© 1995 American Heart Association, Inc.
Articles |
Magnetic Resonance Imaging–Assessed Adipose Tissue and Serum Lipid and Insulin Concentrations in Growth Hormone–Deficient Adults
Effect of Growth Hormone Replacement
From the Department of Endocrinology, University Hospital Utrecht, Utrecht, and the Department of Internal Medicine (R.-J.M.B.), University Hospital Maastricht, Maastricht, Netherlands.
Correspondence to H.P.F. Koppeschaar, Department of Endocrinology, University Hospital Utrecht, Postbox 85500, 3508 GA Utrecht, Netherlands.
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Abstract |
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Abstract The visceral and subcutaneous abdominal adipose tissue (AT) areas and the subcutaneous hip AT area were assessed by magnetic resonance imaging (MRI) in relation to serum lipid and plasma insulin levels in 12 growth hormone–deficient (GHD) adults before and after 6 months of replacement therapy with recombinant human growth hormone (rhGH) and in 12 healthy control subjects. Compared with control subjects, GHD patients had a significantly increased amount of visceral AT, which was inversely related with plasma HDL cholesterol and positively correlated with plasma triglyceride levels. Visceral AT was not associated with plasma total and LDL cholesterol or plasma insulin concentrations. GHD patients also had elevated serum total cholesterol, LDL cholesterol, and triglyceride levels compared with control subjects. After 6 months of rhGH replacement therapy the mean visceral, subcutaneous abdominal, and subcutaneous hip AT areas and serum concentration of total cholesterol decreased significantly, whereas serum HDL cholesterol concentration increased significantly. No significant correlations were found between changes in the amount of AT and changes in serum lipid and plasma insulin levels.
Key Words: adipose tissue • serum lipids • plasma insulin • magnetic resonance imaging • growth hormone–deficient adults
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Recent data show that GHD in adults is associated with increased mortality due to cardiovascular causes despite adequate replacement therapy with glucocorticoids, thyroxine, and sex hormones.1 GHD is associated with an increased BF mass and a decreased fat-free mass.2 3 4 5 6 Moreover, the increased amount of BF is located mainly in the abdominal region, and the amount of visceral fat appears to decrease during replacement therapy with rhGH.3 GHD patients have high triglyceride and total serum cholesterol levels due to increased LDL-C7 8 9 10 11 12 and low HDL-C,10 11 and insulin sensitivity is reduced.13 14 The mechanisms underlying these lipid profiles and insulin resistance in GHD patients are not well understood.15 To our knowledge, no study has investigated the association between visceral AT and plasma lipid and insulin concentrations in GHD adults before and after rhGH replacement therapy.
The aim of the study was to assess the relation between the visceral abdominal, subcutaneous abdominal, and subcutaneous hip AT areas as assessed by MRI and serum lipid and plasma insulin levels in healthy control subjects and GHD adults before and after 6 months of rhGH replacement therapy.
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Methods |
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Subjects
Seven men and five women (25 to 60 years of age) known to have GHD for at least 2 years (mean, 11.3 years; range, 3 to 20 years) were included in the study. Hypopituitarism was treated according to general standards. Secondary hypothyroidism (11 patients) was treated with levothyroxine 75 to 200 µg daily (average dose, 134 µg) to obtain free thyroxine plasma levels in the upper part of the normal range. Secondary hypogonadism in 6 men was treated with testosterone undecanoate 80 mg BID PO or testosterone esters 250 mg IM every 3 weeks, and 3 women were treated with cyclic estrogen (30 µg ethinylestradiol) and progesterone (150 µg levonorgestrel) therapy. Secondary adrenal insufficiency was present in all patients and was treated with cortisone acetate 10 to 37.5 mg daily (average dose, 28.3 mg). During rhGH treatment no adjustment in any replacement dose of any patient was made. GHD was defined as a peak plasma growth hormone concentration
5 µg/L to
arginine infusion. After arginine infusion, GH was not detectable in 10
patients; in the other 2 patients peak plasma GH concentrations were
1.0 and 2.9 µg/L.
The control group consisted of 12 healthy adult volunteers (7 men and 5
women) matched for age, body height, weight, and BMI (Table 1
).
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Design
The study had a randomized double-blind design in which rhGH
(Pharmacia AB, Peptide Hormones) or placebo was administered for 6
months. Thereafter, all GHD patients were treated with daily
subcutaneous injections of rhGH for 6 months. The first month's dose
was 0.125 IU · kg-1 · wk-1,
followed by 0.25 IU · kg-1 · wk-1 for
5 months. MRI assessments were performed at 6 and 12 months, and in
this study we describe the subjects who received placebo during the
first half-year and rhGH for the second half-year. The patients were
studied as outpatients at the Department of Endocrinology. The aims and
methods of the study were explained to the patients and control
subjects, and an informed consent was obtained. The study was approved
by the ethics committee of the University Hospital of
Utrecht.
Body Composition
Body height was measured to the nearest millimeter by using a
wall-mounted stadiometer, and body weight was measured to the
nearest 0.05 kg. BMI was calculated as weight in kilograms divided by
height in meters squared.
BF was assessed by bioelectrical impedance analysis (tetrapolar BIA-101 analyzer, RJL Systems) based on resistance and reactance measurements. Resistance and reactance were measured in ohms after application of an alternating current of 800 µA at 50 kHz with the electrodes placed as described by Lukaski et al.16
AT area at the abdominal and hip level was assessed by using MRI scanning. MRI was performed with a 1.5-T whole-body scanner (Gyroscan S15, Philips Medical Systems) by using a multislice inversion recovery sequence with a 300-msec inversion time, 820-msec repetition time, and 20-msec echo time. This sequence highlights the AT while effectively suppressing all other tissues.17 A transverse scan at the abdominal level consisting of three 10-mm-thick slices with a gap of 2 mm was taken halfway between the lower rib margin and the iliac crest. Similarly, at the hip level a scan was taken at the level of the great trochanter. We used a 179x256 acquisition matrix and a 500-mm field of view with four averages at the abdominal level and two averages at the hip level. Increasing the number of signal averages suppresses motion artifacts. The acquisition time of one experiment was 15 minutes (10 minutes for the abdominal area and 5 for the hip area).
Analysis of the 12-bit images was performed on a Sparc-2 workstation (Sun) by using software developed at the Department of Biomedical Engineering at the Free University Hospital, Amsterdam. In this program, partial volume effects are taken into account as described by Fowler et al.18 The average of the three slices per examination level was used in the statistical analysis. A seed-growing method was used for calculating AT areas. At the abdominal level the area of visceral AT was first distinguished from the area of subcutaneous AT by tracing a line. After a seed-point was positioned in a part of the AT depot with typical signal intensity, the boundaries of the defined region were grown toward interactively set threshold intensities. All measurements were performed by the same observer and repeated in a second session. The observer was blinded with regard to the treatment group. The intraobserver differences, which were expressed as coefficients of variation,19 were 2.9% for the visceral AT area in healthy control subjects and 2.0% and 3.7% before and after rhGH replacement in GHD adults, respectively; respective values for the subcutaneous abdominal AT area were 0.9%, 0.9%, and 1.7%, and for the subcutaneous hip AT area they were 0.8%, 0.9%, and 1.4%. The visceral/subcutaneous AT ratio was calculated as the visceral AT area divided by the subcutaneous AT area at the abdominal level.
Biochemical Analysis
Blood samples were drawn in the morning after an overnight fast.
Plasma GH concentration was determined by using the radioimmunoassay of
the Oris Industry Co, which has a lower detection limit of
0.50±0.04 mIU/L (1 µg/L=1 ng/mL=2 mIU/L); the intra- and interassay
coefficients of variation were 7.7% and 11%, respectively.
Cholesterol and triglyceride levels were
measured by using a fully automated Hitachi 717 analyzer;
reagents for the enzymatic applications were obtained from
Boehringer Mannheim. The phosphotungstic acid–magnesium
chloride precipitation method was used to measure HDL-C. LDL-C was
calculated by the Friedewald formula (in millimoles per liter,
LDL-C=total
cholesterol-0.45xtriglyceride-HDL-C).20
Insulin concentration was measured by radioimmunoassay.
Statistical Analyses
Statistical analyses were performed with the SPSS
PC program (version 4.0.1) (SPSS). All values are expressed as
mean±SEM. The nonparametric Mann-Whitney U test
was used to test for differences between patients and control subjects
and between men and women. Wilcoxon's signed-rank test was
used to test for the effects of rhGH replacement. Spearman's rank
correlation test was used to assess the relationships among the
variables. Differences were considered significant if the
probability value was <.05.
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Results |
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Total BF, AT Areas, and Serum Lipid and Plasma Insulin Levels in GHD Patients and Healthy Control Subjects
Compared with control subjects, GHD patients had a significantly greater amount of total BF as assessed by bioelectrical impedance analysis. Visceral AT area (P=.003) and subcutaneous abdominal AT area (P=.013) were significantly larger in the patients, whereas no difference was found in subcutaneous hip AT area (P=.299). The patients had a significantly higher visceral/subcutaneous AT ratio than did the control subjects (P=.033) (Table 2
). GHD patients had higher
concentrations of total cholesterol (P=.024),
LDL-C (P=.049), and triglycerides
(P=.035) than did healthy control subjects. The
concentrations of HDL-C (P=.505) and plasma insulin
(P=.614) did not differ between GHD patients and control
subjects (Table 2).
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Changes in Body Composition, AT Areas, and Serum Lipid and Plasma
Insulin Levels After 6 Months of rhGH Replacement
Therapy
Table 3 shows the changes in body composition, AT
areas, and serum lipid and plasma insulin levels after 6 months of
replacement therapy with rhGH. Body weight (P=.239) and BMI
(P=.308) were not changed, but after 6 months of rhGH
replacement therapy, total BF (P=.004), visceral AT area
(P=.002), and subcutaneous abdominal AT area
(P=.019) decreased. There was also a significant reduction
in subcutaneous hip AT area (P=.006) and the
visceral/subcutaneous AT ratio (P=.004). The relative
decreases in AT areas, denoted as a percentage of their baseline level,
were 38.2% for visceral abdominal AT (men, 42.6%; women, 31.9%),
15.6% for subcutaneous abdominal AT (men, 15.3%; women, 16.2%), and
12.4% for subcutaneous hip AT (men, 14.0%; women, 9.7%). No
significant differences were found in visceral AT area, subcutaneous
abdominal AT area, and subcutaneous hip AT area between the healthy
control subjects and the GHD patients treated for 6 months with rhGH.
The serum concentration of total cholesterol
decreased significantly (P=.049), whereas HDL-C increased
significantly (P=.019). No significant change was found in
serum LDL-C (P=.131) and serum triglyceride
(P=.638) concentrations. After the 6-month replacement
therapy with rhGH, no significant differences were found in serum
concentrations of total cholesterol, HDL-C, and LDL-C
between patients and control subjects. Compared with control subjects,
serum triglyceride levels were still significantly higher
in GHD patients after 6 months of replacement therapy with rhGH.
Fasting plasma insulin concentrations increased significantly after 6
months of rhGH replacement therapy (P=.018) (Table 3).
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Relations Between AT Areas and Serum Lipid and Plasma Insulin
Levels
The visceral AT area was positively correlated with serum
triglyceride (r=.560, P<.05) and
inversely correlated with HDL-C (r=-.761,
P<.01) levels in healthy control subjects and GHD patients
before (r=.664, P<.01; r=-.554,
P<.05, respectively) and after (r=.601,
P<.05; r=-.518, P<.05,
respectively) rhGH replacement therapy. Serum HDL-C level was inversely
correlated with the amount of subcutaneous abdominal AT in control
subjects (r=-.578, P<.05). In control subjects,
serum concentrations of triglycerides (r=.546,
P<.05) and HDL-C (r=-.655, P<.05)
correlated with the visceral/subcutaneous AT ratio. In GHD patients at
6 months, serum concentrations of triglycerides correlated
with the amount of subcutaneous abdominal AT area (r=.692,
P<.05). A significant inverse relationship between serum
LDL-C and visceral AT was found in GHD patients at baseline
(r=-.578, P<.05), whereas these
parameters were not correlated in control subjects or GHD
patients after 6 months of rhGH replacement therapy. No significant
correlations were found between AT areas and plasma insulin
concentrations (Table 4).
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No significant correlations were found between changes in AT areas and
serum lipid or plasma insulin levels with the exception of a
significant negative correlation between the changes in visceral AT
area and serum total cholesterol concentration
(r=-.507, P<.05) (Table 5).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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To our knowledge, this is the first study in which the AT deposition in different parts of the body is compared with plasma lipid and insulin concentrations in GHD adults. We found that GHD patients had a significantly increased visceral AT area that was inversely related with plasma HDL-C levels and positively correlated with plasma triglyceride levels, features known to be associated with increased risk of arteriosclerosis. After 6 months of rhGH replacement therapy the amount of visceral AT decreased markedly and was not significantly different from that of healthy control subjects. Notwithstanding the significant decrease of visceral AT, we still found an inverse association of visceral AT with HDL-C and a positive correlation of visceral AT with triglyceride levels. In contrast, visceral AT was not associated with the levels of plasma total cholesterol, LDL-C, or plasma insulin. GHD patients compared with control subjects had elevated serum total cholesterol, LDL-C, and triglyceride levels. After 6 months of rhGH replacement therapy, serum concentration of total cholesterol decreased significantly, whereas serum HDL-C concentration increased significantly; the triglyceride concentration remained unchanged.
Other investigators report that during rhGH replacement therapy serum concentrations of total cholesterol decrease5 21 22 23 or remain unaltered,6 24 25 26 that plasma triglyceride concentrations do not change significantly,5 6 23 24 25 and that HDL-C concentrations increase23 24 or remain unchanged.22 26 The mechanisms responsible for the changes in plasma lipid concentrations are not well established. Two recent studies23 27 show an increase in LDL receptor expression after rhGH replacement therapy, which may improve the clearance of VLDL and LDL from the circulation, thus accounting for the decrease in LDL-C. Furthermore, GH may stimulate the peripheral uptake of lipids into muscle, which is mediated by lipoprotein lipase. In addition, the effects of GH on plasma lipids may be regulated partly via insulin.23
The amount of visceral AT could also contribute to the altered lipid metabolism. Our study shows that adult GHD patients have an increased visceral and subcutaneous abdominal AT area compared with healthy control subjects. Six months of rhGH replacement therapy reduced the visceral, subcutaneous abdominal, and subcutaneous hip AT areas of the GHD patients. The most pronounced reduction was in the visceral AT area. Bengtsson et al3 report similar findings after using computerized tomography to assess changes in visceral AT in GHD patients during rhGH replacement therapy. The more pronounced reduction in the visceral AT area compared with the other AT areas during rhGH replacement therapy might be due to a higher rate of lipolysis in the visceral fat cells and a GH-induced reduction of the antilipolytic effect of insulin on these fat cells.28 Both in healthy control subjects and GHD patients at baseline and after 6 months of rhGH replacement therapy we found a significant negative correlation between HDL-C levels and visceral AT and a significant positive correlation between plasma triglyceride levels and visceral AT. The association between serum triglycerides and visceral AT is in agreement with the high lipolytic activity of intra-abdominal AT, which, by exposing the liver to high free fatty acid concentrations, stimulates triglyceride synthesis.29
The mechanism responsible for the association between visceral AT and HDL-C level is not well established. Després et al29 suggest that the influence of visceral AT on HDL-C concentrations is mediated by hepatic triglyceride lipase, resulting in reduced HDL levels. In agreement with studies in obese subjects,30 31 32 we found no significant correlations between the visceral, subcutaneous abdominal, and subcutaneous hip AT areas and total cholesterol and LDL-C levels in either healthy control subjects or GHD patients after 6 months of rhGH replacement therapy. This could be due to the particle size and composition of LDL-C.32 33 Our finding that visceral AT was inversely related with LDL-C concentrations in GHD patients at baseline is difficult to explain and could partly be due to the above-mentioned composition of LDL-C.
Regardless of the influence of visceral AT on plasma lipid levels, the well-established association of visceral AT with insulin resistance must be taken into account.34 In GHD adults insulin sensitivity is decreased.35 Furthermore, O'Neal et al36 report that 1 week after the initiation of rhGH replacement therapy in GHD patients mild glucose intolerance, hyperinsulinemia, and insulin resistance occurred that returned to baseline values except for a persistent modest elevation of fasting insulin levels. In accordance with other studies,5 23 we found significantly increased fasting insulin concentrations after 6 months of rhGH replacement therapy. No significant correlations between plasma insulin and visceral AT area were observed in our study.
No significant correlations between changes in the visceral, subcutaneous abdominal, and subcutaneous hip AT areas and changes in serum lipid levels were found with the exception of a negative correlation between the decreases in the visceral AT area and total serum cholesterol concentration. This could be partly explained by the relatively large within-person variations in the variables37 38 ; similar variations are also reported by Leenen et al30 in a study of obese subjects after weight loss. This may also be due to the fact that we determined only a given AT area in the abdominal and hip region.
In summary, our study shows that GHD patients compared with healthy control subjects have markedly increased visceral AT and dyslipoproteinemia characteristics, both of which are associated with an increased risk of arteriosclerosis. After 6 months of rhGH replacement therapy, the amount of visceral AT and the plasma lipid profile, except the serum triglyceride level, were not significantly different from those of healthy control subjects. It appears that in GHD adults visceral AT is a major determining factor for the increase in atherogenic plasma lipids.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by Pharmacia AB, Peptide Hormones, Stockholm, Sweden.
Received March 10, 1995; accepted June 23, 1995.
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References |
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