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Growth Hormone Reduces Inflammation in Postmenopausal Women with Abdominal Obesity: A 12-Month, Randomized, Placebo-Controlled Trial

Departments of Endocrinology (C.F., B.-Å.B., J.S., G.J.), Medicine (B.A.), and Diagnostic Radiology (L.L.), Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden

Address all correspondence and requests for reprints to: Celina Franco, M.D., Department of Endocrinology, Gröna Stråket 8, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden. E-mail: celina.franco{at}medic.gu.se.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: Abdominal obesity is associated with low GH secretion, elevated circulating markers of inflammation, and increased risk of cardiovascular disease.

Objective: The objective was to study the effect of GH treatment on inflammatory markers and vascular adhesion molecules in postmenopausal women with abdominal obesity.

Design: Forty women aged 51–63 yr received GH (0.67 mg/d) in a randomized, double-blind, placebo-controlled, 12-month trial. Measurements of inflammatory markers [highly sensitive C-reactive protein (CRP), IL-6, and amyloid polypeptideA] and markers of endothelial dysfunction (soluble E-selectin, vascular adhesion molecule-1, intercellular molecule-1, and matrix metalloproteinase-9) were performed at baseline and after 6 and 12 months of treatment.

Results: After 12 months, the mean IGF SD score was 0.9 ± 1.5 and –0.8 ± 0.6 in the GH and placebo groups, respectively. GH treatment reduced CRP and IL-6 levels compared with placebo (P = 0.03 and P = 0.05, respectively), whereas the markers of endothelial dysfunction were unaffected. Within the GH-treated group, a reduction was shown in CRP (4.3 ± 4 to 3.0 ± 3 mg/liter; P < 0.05) and in IL-6 (4.4 ± 2 to 3.3 ± 2 ng/liter; P < 0.01). In the GH-treated group, the decrease in CRP and IL-6 correlated with a reduction in visceral adipose tissue (r = 0.7, P < 0.001 and r = 0.5, P < 0.05, respectively).

Conclusion: GH treatment in postmenopausal women with abdominal obesity reduced serum markers of systemic inflammation. Circulating markers of endothelial dysfunction were unaffected by treatment.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
ABDOMINAL OBESITY IS associated with reduced spontaneous GH secretion (1) and elevated biomarkers of systemic inflammation. C-reactive protein (CRP) is an important predictor of cardiovascular disease (CVD) events (2) because it modulates the expression of cellular adhesion molecules (3) and reduces nitric oxide synthesis (4). Furthermore, circulating vascular adhesion molecule (VAM) levels reflect endothelial dysfunction and atherosclerosis (2). Circulating VAMs correlate positively with body mass index (BMI), whereas there has been no clear relationship between these markers and adipose tissue (AT) distribution (5).

Hypopituitary patients with GH deficiency accumulate abdominal fat and exhibit the same metabolic risk factors as those present in patients with the metabolic syndrome (6). GH-deficient patients not receiving GH replacement have premature atherosclerosis (7), increased CVD mortality (7), and increased levels of CRP and IL-6 that decrease in response to GH replacement (8). Matrix metalloproteinases (MMPs) are proteolytic enzymes associated with atherosclerosis and plaque instability (9). Two-year GH replacement in hypopituitary men and women reduced plasma MMPs, vascular endothelial growth factor, and abdominal fat (10), suggesting that GH exerts beneficial effects on the atherosclerotic process.

We recently reported that 1-yr GH treatment in abdominally obese women reduced visceral adipose tissue (VAT) and low-density lipoprotein cholesterol, whereas body weight was unaffected (11). Insulin sensitivity improved after 12 months within the GH-treated group, but there was no between-group difference (11). The aim of this study was to investigate the effect of 12-month GH treatment on inflammatory serum markers and VAMs in postmenopausal women with abdominal obesity.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Forty postmenopausal women with abdominal obesity were randomized to either GH or placebo treatment for 12 months. The effect of this treatment on body composition, insulin sensitivity, and serum lipid pattern has been reported previously (11). Inclusion criteria in the study were age of 50–65 yr, a BMI between 25 and 35 kg/m², a serum IGF-I concentration between –1 to –2 SD score, and a waist-to-hip ratio of more than 0.85. The criteria for exclusion were diabetes mellitus, CVD, claudicatio intermittens, stroke, malignancy, and other hormone treatment.

Ethics

Informed consent was obtained from each patient before entry into the study. The study was approved by the Ethics Committee at the University of Göteborg and by the Medical Products Agency (Uppsala, Sweden).

Treatment

The subjects were treated with either GH (n = 19) or placebo (n = 20), administered sc before bedtime. The initial dose of GH was 0.13 mg/d and was subsequently titrated during 5 wk and after 6 wk, to the final dose (0.51 vs. 0.65 mg/d in the GH vs. placebo group). The dose was reduced by half in the event of side effects (11).

Study design

The design was a prospective, randomized, parallel and placebo-controlled study performed at a single center (11). Measurements of circulating inflammatory markers and VAMs, as well as other laboratory efficacy measurements, were performed at baseline and at 6 and 12 months. Insulin sensitivity was assessed at baseline and 6 and 12 months as the glucose disposal rate using a euglycemic hyperinsulinemic glucose clamp, after an overnight fast. Computed tomography scans to measure regional fat distribution and thigh muscle mass and total body potassium to determine body fat (BF) and fat free mass were assessed at baseline and 12 months as described previously (11).

Biochemical assays

Serum IGF-I was determined by RIA after an HCl/ethanol extraction (Nichols Institute Diagnostics, San Juan Capistrano, CA). CRP was measured using a (latex) highly sensitive immunoturbidimetric assay (detection limit, 0.03 mg/liter; Tina-quant; Roche Diagnostics, Indianapolis, IN) determined on a Roche/Hitachi analyzer. IL-6 was measured using a high-sensitivity ELISA kit (R & D Systems, Abingdon, UK). Serum amyloid A (SAA) was determined by a highly sensitive latex agglutination assay using particle-enhanced immunonephelometry on the Behring Nephelometer II (Dade Behring, Marburg, Germany). Soluble E-selectin, vascular adhesion molecule-1 (VCAM-1), and intercellular molecule-1 (ICAM-1) were measured using quantitative sandwich ELISA (R & D Systems, Minneapolis, MN). Plasma MMP-9 was measured by ELISA (GE Healthcare, Uppsala, Sweden).

Statistical methods

The descriptive statistical results are presented as the mean ± SEM. The results have been analyzed on an intention-to-treat basis. Unpaired t tests were used for between-group analyses at baseline. Log transformation before statistical analysis was used for variables with skewed distribution. Between-group treatment effects were analyzed using one-way ANOVA for repeated measurements. Correlation analyses were calculated using Spearman’s R. A two-tailed P value 0.05 was considered significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The GH and placebo groups were comparable at baseline in terms of age (mean, 58; range, 51–63 vs. 56.5; range, 51–63 yr; P = 0.1), BMI (30.6 ± 3.0 vs. 30.0 ± 3.6 kg/m²; P = 0.5), waist circumference (104 ± 6 vs. 103 ± 7 cm; P = 0.5), and serum IGF-I. None of the women received lipid-lowering therapy or estrogen replacement. All the subjects had low serum estradiol concentrations (Table 1). In the GH-treated group, one woman was excluded because of type 2 diabetes mellitus diagnosed at the baseline visit.

The 12-month GH treatment reduced serum levels of CRP and IL-6 compared with placebo (Table 1 and Fig. 1, A and B). Within-group analysis revealed a reduction in serum IL-6, CRP, and MMP-9 in the GH-treated group after 6 months, with an additional reduction in IL-6 and MMP-9 after 12 months. No between-group treatment effects in circulating SAA, E-selectin, VCAM-1, ICAM-1, or MMP-9 were observed (Table 1).

View larger version (6K): [in this window] [in a new window]   FIG. 1. Effect of GH/placebo treatment on CRP (A) and IL-6 (B) expressed as mean and SEM, after 6 and 12 months. *, P < 0.05 and **, P < 0.01, within groups analysis at the given time point vs. baseline.

In the GH-treated group, the percentage reduction in serum CRP correlated positively with the percentage reduction in VAT (r = 0.7; P < 0.001) and abdominal sc adipose tissue (r = 0.6; P < 0.01) and negatively with the percentage increase in liver attenuation (r = –0.5; P < 0.05). The reduction in serum IL-6 correlated positively with the reduction in VAT (r = 0.5; P < 0.05) and negatively with the increase in thigh muscle mass (r = –0.6; P < 0.01). Positive correlations were found between the percentage change in SAA and abdominal sc adipose tissue (r = 0.8; P < 0.001), VAT (r = 0.5; P = 0.02), and liver attenuation (r = –0.5; P = 0.03). No correlation was found between the changes in markers of inflammation or endothelial dysfunction and glucose disposal rate (data not shown).

Changes in serum CRP and IL-6 correlated inversely with the rise in serum IGF-I (r = –0.6, P < 0.01 and r = –0.5, P < 0.05, respectively) in the GH-treated group but not in the placebo-treated group. The reduction in CRP correlated positively with serum aspartate aminotransferase (r = 0.6; P < 0.05) and alanine aminotransferase (r = 0.6; P < 0.01).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We found a reduction in serum CRP and IL-6 concentrations after 6 and 12 months of GH treatment compared with placebo in postmenopausal women with abdominal obesity, whereas no effect was seen in SAA or circulating markers of endothelial dysfunction.

Our findings suggest that GH attenuates the state of chronic inflammation associated with the metabolic syndrome. In support of this hypothesis, women with severe GH deficiency attributable to hypothalamic-pituitary disease have increased CRP and IL-6 concentrations (12), and GH replacement reduced CRP and IL-6 levels in men with hypopituitarism (8). GH might exert its effect on the inflammatory process by a direct effect or by an indirect effect mediated by IGF-I, on the immune system (13) or endothelial cells (14). GH also upregulates several of the suppressor of cytokine signaling proteins (15), which can attenuate the signaling of cytokines in adipose tissue and in the liver, thereby reducing hepatic CRP production.

It is also possible that the reduction in systemic inflammation by GH was mediated by the improvement of regional fat distribution (12). Baseline serum CRP and IL-6 concentrations were not correlated with total BF, although they correlated negatively with intraabdominal fat and hepatic fat content. Intraabdominal fat is particularly metabolically active, exhibiting not only high lipolytic activity but also an increased release of IL-6 and other cytokines (16). In addition, nonalcoholic fatty liver disease has been associated with increased hepatic production of cytokines and CRP, mainly induced by IL-6 (17). On these bases, the reduction in serum CRP and IL-6 concentrations in this study may be mediated by the GH-induced decrease in visceral fat mass and hepatic fat content. The reduction in serum IL-6 and CRP could also be directly mediated by IGF-I as suggested by the inverse association between the increase in serum IGF-I and the reduction in serum CRP and IL-6. Conversely, the increase in serum IGF was also associated with a reduction in the hepatic fat content and VAT. So, although direct effects of GH and IGF-I cannot be excluded, it may be more likely that the reduction in CRP and IL-6 occurred as an effect of the GH-induced reduction in VAT and hepatic fat content.

The 12 months of GH treatment had no effect on markers of endothelial dysfunction in this study. In contrast, in a previous open study, GH replacement increased circulating VCAM-1 levels compared with healthy controls (14). The patients and controls were not, however, matched for BMI and smoking habits, and in vitro analysis of human umbilical vein endothelial cells failed to demonstrate a direct effect by either GH or IGF-I on VCAM-1 expression. Other studies of GH-deficient adults have failed to demonstrate effects of GH replacement on circulating levels of VAMs (18, 19). In hypopituitary patients of both genders, long-term GH replacement reduced MMP-9 levels (10). In our study, plasma MMP-9 decreased in the GH-treated women, but there was no between-group difference. A possible explanation to the difference in the outcome of these studies could be related to differences in the populations studied.

There is some evidence suggesting that GH can affect atherosclerosis in GH-deficient adults, with a reduction in early atherosclerotic plaques in the carotid arteries (20). We have not specifically studied atherosclerotic processes, but the result of this trial does not support a direct effect of GH treatment on VAMs. Recent data from our group suggest that important risk factors for atherosclerosis and its progress, such as BF distribution, serum lipid pattern (11), and subclinical inflammation, are, however, significantly improved by GH treatment.

It is finally important to confirm that there was an even distribution of factors among the groups that may influence the inflammatory process, such as weight changes, smoking habits, and concomitant antihypertensive therapy (11).

In conclusion, GH treatment in postmenopausal women with abdominal obesity demonstrated a reduction in serum inflammatory markers that were associated with a reduction in abdominal obesity and hepatic fat content. This suggests an overall reduction in the risk of CVD. VAM levels were not influenced by GH treatment. It remains to be determined whether prolonged GH treatment can reduce the progress of atherosclerosis.

	Acknowledgments

 
We thank the staff at the Research Centre for Endocrinology and Metabolism, the Department of Body Composition and Metabolism, the staff at the Academy’s Medical Research Centre, and the Wallenberg Laboratory.

	Footnotes

 
This study was supported by funds from the Sahlgrenska Academy (University of Göteborg, Göteborg, Sweden).

Disclosure Statement: C.F. has nothing to declare. B.A. has received consulting fees and has received lecture fees from a commercial sponsor. L.L. has received consulting fees from Abbot, Mentice, and Johnson & Johnson and has received lecture fees from Medtronic, Biotronic, and Bard. B.-Å.B. has received lecture fees from a commercial sponsor. J.S. has received lecture fees from Pfizer, and G.J. has received lecture fees from Novo Nordisk, Pfizer, and Ipsen.

First Published Online April 24, 2007

Abbreviations: BF, Body fat; BMI, body mass index; CRP, C-reactive protein; CVD, cardiovascular disease; ICAM-1, intercellular molecule-1; MMP, matrix metalloproteinase; SAA, serum amyloid A; VAM, vascular adhesion molecule; VAT, visceral adipose tissue; VCAM, vascular adhesion molecule-1.

Received January 11, 2007.

Accepted April 17, 2007.

	References

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