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Cardiac Mass and Function, Carotid Artery Intima-Media Thickness, and Lipoprotein Levels in Growth Hormone-Deficient Adolescents

Pediatric Endocrine Unit (R.L., P.G., S.E.) and Division of Cardiology (E.L., R.R.-C.), Hospital de Clinicas Caracas, and Endocrine Research Laboratory (O.V.), Hospital Central "Dr. Carlos Arvelo," Caracas, Venezuela

Address correspondence and requests for reprints to: Roberto Lanes, M.D., M-209, P.O. Box 020010, Miami, Florida 33102. E-mail: lanes{at}telcel.net.ve

	Abstract

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The objective of our study was to evaluate whether cardiac mass and function, carotid artery intima-media thickness, and serum lipid and lipoprotein(a) levels are abnormal in adolescents with GH deficiency.

Young adults with childhood-onset and adulthood-onset GH deficiency have been found to have a higher cardiovascular risk, as manifested among other factors by reduced left ventricular mass, impaired systolic function, significant increase in arterial intima-media thickness, and dyslipidemia.

Twelve adolescents (seven males and five females) with GH deficiency (10 idiopathic and 2 organic), with an age of 14.2 ± 2.8 yr and a height of 140.6 ± 17.9 cm (height SD score, -2.6 ± 0.3), were studied. Six children had received GH in the past but were off therapy for several years, whereas six patients had never been treated with GH. Fasting blood samples were obtained for serum lipids and lipoprotein(a) analysis. Patients underwent transthoracic M-mode and two-dimensional echocardiographic evaluation for measurement of interventricular septal thickness, left ventricular posterior wall thickness, and left ventricular mass, as well as left ventricular ejection fraction at rest and pulmonary venous flow velocities; carotid artery intima-media thickness was measured using high-resolution mode B ultrasound. Seven GH-deficient (GHD) adolescents on GH at the time of the study and 19 healthy adolescents, all comparable for age, pubertal status, height, weight, blood pressure, and pulse, participated in this study as controls.

Interventricular septal thickness (6.5 ± 1.3 vs. 7.0 ± 1.5 mm), left ventricular posterior wall thickness (7.0 ± 1.8 vs. 7.5 ± 2.0 mm), and left ventricular mass after correction for body surface area (71.2 ± 21.8 vs. 70.7 ± 18.0 g/m²) were similar in untreated GHD patients and healthy controls. Similarly, the left ventricular ejection fraction at rest was similar in untreated GHD subjects and controls (70.0 ± 0.7 vs. 70.0 ± 0.6%), as were the pulmonary venous flow velocities (0.54 ± 0.16 vs. 0.55 ± 0.10 m/s for diastolic peak velocity; 0.51 ± 0.16 vs. 0.50 ± 0.09 m/s for systolic peak velocity; and 0.19 ± 0.06 vs. 0.19 ± 0.05 m/s for atrial reversal filling). Carotid artery intima-media thickness (0.60 ± 0.02 mm and 0.59 ± 0.02 mm for the right and left carotid arteries, respectively) was also normal in our untreated GHD patients when compared with healthy controls. In addition, all echocardiographic measurements were similar in GHD subjects on or off GH at the time of the study.

Low-density lipoprotein cholesterol levels were increased in untreated GHD patients when compared with healthy controls (3.17 ± 0.70 vs. 2.33 ± 0.36 mmol/L; P < 0.01), whereas total cholesterol, high-density lipoprotein cholesterol, and triglyceride concentrations were similar to that of controls. Total cholesterol levels were increased in our untreated GHD adolescents when compared with GHD subjects receiving GH therapy at the time of the study, while low-density lipoprotein cholesterol and triglyceride levels were also elevated, although not significantly. Lipoprotein(a) levels were elevated in untreated GHD adolescents when compared with healthy controls, and untreated GHD subjects had higher lipoprotein(a) concentrations than GH-treated patients.

GHD adolescents, regardless of whether or not they received GH therapy, do not seem to show alterations in cardiac mass and function or early atherosclerotic changes. They must, however, be followed carefully because they already present cardiovascular risk factors such as dyslipidemia, which may increase their cardiovascular morbidity over time.

	Introduction

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GH DEFICIENCY has been implicated in the regulation of cardiovascular function and has been postulated to be one of the main factors responsible for the increased mortality from cardiovascular disease in both young and older patients with childhood- and adulthood-onset GH deficiency (1, 2, 3).

Adult subjects with GH deficiency have been shown to have increased cardiovascular risk factors, including hyperlipidemia, an increase of body fat, premature atherosclerosis, decreased fibrinolytic activity, increased peripheral insulin resistance, increased frequency of impaired glucose tolerance, abnormal cardiac structure, and impaired cardiac performance (4, 5). The impairment of cardiac performance is manifested primarily by a reduction in left ventricular mass, inadequacy of ejection fraction, and abnormalities of left ventricular diastolic filling in patients with both childhood-onset and adulthood-onset GH deficiency (5, 6, 7).

Short- and long-term GH treatment has been shown to exert beneficial effects on abdominal fat distribution, low-density lipoprotein (LDL) cholesterol, and to enhance cardiac function, increase cardiac mass, and reverse diastolic abnormalities in adults with hypopituitarism and GH deficiency (8, 9). However, it remains to be seen whether GH replacement therapy will reduce the cardiac death rate of these patients.

Young GH-deficient (GHD) adults have been shown to have an increased number of atheromatous plaques in the carotid and the femoral arteries. Increased intima-media thickness of the carotid arteries, increased stiffness of the carotid artery wall, and impaired flow-mediated endothelium-dependent dilation of the brachial artery have also been reported in this group of patients (10, 11). GH treatment of hypopituitary GHD men has recently been found to reverse early morphological and functional atherosclerotic changes in major arteries and may be indicative of a beneficial effect of GH treatment on the vascular system (11, 12).

Adolescents with GH deficiency may already present some early cardiovascular alterations, which may place them at a higher risk for cardiovascular disease at an early age, although, to our knowledge, the echocardiographic status of the heart and the carotid arteries has not been studied in GHD patients of this age group. Johannsson and Albertsson-Wikland (13) have very recently demonstrated that discontinuation of GH therapy in adolescents with severe GH deficiency continuing into adulthood results in the accumulation of cardiovascular risk factors such as an increase in total body and abdominal fat mass, a decrease in lean body mass, and an increase in total cholesterol, LDL cholesterol, and apolipoprotein B, with a decrease in the levels of high-density lipoprotein (HDL) cholesterol.

To evaluate the cardiovascular status of a group of adolescents with GH deficiency, we have evaluated their cardiac mass and function, as well as their carotid intima-media thickness by echocardiographic and Doppler studies, and have measured their serum lipids and lipoprotein(a) levels.

	Materials and Methods

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Twelve adolescents with GH deficiency (seven males and five females) with a mean chronological age of 14.2 ± 2.8 yr, mean bone age of 12.8 ± 1.6 yr, and a mean height of 140.6 ± 17.9 cm (height SD score, -2.6 ± 0.3) were studied. GH deficiency had been diagnosed a mean of 5.2 ± 2.8 yr ago by means of two stimulation tests (clonidine and larodopa; peak GH concentrations of 3.4 ± 2.6 µg/L and 3.4 ± 2.4 µg/L, respectively), as well as reduced insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3) levels for age (113.3 ± 79.7 ng/mL and 2167.8 ± 630.5 ng/mL, respectively). Ten patients had idiopathic, isolated GH deficiency, whereas two subjects had organic, isolated GH deficiency (one with a craniopharyngioma and one with a macroadenoma, all treated only with surgery); all had entered puberty (Tanner stages II–IV). Six children had received GH in the past for a period of 1.8 ± 0.4 yr but were off therapy at the time of the study for a mean of 3.4 ± 1.8 yr (because of their inability to either obtain this medication through the social security system or to purchase it), whereas six patients had never been treated with GH. All patients had normal blood pressures and pulse, as well as normal serum cortisol and thyroid function tests, at the time of the study; LH, FSH, and testosterone/estradiol levels were appropriate for age. Seven adolescents with GH deficiency, on GH treatment for the last 3.8 ± 1.2 yr (4 males and 3 females; 6 with idiopathic, isolated GH deficiency and 1 with organic, isolated GH deficiency) with a mean chronological age of 14.4 ± 2.6 yr, mean bone age 13.4 ± 2.0 yr, and a mean height SD score of -2.5 ± 0.2, and 19 healthy adolescents, all comparable for age, pubertal status, body height, body weight, blood pressure, and pulse, participated in the study as controls.

Blood samples were drawn in the morning after an overnight fast in all subjects. Serum concentrations of IGF-I and IGFBP-3 were determined in all subjects (GH deficient and controls) using a two-site immunoradiometric assay (Diagnostics Systems Laboratories, Inc., Webster, TX), with inter- and intra-assay coefficients of variation for IGF-I (3.9–7% and 3.8–7.4%, respectively) and with inter- and intra-assay coefficients of variation for IGFBP-3 (4.2–8.3% and 5.3–6.7%, respectively). GH levels were obtained in all GHD patients following oral administration of 100 µg clonidine/m² and of 250–500 mg larodopa, as described previously (14, 15), and measured using a immunoradiometric assay (Immunotech, Marseille, France) with inter- and intra-assay coefficients of variation of 13.43–14.03% and 0.66–1.29%, respectively. Serum total cholesterol and triglyceride concentrations were measured in all subjects (GH deficient and controls) by the enzymatic method (Roche Diagnostics, Basel, Switzerland). HDL cholesterol was assessed after precipitation of apo B-containing lipoproteins, and LDL was calculated according to the Friedwald formula. Lipoprotein(a) levels were measured using an enzyme-linked immunosorbent assay for the determination of Lp(a) in plasma or serum (N.V. Innogenetics S.A., Antwerp, Belgium), as described previously (16). Intra-assay and interassay coefficients of variation were 9.0% and 6.5%, respectively. We were, however, unable to determine apo(a) sizes in each individual, so as to adjust for differences noted between the groups studied.

Echocardiography was performed by one of two pediatric cardiologists (E.L. and R.R.-C.) who also evaluated all echocardiographic tracings. Transthoracic echocardiographic measurements were performed with a Hewlett-Packard Co. 5500 machine (Palo Alto, CA) and 2.5-, 3.5-, and 7.5-mHz transducers, according to the recommendations of the American Society of Echocardiography (17). M-mode echocardiography was used to measure left atrial and ventricular dimensions and left ventricular wall thickness, allowing for the calculation of left ventricular mass. Stroke volume and cardiac output were measured using pulsed Doppler echocardiography at the left ventricular outflow tract using two-dimensional echocardiography. Carotid sonography was performed with the subject in supine position with a slight rotation of the neck using high-resolution mode B ultrasound. The probe was placed along the vessel axis to obtain a longitudinal scan of the common carotid arteries. Intima-media thickness was measured 1.5 cm proximal to the carotid artery bifurcation, and the mean of three measurements of each artery was reported in this study.

Results are reported as mean ± SD. This study was performed with parental consent and with the approval of the ethics committees of the hospital. Between-group comparisons were made by means of the two-tailed t test. P values less than 0.05 were considered statistically significant.

	Results

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LDL cholesterol levels were increased in our untreated GHD patients compared with healthy controls (3.17 ± 0.70 mmol/L in GHD patients vs. 2.33 ± 0.36 mmol/L in controls; P < 0.01), whereas total cholesterol, HDL cholesterol, and serum triglyceride concentrations were similar in untreated GHD adolescents and healthy controls (4.60 ± 0.64 vs. 4.29 ± 0.41 mmol/L for total cholesterol; 1.17 ± 0.42 vs. 1.15 ± 0.22 mmol/L for high density lipoprotein cholesterol; and 0.71 ± 0.28 vs. 0.80 ± 0.32 mmol/L for triglycerides, in untreated GHD patients and in healthy controls, respectively). Lipoprotein(a) concentrations were increased in untreated GHD subjects when compared with healthy controls (Table 1).

All echocardiographic measurements were similar in GHD patients on or off GH at the time of this study (Table 2). However, untreated GHD adolescents had elevated total cholesterol and lipoprotein(a) levels when compared with GH-treated GHD patients; LDL cholesterol and triglyceride concentrations were also higher, but not significantly so, in this group of untreated GHD patients, whereas HDL cholesterol concentrations were similar in both untreated and GH-treated GHD subjects (Table 3). When our untreated GHD patients were subdivided into those who had received, but had subsequently discontinued, GH therapy several years ago and those who had never been treated with GH, no difference was noted in either their echocardiographic studies or their serum lipid levels.

	Discussion

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Because many of these abnormalities have already been detected in young adults with GH deficiency (8, 10), and because the discontinuation of GH treatment in GHD adolescents results in the accumulation of important cardiovascular risk factors such as an increase in the amount of body and abdominal fat and in the concentrations of total and LDL cholesterol (13), we decided to evaluate a group of adolescents with GH deficiency to determine whether they already presented with abnormal lipid and lipoprotein(a) concentrations, with alterations in their cardiovascular structure or function or with early atherosclerotic changes.

Our untreated GHD adolescents had elevated LDL cholesterol levels when compared with healthy controls. Total cholesterol and HDL cholesterol levels, as well as triglyceride concentrations, were, however, similar to healthy controls. These results are similar to those reported in adult GHD patients by Capaldo et al. (10). Abnormalities in serum lipids in GHD patients may be due to an increase in the secretion rate and a reduction in the clearance rate of very low density lipoproteins (VLDLs) (18). The increased VLDL-apo B secretion is probably related to the abdominal obesity of GHD patients, because abdominal obesity when combined with insulin resistance increases VLDL-apo B secretion from the liver (19). Short-term GH treatment, however, increases the VLDL-apo B clearance rate.

In GHD patients off GH at the time of our study, total cholesterol levels were significantly increased, whereas LDL cholesterol and triglyceride concentrations were also elevated, although not significantly, when compared with GHD adolescents on GH at the time of this study. Our results in untreated GHD adolescents are similar to those recently reported by Johannsson and Albertsson-Wikland (13), who noted an increase of total and LDL cholesterol after discontinuation of GH treatment in GHD adolescents. In their study, however, serum triglycerides were elevated while on GH therapy and were thereafter reduced after terminating GH treatment; this is in contrast to observations in untreated GHD adults who also had elevated serum triglyceride concentrations.

Lipoprotein(a) is an independently atherogenic lipoprotein that can be thrombogenic and may be used as a plasmatic marker for individuals at risk for cardiovascular events (16). Although Capaldo et al. (10) found no difference in lipoprotein(a) levels between untreated childhood-onset GHD adults and controls, our untreated GHD adolescents had elevated lipoprotein(a) levels when compared with healthy controls. The effect of GH treatment on lipoprotein(a) in this group of patients is not clear, as Olivecrona et al. (20) found plasma lipoprotein(a) concentrations to increase both in adults with GH deficiency and in normal volunteers after recombinant GH treatment, whereas Pfeifer et al. (11) found GH treatment in GHD adults to have no effect on lipoprotein(a). In GH-treated GHD adolescents we found lower concentrations of lipoprotein(a) than in our untreated patients.

It is, however, important to point out that the differences in lipoprotein(a) levels noted between healthy controls and untreated and treated GHD adolescents may not be due to the GH treatment, but rather reflect a different distribution of apo(a) sizes between the groups. Apo(a) size, to a large extent, determines lipoprotein(a) plasma levels, so that difference in apo(a) size distribution between the groups could be a major cause of difference in lipoprotein(a) levels. Moreover, because lipoprotein(a) is affected by genetic factors to a much larger degree than other lipids, cross-sectional comparisons require large sample sizes to be meaningful; therefore, conclusions regarding lipoprotein(a) in a small number of subjects have to be viewed with caution.

In young adults with GH deficiency, the impairment of cardiac performance is manifested as a reduction in left ventricular mass, an inadequate ejection fraction, and in abnormalities of left ventricular diastolic filling (5, 6, 7). In these patients, GH administration has been shown to increase left ventricular mass and function (8, 9). In untreated GHD adolescents, we were, however, unable to find any abnormalities in cardiac mass because the interventricular septal thickness, the left ventricular posterior wall thickness, and the left ventricular mass after correction for body surface area were all similar to that of healthy controls. Cardiac function of untreated GHD adolescents was also not different from that of healthy controls, because these adolescents had a normal left ventricular ejection fraction at rest, as well as normal pulmonary venous flow velocities.

Recent studies have reported an increased intima-media thickness, with more atheromatous plaques in the carotid and the femoral arteries of GHD adults when compared with controls matched for age, sex, and body weight (10). This increased intima-media thickness, which represents the earliest morphological change in the arterial wall in the process of atherogenesis, has been detected in the absence of clear-cut abnormalities of the classic vascular risk factors (10); GH treatment has been, very recently, shown to reverse early atherosclerotic changes in GHD adults. Carotid artery intima-media thickness for both the right and left carotid arteries was, however, similar to that of healthy controls in our untreated GHD adolescents (11, 12).

We were unable to detect any difference in cardiac mass or function or in carotid artery intima-media thickness between patients on or off GH therapy at the time of the study. In addition, GHD adolescents, off GH at the time of the study, but who had received GH therapy several years ago, were found to have cardiovascular echocardiographic findings similar to those of GHD patients who had never been treated with GH. The duration of GH deficiency did not seem to affect the cardiovascular findings of our population of adolescents.

From our study, we can conclude that GHD adolescents, regardless of whether they received prior GH treatment, do not seem to show alterations in cardiac mass or function or early atherosclerotic changes. This group of patients, however, needs to be followed carefully as they enter into adulthood because they already present cardiovascular risk factors such as dyslipidemia, which may contribute to increased cardiovascular morbidity at an early age.

Received April 30, 2000.

Revised July 25, 2000.

Revised November 6, 2000.

Accepted November 13, 2000.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lanes, R. Articles by Revel-Chion, R. Search for Related Content PubMed PubMed Citation Articles by Lanes, R. Articles by Revel-Chion, R.