormonal, and cardiac changes over 2 yr of GH replacement therapy in patients with GHD compared with controls

 
Cardiac morphology and function

At study entry, heart rate, SBP, and DBP were similar in the two groups. During years 1 and 2 of GH therapy, heart rate, SBP, and DBP remained unchanged.

As shown in Table 2Go, LVPWT, LVEDD, and LVMi were significantly reduced in GHD children compared with controls (P < 0.002). LV systolic function, measured by FS and LVEF, and diastolic function, measured by E/A ratio and IRT, were similar in GHD children and controls. IST, LVPWT, LVESD, LVEDD, and LVMi significantly increased during the first year of GH therapy compared with pretreatment values (P < 0.0001) and then remained unchanged during the second year of GH replacement. LV systolic performance and diastolic filling did not change significantly during treatment (Table 2Go). After 2 yr, LVMi in children with GHD was similar to that measured in controls; none of the patients developed cardiac hypertrophy. The increase of LVMi was significantly correlated with the increase of IGF-I levels (r = 0.63; P < 0.0001).

No significant differences were observed in cardiac morphology and function between males and females with GHD both at baseline (LVMi, 50.4 ± 2.0 vs. 50.2 ± 3.0 g/m2; LVEF, 65.7 ± 1.4 vs. 64.4 ± 1.7%; E/A, 1.8 ± 0.1 vs. 1.8 ± 0.2, respectively) and after 2 yr of GH replacement therapy (LVMi, 67.8 ± 2.0 vs. 68.5 ± 2.5 g/m2; LVEF, 63.9 ± 1.1 vs. 66.6 ± 1.5%; E/A, 1.8 ± 0.1 vs. 1.8 ± 0.2, respectively). In both males and females, LVMi significantly improved after 2 yr of therapy (P < 0.0001), whereas cardiac function remained unchanged.

Metabolic and lipid profile

At baseline BMI, lipid profile, fasting blood glucose and insulin levels, as well as HOMA index were comparable with those recorded in the control group (Table 3Go). After 2 yr of GH replacement therapy, BMI remained unchanged and total cholesterol and AI significantly decreased compared with both pretreatment (P < 0.007 and P < 0.0001, respectively) and control (P < 0.0001 and P < 0.03, respectively) values. The decrease in AI was significantly correlated with the increase in IGF-I levels (r = –0.26; P < 0.05). A mild increase in fasting insulin levels and HOMA index was observed, both values being higher than baseline (P < 0.001 and P < 0.0001, respectively) and control (P < 0.01) values after 2 yr of GH therapy. These values were, however, within the normal range for age (28).


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  		TABLE 3. Clinical and metabolic parameters in patients with GHD at baseline and over 2 yr of GH replacement therapy compared with controls

 
No significant differences between males and females with GHD were observed in metabolic parameters at baseline and after GH replacement therapy (data not shown). AI decreased from 3.5 ± 0.2 to 2.4 ± 0.1 (P < 0.005) in males and from 3.6 ± 0.3 to 2.4 ± 0.1 (P < 0.0001) in females after 2 yr of GH treatment, whereas a mild increase in HOMA index was observed compared with baseline values in both males (from 0.7 ± 0.07 to 1.8 ± 0.2; P < 0.003) and females (from 0.8 ± 0.1 to 2.3 ± 0.3; P < 0.009).

Cardiovascular and metabolic findings in children with severe GHD

In 13 children with severe GHD, LVPWT (5.1 ± 0.3 mm), LVESD (20.8 ± 0.5 mm), LVEDD (34.4 ± 0.8 mm), and LVMi (46.3 ± 1.6 g/m2) were significantly reduced compared with the 17 children with partial GHD (LVPWT, 5.7 ± 0.9 mm, P < 0.04; LVEDS, 22.9 ± 0.8 mm, P < 0.03; LVEDD, 36.7 ± 0.8 mm, P < 0.05; LVMi, 53.0 ± 2.2 g/m2, P < 0.03). The LVMi was, however, significantly reduced also in the group with partial GHD compared with controls (60.3 ± 2.5 g/m2; P < 0.005) (Fig. 1Go). Cardiac function was similar in children with severe or partial GHD (data not shown). At baseline, HDL cholesterol (1.2 ± 0.1 vs. 1.5 ± 0.1 mmol/liter; P < 0.02) was lower in children with severe than in those with partial GHD, whereas AI (3.7 ± 0.3 vs. 3.0 ± 0.1; P < 0.03) was significantly higher in children with severe than in those with partial GHD. A significant decrease in AI was observed during GH replacement in both children with severe GHD (to 3.0 ± 0.3 after 1 yr and to 2.6 ± 0.3 after 2 yr; P < 0.01) and partial GHD (to 2.5 ± 0.2 after 1 yr and to 2.3 ± 0.1 after 2 yr; P < 0.0001) (Fig. 2Go). At study entry, the HOMA index was comparable with controls (0.8 ± 0.3) in both severe GHD (0.8 ± 0.4) and partial GHD (0.6 ± 0.1) children. During GH treatment, the HOMA index increased more significantly in the group with partial GHD (to 1.4 ± 0.4 after 1 yr and to 2.2 ± 0.4 after 2 yr of GH; P < 0.003). After 2 yr of therapy, the HOMA index was higher in the group with partial GHD than in controls (0.9 ± 0.3; P < 0.02), although the increase was not statistically significant compared with children with severe GHD (1.3 ± 0.2; P < 0.08) (Fig. 3Go). At 2 yr, the dose of GH received by children with partial GHD (35 ± 0.8 µg/kg·d) was higher than that received by the group with severe GHD (30 ± 1.0 µg/kg·d; P < 0.002).


Figure 1
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  		FIG. 1. Mean ± SEM measurements of the LVMi, before and during 2-yr GH therapy, in children with severe GHD compared with children with partial GHD and controls. *, P < 0.03 comparing children with severe vs. partial GHD at study entry. §, P < 0.005 comparing both children with severe and partial GHD vs. controls at study entry.

 

Figure 2
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  		FIG. 2. Mean ± SEM values of AI in children with severe GHD compared with children with partial GHD and controls, before and during 2-yr GH therapy. *, P < 0.03 comparing children with severe vs. partial GHD at study entry. §, P < 0.01 analyzing the effect of GH treatment during the study in the group with severe GHD. #, P < 0.0001 analyzing the effect of GH treatment in the group with partial GHD.

 

Figure 3
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  		FIG. 3. Mean ± SEM values of the HOMA index in children with severe GHD compared with children with partial GHD and controls before and during 2 yr of GH therapy. *, P < 0.003 analyzing the effect of GH treatment during the study in the group with partial GHD. §, P < 0.02 comparing children with partial GHD vs. controls after 2 yr of follow-up.

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
A large number of studies have documented that adults (1, 2, 3, 4, 5) as well as adolescents (6, 7, 8, 29) with severe GHD have a cluster of cardiovascular risk factors that could place them at a higher risk of cardiovascular morbidity. It is now established that atherosclerotic CVD begins in childhood (19, 20). Relatively few studies, however, have investigated whether GHD in children is associated with increased risk factors for CVD. Shulman et al. (17) in a prospective, uncontrolled, study enrolling 10 children with GHD documented a reduced LVM that significantly increased after 1 yr of GH therapy, whereas cardiac function was not modified. The major drawback of the study by Shulman et al. was the lack of a control group. In a previous short-term case-control study (18), we also demonstrated that heart size was significantly reduced in 12 GHD children and increased significantly after 1 yr of GH replacement.

The results of the current observational, open, prospective, case-control study further support the evidence of a significant reduction in cardiac size without changes of cardiac function in children with GHD. One year of GH replacement normalizes IGF-I levels and cardiac mass, and prolonged GH replacement for 2 yr does not further modify cardiac morphology and function. Therefore, replacement GH treatment, in the dose of 30 µg/kg·d, does not have any hypertrophic effect on the heart.

In a previous study on 14 adolescents with partial GHD, Radetti et al. (16) reported that LVM and systolic and diastolic functions did not differ from a control group after 1 yr of GH therapy at a relatively high dose of GH (44 µg/kg·d). After 5 yr of GH treatment, however, an increase in LVM and a mild impairment in LV diastolic function was observed (16). The major drawback of that study was the lack of baseline data. The different results with respect to the present study may depend on different GH dosages, duration of GH treatment, and degree of GHD. In particular, the different degree of GHD may result in a different response to GH replacement, which might ultimately result in a varied increase in cardiac size. The results of the present study indicate that children with severe GHD have a more evident reduction in LVM than children with partial GHD, although in both groups LVM was significantly reduced compared with controls. Using a standard dose of GH, we did not observe any different response between the two groups. After 2 yr of GH replacement, severe GHD, partial GHD, and controls had similar cardiac size. Altogether, these results indicate that GH, directly or indirectly through IGF-I, is not only involved in the regulation of somatic growth in children but also in cardiac growth, probably through the modulation of the size of cardiomyocytes (30).

We did not observe significant gender-related differences on cardiac mass and function both at baseline and in the long-term effects of GH replacement therapy.

Several studies have investigated plasma lipoproteins in children with GHD, providing conflicting results (10, 11, 13, 14, 15). In adults with untreated GHD and in adolescents with severe childhood-onset GHD at discontinuation of GH, the most common lipid pattern is represented by increased total and LDL cholesterol and decreased HDL cholesterol levels, increased triglycerides, and AI (1, 7, 8, 31). Conversely, the majority of the studies in children with GHD failed to find abnormalities in the lipid profile at baseline (10, 11, 13, 14, 15). The difference between adults and children with GHD may reflect the population trend for a rise in cholesterol and LDL cholesterol with increasing age.

In the present study, as in our previous studies (14, 18), we did not find any difference in lipid profile between GHD children and controls at baseline. During 2 yr of GH treatment, we observed an improvement in lipid profile, with a significant decrease in total cholesterol and in AI compared with both the baseline and the control levels. In agreement with others (12), we did not observe significant gender-related differences in the long-term effects of GH replacement therapy.

This beneficial effect of GH treatment on AI has been reported in other short- and long-term studies evaluating the efficacy of GH therapy on lipid profile in GHD children (10, 11, 12, 14). In a 6 yr follow-up study, van der Sluis et al. (13) documented a long-term beneficial effect of GH therapy on AI, as well as on HDL cholesterol in GHD children. It is well known that abnormalities in lipid profile may severely increase the coronary risk of GHD patients (32); thus, the decrease in the total/HDL cholesterol ratio during GH therapy can be clinically relevant to the prevention of CVD in midlife, because it represents one of the most efficient predictors of coronary heart disease in adults (33).

The exact mechanisms that underlie these changes are not fully understood, but GH may act through the regulation of both the activity of the cholesterol 7 {alpha}-hydroxylase enzyme and the regulation of LDL cholesterol receptor numbers (34). However, other mechanisms are likely to be involved and require additional investigation.

Concern has been expressed that GH administration in children and adolescents may cause or exacerbate, in predisposed individuals, type 2 diabetes mellitus (35). The effect of GH treatment in adults with GHD on glucose metabolism is still a matter of debate. Most short-term studies have reported a deterioration of insulin sensitivity, whereas long-term studies suggested that, after an initial worsening, insulin sensitivity returned toward baseline values (36). Children with GHD do not have insulin resistance at baseline; on the contrary, they have in infancy a tendency toward fasting hypoglycemia, whereas susceptibility to hypoglycemia diminishes with age and paradoxically GH-deficient adults may show insulin resistance even before GH replacement therapy. The effect of GH therapy on glucose metabolism in children with GHD has not been extensively investigated. Previous studies in short children have shown that short-term GH replacement was associated with development of insulin resistance and peripheral hyperinsulinemia, as measured by the hyperglycemic clamp technique or using oral glucose tolerance testing, even if insulin levels remained within the physiological range of normal control children (37, 38). In short small-for-gestational-age children, GH replacement induces high fasting insulin levels with normal glucose levels, suggesting insulin resistance in these patients. However, 6 months after GH discontinuation, insulin levels returned to normal values compared with a control group (39). No case of impaired glucose tolerance or diabetes was recorded in a large group of 128 GHD children treated with GH for a period of 6 yr, but a significant decrease in insulin sensitivity was detected during the first year of GH therapy (40).

In the present study, we observed a mild increase in insulin resistance after 2 yr of GH treatment, especially in children with partial GHD who were receiving a slightly higher dose of GH. However, additional follow-up is necessary to evaluate whether insulin sensitivity will continue to worsen as an effect of GH therapy, or this mild increase may instead represent a component of the anabolic process of somatic development as is clearly evident in puberty.

In conclusion, GHD in children is associated with a significantly reduced cardiac size and with a normal cardiac function. Two years of GH replacement normalizes cardiac morphology and does not modify cardiac function. GHD is not associated with a clear-cut impairment of lipid profile, but 2 yr of GH replacement therapy exerts a beneficial effect on it by reducing total cholesterol and AI. On the contrary, a trend toward an increase in insulin resistance is observed during GH treatment. The potential long-term negative effect of insulin resistance determined by GH replacement on cardiovascular morbidity is still to be determined.


   Acknowledgments
 
We thank Prof. Luigi Greco for his useful advice in the statistical analysis of the data.


   Footnotes
 
The authors have nothing to declare.

First Published Online January 10, 2006

Abbreviations: AI, Atherogenic index; BMI, body mass index; CVD, cardiovascular disease; DBP, diastolic blood pressure; E/A, ratio between maximal early diastolic flow velocity and maximal late diastolic flow velocity; FS, fractional shortening; GHD, GH deficiency; HDL, high-density lipoprotein; HOMA, homeostasis model of assessment; IRT, isovolumetric relaxation time; IST, interventricular septum thickness; LDL, low-density lipoprotein; LV, left ventricular; LVEDD, LV end-diastolic diameter; LVEDV, LV end-diastolic volume; LVEF, LV ejection fraction; LVESD, LV end-systolic diameter; LVESV, LV end-systolic volume; LVM, LV mass; LVMi, LV mass index; LVPWT, LV posterior wall thickness; SBP, systolic blood pressure; SDS, SD score.

Received May 4, 2005.

Accepted January 4, 2006.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Carrol PV, Christ ER 1998 Growth hormone deficiency in adulthood and the effect of growth hormone replacement: a review. J Clin Endocrinol Metab 83:382–395[Abstract/Free Full Text]
  2. Sesmilo G, Biller BM, Llevadot J, Hayden D, Hanson G, Rifai N, Klibanski A 2000 Effects of growth hormone administration on inflammatory and other cardiovascular risk markers in men with growth hormone deficiency. A randomized, controlled clinical trial. Ann Intern Med 133:111–122[Abstract/Free Full Text]
  3. Colao A, Marzullo P, Di Somma C, Lombardi G 2001 Growth hormone and the heart. Clin Endocrinol (Oxf) 54:137–154[CrossRef][Medline]
  4. McCallum RW, Petrie JR, Dominiczak AF, Connell JM 2002 Growth hormone deficiency and vascular risk. Clin Endocrinol (Oxf) 57:11–24[CrossRef][Medline]
  5. Rosen T, Bengtsson BA 1990 Premature mortality due to cardiovascular disease in hypopituitarism. Lancet 336:285–288[CrossRef][Medline]
  6. Johannsson G, Albertsson-Wikland K, Bengtsson BA 1999 Discontinuation of growth hormone (GH) treatment: metabolic effects in GH-deficient and GH-sufficient adolescent patients compared with control subjects. Swedish Study Group for Growth Hormone Treatment in Children. J Clin Endocrinol Metab 84:4516–4524[Abstract/Free Full Text]
  7. Lanes R. Gunczler P, Lopez E, Esaa S, Villaroel O, Revel-Chion R 2001 Cardiac mass and function, cariotid artery intima-media thickness, and lipoprotein levels in growth hormone-deficient adolescents. J Clin Endocrinol Metab 86:1061–1065[Abstract/Free Full Text]
  8. Colao A, Di Somma C, Salerno M, Spinelli L Orio F, Lombardi G 2002 The cardiovascular risk of GH-deficient adolescents. J Clin Endocrinol Metab 87:3650–3655[Abstract/Free Full Text]
  9. Carroll PV, Drake WM, Maher KT, Metcalfe K, Shaw NJ, Dunger DB, Cheetham TD, Camacho-Hubner C, Savage MO, Monson JP 2004 Comparison of continuation or cessation of growth hormone (GH) therapy on body composition and metabolic status in adolescents with severe GH deficiency at completion of linear growth. J Clin Endocrinol Metab 89:3890–3895[Abstract/Free Full Text]
  10. Kohno H, Ueyama N, Yanai S, Ukaji K, Honda S 1994 Beneficial effect of growth hormone on atherogenic risk in children with growth hormone deficiency. J Pediatr 126:953–955
  11. Boot AM, Engels MAMJ, Boerma GJM, Krenning EP, De Muinck Keizer-Schrama SMPF 1997 Changes in bone mineral density, body composition, and lipid metabolism during growth hormone (GH) treatment in children with GH deficiency. J Clin Endocrinol Metab 82:2423–2428[Abstract/Free Full Text]
  12. Kuromaru R, Kohno H, Ueyama N, Hassan HM, Honda S, Hara T 1998 Long-term prospective study of body composition and lipid profiles during and after growth hormone (GH) treatment in children with GH deficiency: gender-specific metabolic effects. J Clin Endocrinol Metab 83:3890–3896[Abstract/Free Full Text]
  13. van der Sluis IM, Boot AM, Hop WC, De Rijke YB, Krenning EP, de Muinck Keizer-Schrama SM 2002 Long-term effects of growth hormone therapy on bone mineral density, body composition, and serum lipid levels in growth hormone deficient children: a 6-year follow-up study. Horm Res 58:207–214[CrossRef][Medline]
  14. Esposito V, Di Biase S, Lettiero T, Labella D, Simeone R, Salerno M 2004 Serum homocysteine concentrations in children with growth hormone (GH) deficiency before and after 12 months GH replacement. Clin Endocrinol (Oxf) 61:607–611[Medline]
  15. Lanes R, Paoli M, Carrillo E, Villaroel O, Palacios A 2003 Cardiovascular risk of young growth-hormone-deficient adolescents. Differences in growth-hormone-treated and untreated patients. Horm Res 60:291–296[CrossRef][Medline]
  16. Radetti G, Crepaz R, Paganini C, Gentili L, Pitscheider W 1999 Medium-term cardiovascular effects of high-dose growth hormone treatment in growth hormone-deficient children. Horm Res 52:247–252[Medline]
  17. Shulman DI, Root AW, Diamond FB, Bercu BB, Martinez R, Boucek RJ 2003 Effect of one year of recombinant human growth hormone (GH) therapy on cardiac mass and function in children with classical GH deficiency. J Clin Endocrinol Metab 88:4095–4099[Abstract/Free Full Text]
  18. Salerno M, Esposito V, Spinelli L, Di Somma C, Farina V, Muzzica S, de Horatio LT, Lombardi G, Colao A 2004 Left ventricular mass and function in children with GH deficiency before and during 12 months GH replacement therapy. Clin Endocrinol (Oxf) 60:630–636[CrossRef][Medline]
  19. Berenson GS, Srinivasan SR, Nicklas TA 1998 Atherosclerosis: a nutritional disease of childhood. Am J Cardiol 82:22T–29T
  20. Kavey RE, Daniels SR, Lauer RM, Atkins DL, Hayman LL, Taubert K; American Heart Association 2003 American Heart Association guidelines for primary prevention of atherosclerotic cardiovascular disease beginning in childhood. Circulation 107:1562–1566[CrossRef][Medline]
  21. GH Research Society 2000 Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary of the GH research society. J Clin Endocrinol Metab 85:3990–3993[Free Full Text]
  22. Tanner JM, Whitehosue RH, Takaishi M 1966 Standards from birth to maturity for height, weight, height velocity and weight velocity: British children, 1965. Arch Dis Child 41:613–635[Medline]
  23. Castelli WP 1996 Lipid, risk factors and ischaemic heart disease. Atherosclerosis 124:S1–S9
  24. Friedewald WT, Levy RI, Fredrickson DS 1972 Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18:499–502[Abstract]
  25. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC 1985 Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419[CrossRef][Medline]
  26. Feigenbaum H 1979 Echocardiography. 2nd ed. Philadelphia: Lea and Febiger
  27. Schiller NB 1991 Two-dimensional echocardiographic determination of left ventricular volume, systolic function, and mass. Summary and discussion of the 1989 recommendations of the American Society of Echocardiography. Circulation 84(Suppl 3):I280–I287
  28. Hrebicek J, Janout V, Malincikova J, Horakova D, Cizek L 2002 Detection of insulin resistance by simple quantitative insulin sensitivity check index QUICKI for epidemiological assessment and prevention. J Clin Endocrinol Metab 87:144–147[Abstract/Free Full Text]
  29. Colao A, Di Somma C, Rota F, Di Maio S, Salerno M, Klain A, Spiezia S, Lombardi G 2005 Common carotid intima-media thickness in growth hormone (GH)-deficient adolescents: a prospective study after GH withdrawal and restarting GH replacement. J Clin Endocrinol Metab 90:2659–2665[Abstract/Free Full Text]
  30. Cittadini A, Stromer H, Katz SE, Clark R, Moses AC, Morgan JP, Douglas PS 1996 Differential cardiac effects of growth hormone and insulin-like growth factor-1 in the rat. A combined in vivo and in vitro evaluation. Circulation 93:800–809[Medline]
  31. Boger RH, Skaminra C, Bode-Boger SM, Brabant C, Von Zur Muhlen A, Frolich JC 1996 Nitric oxide mediates the hemodynamic effects of recombinant growth hormone in patients with acquired growth hormone deficiency. J Clin Invest 98:2706–2713[Medline]
  32. Abdu TA, Neary R, Elhadd TA, Akber M, Clayton RN 2001 Coronary risk in growth hormone deficient hypopituitary adults: increased predicted risk is due largely to lipid profile abnormalities. Clin Endocrinol (Oxf) 55:209–216[CrossRef][Medline]
  33. Kannel WB, Wilson PWF 1992 Efficacy of lipid profiles in prediction of coronary disease. Am Heart J 124:768–774[CrossRef][Medline]
  34. Rudling M, Parini P, Angelin B 1997 Growth hormone and bile acid synthesis. Key role for the activity of hepatic microsomal cholesterol 7{alpha}-hydroxylase in the rat. J Clin Invest 99:2239–2245[Medline]
  35. Cutfield WS, Wilton P, Bennmarker H, Albertsson-Wikland K, Chatelain P, Ranke MB, Price DA 2000 Incidence of diabetes mellitus and impaired glucose tolerance in children and adolescents receiving growth-hormone treatment. Lancet 355:610–613[CrossRef][Medline]
  36. Giavoli C, Porretti S, Ronchi CL, Cappiello V, Ferrante E, Orsi E, Arosio M, Beck-Peccoz P 2004 Long-term monitoring of insulin sensitivity in growth hormone-deficient adults on substitutive recombinant human growth hormone therapy. Metabolism 53:740–743[Medline]
  37. Heptulla RA, Boulware SD, Caprio S, Silver D, Sherwin RS, Tamborlane WV 1997 Decreased insulin sensitivity and compensatory hyperinsulinemia after hormone treatment in children with short stature. J Clin Endocrinol Metab 82:3234–3238[Abstract/Free Full Text]
  38. Walker J, Chaussain JL, Bougneres PF 1989 Growth hormone treatment of children with short stature increases insulin secretion but does not impair glucose disposal. J Clin Endocrinol Metab 69:253–258[Abstract]
  39. Hokken-Koelega AC, De Waal WJ, Sas TC, Van Pareren Y, Arends NJ 2004 Small for gestational age (SGA): endocrine and metabolic consequences and effects of growth hormone treatment. J Pediatr Endocrinol Metab 17(Suppl 3):463–469
  40. Radetti G, Pasquino B, Gottardi E, Contadin IB, Rigon F, Aimaretti G 2004 Insulin sensitivity in growth hormone-deficient children: influence of replacement treatment. Clin Endocrinol (Oxf) 61:473–477[CrossRef][Medline]



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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.
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Is left ventricular performance effectively preserved in children with growth hormone deficiency?
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