Circulating asymmetric dimethylarginine and lipid profile in pre-pubertal children with growth hormone deficiency: Effect of 12-month growth hormone replacement therapy

https://doi.org/10.1016/j.ghir.2014.08.001Get rights and content

Abstract

Objective

Growth hormone deficiency (GHD) in adults is associated with cardiovascular complications, which lead to reduced life expectancy. At present, data on cardiovascular risk factors in GHD children are limited. The aim of this study was to evaluate whether pre-pubertal GHD children have increased cardiovascular risk factors, and whether 12-month growth hormone (GH) treatment can reverse them.

Design

Twenty pre-pubertal GHD children (6 boys, mean (± SD) age: 9.5 ± 1.8 years) were matched for sex and age with 20 healthy controls (6 boys, mean (± SD) age: 8.8 ± 1.5 years). Asymmetric dimethylarginine (ADMA), lipid profile, glucose metabolism parameters, IGF-1, blood pressure and anthropometric parameters were assessed at baseline and after 12 months of GH treatment.

Results

At baseline, GHD patients showed significantly higher ADMA levels (median [interquartile range]: 78.5 [69.6–123.5] vs 54.0 [38.3–60.8] ng/ml, p < 0.001), total cholesterol (mean ± SD: 177.5 ± 30.4 vs 150.1 ± 21.4 mg/dl; p = 0.004) and LDL-cholesterol (mean ± SD: 111.2 ± 22.2 vs 84.9 ± 15.9 mg/dl; p < 0.001) than controls. After 12-month GH treatment, ADMA (median [interquartile range]: 55.4 [51.2–73.8] ng/ml), total cholesterol (mean ± SD: 155.6 ± 43.2 mg/dl), and LDL-cholesterol (mean ± SD: 95.4 ± 32.1 mg/dl) significantly decreased in GHD children, reaching values comparable to those in controls.

Conclusions

This study showed that, as in adults, pre-pubertal GHD children manifest increased cardiovascular risk markers and that 12-month GH treatment can improve them.

Introduction

Adults with growth hormone deficiency (GHD) are known to have reduced life expectancy because of increased cardiovascular and cerebrovascular events [1].

Previous studies have reported that adults as well as adolescents with severe GHD have a cluster of cardiovascular risk factors, including abnormal lipid profile, abdominal obesity, insulin resistance, hypertension, reduced exercise capacity, increased carotid intima-media thickness, and impaired cardiac morphology and function [2], [3], [4].

Impaired vascular reactivity, reduced bioavailability of nitric oxide (NO) and impaired oxidant-antioxidant status are all alterations detected in subjects with GHD, where they contribute to endothelial dysfunction, which in turn is one of the first events leading to cardiovascular disease [5], [6], [7].

During the last years there has been an increasing interest in a circulating marker of endothelial dysfunction, asymmetric dimethylarginine (ADMA), which is a naturally occurring l-arginine analogue found in plasma and various tissues [8]. ADMA is an endogenous inhibitor of endothelial NO synthase and in this way it contributes to the pathogenesis of endothelial dysfunction [9]. ADMA is considered as an emerging cardiovascular marker and its levels have been found to be increased in patients with hypercholesterolemia, hypertension, coronary artery disease, diabetes mellitus, chronic renal failure and hypopituitarism [10]. Interestingly, adult studies have shown that growth hormone (GH) replacement can decrease ADMA levels [11].

Increased levels of ADMA have also been reported in children and adolescents with pathological conditions, where they have been associated with early markers of atherosclerosis, such as increased carotid artery intima-media thickness [12]. However, up to now there are no studies on ADMA in GHD children. Limited are also pediatric studies [13], [14], [15] assessing other cardiovascular risk factors in children with GHD, and the potential beneficial effect of GH treatment on the cardiovascular profile of young people with this condition.

The aim of the present study was to evaluate ADMA levels along with other cardiovascular risk factors in pre-pubertal children with idiopathic GHD and to test whether 12-month GH replacement therapy could improve their cardiovascular profile.

Section snippets

Study population

We recruited 20 Caucasian pre-pubertal children (6 boys and 14 girls, mean age (± SD): 9.5 ± 1.8 years), who had been referred to the Endocrine Clinic of the Department of Pediatrics, University of Chieti, Italy, between May 2010 and July 2012, for short stature and in whom a diagnosis of GHD was made. These children were a subgroup of patients with a diagnosis of GHD made during that time period and who consecutively agreed to take part in the study.

These patients were matched for sex and age with

General characteristics of the study population at baseline

The baseline clinical and biochemical characteristics of the whole study population are reported in Table 1.

At baseline, GHD and control children were similar for age, sex distribution, weight, BMI and BMI SDS, whereas, as expected, a significant difference was found in height SDS. GHD patients also showed significantly lower IGF-1 SDS than control children (Table 1).

No significant difference between the two groups was found in parameters related to glucose metabolism, such as fasting glucose,

Discussion

In the present study we found elevated ADMA levels and an alteration in lipid profile in pre-pubertal children with GHD compared to age and sex-matched healthy controls. Interestingly, GH treatment was associated with an improvement in cardiovascular profile, as documented by decreased ADMA levels, total cholesterol and LDL-cholesterol, which reached values comparable to those in healthy children.

In adults, GHD is associated with an increased prevalence of premature atherosclerosis [20], [21]

Conflict of interest

None to declare.

References (40)

  • R. Lanes et al.

    Growth hormone deficiency, low levels of adiponectin, and unfavorable plasma lipid and lipoproteins

    J. Pediatr.

    (2006)
  • A. Colao et al.

    Beginning to end: cardiovascular implications of growth hormone (GH) deficiency and GH therapy

    Growth Hormon. IGF Res.

    (2006)
  • D. Capalbo et al.

    Update on early cardiovascular and metabolic risk factors in children and adolescents affected with growth hormone deficiency

    Minerva Endocrinol.

    (2012)
  • C. Gazzaruso et al.

    Cardiovascular risk in adult patients with growth hormone (GH) deficiency and following substitution with GH—an update

    J. Clin. Endocrinol. Metab.

    (2014)
  • D. Capalbo et al.

    Subtle alterations of cardiac performance in children with growth hormone deficiency: results of a two-year prospective, case–control study

    J. Clin. Endocrinol. Metab.

    (2009)
  • L.C. Bailey-Downs et al.

    Growth hormone and IGF-1 deficiency exacerbate high-fat diet-induced endothelial impairment in obese Lewis dwarf rats: implications for vascular aging

    J. Gerontol. A Biol. Sci. Med. Sci.

    (2012)
  • R.N. Rodionov et al.

    Overexpression of dimethylarginine dimethylaminohydrolase protects against cerebral vascular effects of hyperhomocysteinemia

    Circ. Res.

    (2010)
  • H. Miyazaki et al.

    Endogenous nitric oxide synthase inhibitor: a novel marker of atherosclerosis

    J. Cardiol.

    (1999)
  • B. Capaldo et al.

    Abnormal vascular reactivity in growth hormone deficiency

    Circulation

    (2001)
  • Z. Veresh et al.

    Asymmetric dimethylarginine reduces nitric oxide donor-mediated dilation of arterioles by activating the vascular renin–angiotensin system and reactive oxygen species

    J. Vasc. Res.

    (2012)

    • Cited by (16)

    • Metabolic alterations in paediatric GH deficiency

      2016, Best Practice and Research: Clinical Endocrinology and Metabolism
      Citation Excerpt :

      These findings point towards a prothrombotic state in untreated GHD but further studies are necessary. Children with GHD were shown to have an impaired oxidant-antioxidant status with a reduced nitric oxide (NO) bioavailability and vascular reactivity, which in turn led to endothelial dysfunction and CVD [8,66]. Asymmetric dimethylarginine (ADMA) is an endogenous plasmatic inhibitor of endothelial NO synthase and is considered as a cardiovascular marker.

    • Cardiovascular Risk in Growth Hormone Deficiency: Beneficial Effects of Growth Hormone Replacement Therapy

      2016, Endocrinology and Metabolism Clinics of North America
      Citation Excerpt :

      GH therapy would seem to improve both the fasting and the postprandial atherogenic lipoprotein profile of adolescents with GHD, as both these parameters were found to be significantly lower than those of untreated subjects.17 In 2 recent studies, DeMarco and colleagues23 and Capalbo and colleagues9 reported significantly higher levels of triglycerides, total cholesterol, and LDL-cholesterol at baseline in children with GHD when compared with healthy controls; after 12 to 24 months of GH treatment, total cholesterol and LDL-cholesterol significantly decreased, reaching values comparable to those in controls. This beneficial effect of GH treatment has been shown to result from an increased expression of hepatic surface receptors.

    • Exploring the complex dynamics of BMI, age, and physiological indicators in early adolescents

      2024, BMC Pediatrics

    • Comprehensive assessment of cardiovascular disease risk in children with short stature due to isolated growth hormone deficiency: A case-control study

      2022, Journal of Pediatric Endocrinology and Metabolism

    • Case Report: A Clinical and Genetic Analysis of Childhood Growth Hormone Deficiency With Familial Hypercholesterolemia

      2021, Frontiers in Endocrinology

    • Study of lipid profiles levels in Iraqi children with GH deficiency before and after 6 months GH replacement therapy

      2020, Indian Journal of Forensic Medicine and Toxicology
    View all citing articles on Scopus
    View full text
    Copyright © 2014 Elsevier Ltd. All rights reserved.