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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-1466
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 4 2154-2160
Copyright © 2005 by The Endocrine Society

Effects of Growth Hormone-Releasing Hormone on Bone Turnover in Human Immunodeficiency Virus-Infected Men with Fat Accumulation

Polyxeni Koutkia, Bridget Canavan, Jeff Breu and Steven Grinspoon

Massachusetts General Hospital Program in Nutritional Metabolism and Neuroendocrine Unit (P.K., B.C., S.G.), Harvard Medical School, Boston, Massachusetts 02114; and General Clinical Research Center (J.B.), Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

Address all correspondence and requests for reprints to: Steven Grinspoon, M.D., Program in Nutritional Metabolism, Massachusetts General Hospital, 55 Fruit Street, LON 207, Boston, Massachusetts 02114. E-mail: sgrinspoon{at}partners.org.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
GHRH is a potentially appealing strategy to simultaneously improve fat distribution and increase bone turnover in HIV-infected patients. We investigated the effects of GHRH (1 mg sc twice a day over 12 wk) in 31 HIV-infected men with abdominal fat accumulation (age 46 ± 1 yr, body mass index 26.2 ± 0.6 kg/m2) in a randomized, double-blind, placebo-controlled study. We previously reported significant effects of GHRH on IGF-I and truncal fat. In this study, we assessed whether GHRH increased markers of bone turnover. At baseline, 32% of our subjects (n = 10) demonstrated a bone density Z score less than –1.0 SD and greater than or equal to –2.5 SD, and 3% (n = 1) demonstrated a Z score of less than –2.5 SD. IGF-I correlated with N-terminal telopeptide (NTx) (r = 0.49, P = 0.005) and tended to correlate with C-terminal telopeptide (CTx) (r = 0.35, P = 0.06) at baseline. Of the bone resorption markers, CTx increased significantly (0.16 ± 0.07 vs. –0.03 ± 0.03 ng/ml, GHRH vs. placebo, P = 0.02), and NTx tended to increase in response to GHRH (2.8 ± 1.4 vs. –0.5 ± 1.0 nM bone collagen equivalent, GHRH vs. placebo, P = 0.07). Of the bone formation markers, N-terminal propeptide of type 1 procollagen increased (14.6 ± 9 vs. –6.8 ± 3.1 µg/liter, GHRH vs. placebo, P = 0.03) and osteocalcin tended to increase (8.4 ± 3.0 vs. 2.0 ± 1.6 ng/ml, GHRH vs. placebo, P = 0.06) in response to GHRH. The calciotropic hormones, calcium and phosphorus, did not change significantly. The change in IGF-I correlated with the change in NTx (r = 0.45, P = 0.02), CTx (r = 0.38, P = 0.05), and osteocalcin (r = 0.55, P = 0.002). GHRH improves fat distribution and bone metabolism in men with HIV-related fat accumulation. Long-term studies are needed to determine whether the stimulatory effects of GHRH on bone turnover will translate into increased bone density in this population.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
REDUCED BONE MINERAL density (1, 2) and abnormal bone turnover (3, 4, 5) have been reported in HIV-infected patients. Reduced bone density has been shown in association with HIV-lipodystrophy, specifically with the increases of truncal (6) and visceral adiposity. Changes in fat distribution, including loss of sc fat and increased truncal and visceral adiposity, are prevalent among patients receiving antiretroviral therapy (7, 8, 9). Accumulation of abdominal adiposity has been associated with reduced GH levels in HIV-infected men (10, 11). Because it is well known that GH is an important regulator of bone remodeling and growth (12), the reduced GH levels in HIV lipodystrophy are a potential mechanism to explain reduced bone density in this population.

Recently, our group reported that up to 30% of HIV lipodystrophic men are GH deficient as defined by a reduced peak GH response to standard GHRH-arginine stimulation (13). GH deficiency in adults is accompanied by a decrease in bone mass and increased incidence of bone fractures (14), and reduced bone mass is observed in adults with childhood-onset GH deficiency (15). Replacement of GH has been effective at increasing markers of bone formation and bone mineral density in GH-deficient adults without HIV (16, 17, 18, 19). Preliminary studies in HIV have shown absolute or reduced rates of bone formation (3, 4, 5) in association with increased visceral adiposity and low GH levels. Thus, we hypothesized that increasing GH concentrations would increase bone formation over 12 wk in the HIV-infected men with fat accumulation. We used a novel strategy of short-term (3-month) GHRH therapy, which has been shown to increase IGF-I within the physiological range and decrease truncal adiposity in HIV-infected subjects with abdominal fat accumulation (20).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study population

From 2002 to 2003, 31 HIV-infected men with central fat accumulation were recruited through community advertisements and contact with physicians in the multidisciplinary HIV practice at the Massachusetts General Hospital (MGH) in Boston. Inclusion criteria included: men aged 18–60 yr previously diagnosed with HIV infection; stable antiviral regimen for at least 6 wk before enrollment; waist to hip ratio 0.90 or greater; and evidence of at least one of the following recent changes: 1) increased abdominal girth, 2) relative loss of fat in the extremities, or 3) relative loss of fat in the face. A similar algorithm was previously used to identify HIV patients with fat redistribution and decreased GH (10). Subjects with diabetes mellitus (fasting blood glucose > 126 mg/dl); body mass index (BMI) less than 20 kg/m2; hemoglobin less than 9 g/dl; and use of GH, GHRH, oral or parenteral glucocorticoids, megestrol acetate, or antidiabetic agents within the 3 months before study initiation were excluded. Written informed consent was obtained from each subject before testing, in accordance with the Subcommittee on Human Studies at the Massachusetts General Hospital. The effects of GHRH on IGF-I and body composition in this study were recently reported (20).

Clinical research protocol

After a 12-h overnight fast, subjects reported to the General Clinical Research Center for a screening visit. Past and current medications, including the patient’s history of antiviral therapy, were recorded. Subjects had a physical examination that included measurement of the neck, midarm, trunk, and waist to hip ratio. Eligible subjects returned to the General Clinical Research Center at MGH for baseline visit and end-of-study visit at 12 wk. During the baseline and end-of-study visits, the following parameters were evaluated after a 12-h overnight fast: 1) height and weight; 2) IGF-I, IGF binding proteins (IGFBPs) 1 and 3, glucose, hemoglobin A1c, insulin, cholesterol, low-density lipoprotein, high-density lipoprotein and triglyceride, total testosterone; 3) 75-g oral glucose tolerance test for glucose and insulin; 4) CD4 count and viral load; 5) resting energy expenditure and 4-d food record; 6) whole-body dual-energy x-ray absorptiometry (DXA) scan to assess body composition; 7) single-slice abdominal computerized tomography (CT) scan at L4 and midthigh; 8) physician and patient rating of lipodystrophy; and 9) calcium, phosphorus, albumin, 25 hydroxyvitamin D, 1,25 dihydroxyvitamin D, PTH, serum bone-specific alkaline phosphatase (BSAP), N-terminal propeptide of type 1 procollagen (PINP), C-terminal telopeptide (CTx), and N-terminal telopeptide (NTx). Subjects underwent every 20-min sampling for GH from 1900 to 0740 h as previously described (20).

After baseline testing was completed, subjects were randomly assigned to receive sc daily injections of Geref (GHRH 1–29) (1 mg every 12 h; Serono, Rockland, MA) or identical placebo. Randomization codes were available to the study statistician and the MGH pharmacy but not to study investigators. Placebo was manufactured by the MGH pharmacy and was identical with active drug in color and consistency and packaging. Compliance history and vial count were performed at each visit.

Bone density assessment

All scans were performed with a LightSpeed CT scanner (General Electric, Milwaukee, WI). A lateral scout image of the abdomen was obtained to identify the L4 pedicle, which served as a landmark for a single-slice image at this level. The scans were angled parallel to the vertebral endplates. Scan parameters for each image were standardized (144 cm table height, 80 kV, 70 mA, 2 sec, 1-cm slice thickness, 48-cm field of view) (21, 22, 23, 24). A region of interest was placed in the anterior portion of the vertebral body, excluding cortical bone and venous outflow. Density was calibrated against a phantom containing K2HPO4 (24) using Impax workstations (AGFA Diagnostic Software, version 4; AGFA, Ridgefield Park, NJ). The percentage of subjects with a Z score less than –1.0 SD and –2.5 SD or greater and Z score less than –2.5 SD based on age and gender-matched normative data (23, 25) is reported.

Body composition analysis

Anthropometric measurements were determined by standard techniques (26). Whole-body and regional fat were determined by DXA as previously described (27). The precision error in our DXA laboratory is 1.7% for fat mass and 2.4% for fat-free mass. Single-slice cross-sectional abdominal CT scanning was performed to assess the relative distribution of sc and visceral abdominal fat and midthigh sc fat as previously described by Koutkia et al. (20).

GH secretory dynamics

To assess GH pulsatility, we used Cluster (2x2) (28, 29). Cluster is a largely model-free, computerized pulse analysis algorithm that identifies statistically significant pulses in an individual GH time series. The program uses a sliding pooled t test to identify statistically significant increases and decreases in GH concentration (28, 29). We specified individual test cluster sizes for the nadir and peak width of 2 (29).

Laboratory methods

Bone markers. Serum osteocalcin was measured using a two-site immunoradiometric assay detecting intact osteocalcin-(1–49) with an intraassay coefficient of variation (CV) of 3.2–5.2% (Nichols Institute Diagnostics, San Juan Capistrano, CA). Serum PINP was measured by RIA designed for in vitro measurement of intact aminoterminal propeptide of type 1 procollagen concentration in human serum (Orion Diagnostica UniQ kit, DiaSorin, Stillwater, MN). Serum CTx was measured by using the serum cross-laps ELISA, which is an enzyme immunological test for the quantification of degradation products of CTx of type I collagen in human serum (intraassay CV of 5.0–5.4%, Nordic Bioscience Diagnostics, Herlev, Denmark). The serum Osteomark NTx was used to measure the cross-linked NTx (intraassay CV was 4.6%, Ostex International, Inc, Seattle, WA). Serum BSAP was measured by immunoenzymatic technique with sensitivity of 0.1–120 µg/liter (intraassay CV of 2.34–4.17%, Quest Diagnostics Nichols Institute, Chantilly VA).

Calciotropic hormones

Serum 25-hydroxyvitamin D was measured by RIA kit (intraassay CV of 8.6–12.5%, DiaSorin). The 1,25-dihydroxyvitamin D was measured using a competitive ELISA with an intraassay CV of 6.6% (American Laboratory Products Co., Windham, NH). Serum PTH was measured using a two-sided immunoradiometric assay (intraassay CV of 1.8–3.4%, Nicholas Institute Diagnostics)

GH, IGF-I, IGFBP-1, and IGFBP-3

GH was measured by two-site radioimmunometric assay with sensitivity of 0.05 ng/ml (interassay CV of 6.6%, intraassay CV of 4.4%; Corning, Inc., Nichols Institute Diagnostics). IGF-I was measured by two-site radioimmunometric assay with sensitivity of 2.6 ng/ml (interassay CV of 5.1%; intraassay CV of 4.9%; Diagnostics Systems Laboratory Inc., Webster, TX). IGFBP-1 was measured by two-site radioimmunometric assay with sensitivity of 0.33 ng/ml (intraassay CV of 4.2%; Diagnostic Systems Laboratories). IGFBP-3 was measured by two-site radioimmunometric assay with sensitivity of 0.5 ng/ml (intraassay CV of 2.9%; Diagnostic Systems Laboratories).

Hormonal and metabolic parameters

Total testosterone was measured by RIA with sensitivity of 4 ng/dl (intraassay CV ranged 5–11% and interassay CV 5.9–12%, Diagnostic Products).

Glucose, hemoglobin A1c, and lipid concentrations were measured by standard techniques. The CD4 count was determined by flow cytometry (Becton Dickinson, San Jose, CA), and the HIV viral load was determined by ultrasensitive assay (Amplicor HIV-1 monitor assay; Roche, Indianapolis, IN), with limits of detection of 50 copies/ml to 75,000 copies/ml.

Statistical analysis

Univariate regression analyses were performed at baseline relating bone turnover indices to bone density, body composition, and GH secretory parameters. Baseline parameters were compared by t test. Race and antiretroviral use were compared by likelihood ratio. CD4 count and viral load were compared by the Wilcoxon test. Change over time between the treatment groups (GHRH vs. placebo) was compared by t test. Outlier analysis was performed using the Dixon criteria (30). Statistical significance was defined as P ≤ 0.05. Results are mean ± SEM unless otherwise indicated. Statistical analyses were performed using JMP (SAS Institute, Cary, NC).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Demographic characteristics for the HIV-infected patients are shown in Table 1Go. Baseline characteristics, including age, BMI, IGF-I, IGFBP-1, IGFBP-3, bone density measurements, bone formation and resorption markers, and calciotropic hormones did not differ between the treatment groups (P > 0.05 for all baseline comparisons, Table 1Go). Baseline data were obtained for 31 subjects. Two subjects did not complete the study, and follow-up data were obtained in 29 subjects (20).


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  		TABLE 1. Baseline characteristics

 
At baseline, bone density was reduced below the mean for healthy, age-matched men with a mean Z score (number of SDs from the mean) of –0.70 ± 0.16. Thirty-two percent of our subjects (n = 10) demonstrated a bone density Z score less than –1.0 and greater than or equal to –2.5 SD, and 3% (n = 1) demonstrated a Z score of less than –2.5 SD. Bone density assessed by CT correlated positively with GH area during frequent sampling (r = 0.39, P = 0.03) but not IGF-I. Bone density tended to correlate inversely with visceral fat area (r = –0.33, P = 0.07) and positively with BSAP (r = 0.34, P = 0.07) but not with other markers of bone turnover or calcium homeostasis. IGF-I correlated with NTx (r = 0.49, P = 0.005) and tended to correlate with CTx (r = 0.35, P = 0.06) at baseline (Table 2Go). Indices of bone turnover tended to correlate inversely with viral load (Table 2Go).


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  		TABLE 2. Baseline correlations of bone, body composition GH, and immunological parameters in all subjects (n = 31)

 
IGF-I (104 ± 30 vs. 6 ± 11 ng/ml, P = 0.004) and IGFBP-3 (0.25 ± 0.13 vs. –0.15 ± 0.14 µg/ml, P = 0.05) increased significantly in response to GHRH (Table 3Go). Of the bone formation markers, PINP increased significantly in the treated group (14.6 ± 9.0 vs. –6.8 ± 3.1 µg/liter, GHRH vs. placebo, P = 0.03) (Fig. 1Go). Osteocalcin increased more in the GHRH group, compared with the placebo-treated group, and this change approached statistical significance (8.4 ± 3.0 vs. 2.0 ± 1.6 ng/ml, GHRH vs. placebo, P = 0.06). Of the bone resorption markers, CTx increased significantly (0.16 ± 0.07 vs. –0.03 ± 0.03 ng/ml, GHRH vs. placebo, P = 0.02), and NTx tended to increase in response to GHRH (2.8 ± 1.4 vs. –0.5 ± 1.0 nM bone collagen equivalent, GHRH vs. placebo, P = 0.07). The calciotropic hormones, calcium phosphorus, and 25 hydroxyvitamin D did not change significantly (Table 3Go). Bone density did not change significantly over 3 months of treatment with GHRH (P > 0.05).


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  		TABLE 3. Comparison of change from baseline in the treatment groups

 


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  		FIG. 1. A, Change from baseline in PINP (left panel) in the GHRH (dark bars) vs. placebo (light bars) group after 12 wk of treatment with GHRH. *, P = 0.03 GHRH treatment vs. placebo group. Results are mean ± SEM. B, Change from baseline CTx (right panel) in the GHRH (dark bars) vs. placebo (light bars) group after 12 wk of treatment with GHRH. **, P = 0.02 GHRH treatment vs. placebo group. Results are mean ± SEM. BCE, Bone collagen equivalent.

 
Among all patients, change in IGF-I correlated significantly with change in bone markers. The change in IGF-I correlated significantly with change in NTx (r = 0.45, P = 0.02), CTx (r = 0.38, P = 0.05), and osteocalcin (r = 0.55, P = 0.002) (Table 4Go). There was a significant correlation between markers of bone formation and resorption, e.g. the correlation between the change in CTx and osteocalcin (r = 0.65, P = 0.0002).


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  		TABLE 4. Correlations between change in bone markers and change in IGF-I in all subjects

 
In a prior study, we reported positive effects of GHRH on lean mass, visceral adipose tissue (VAT), the VAT to sc adipose tissue (SAT) ratio, trunk to lower extremity fat ratio, and IGF-I (20). Changes in bone markers did not correlate with changes in VAT.

GHRH treatment was generally well tolerated. Changes in glucose and insulin levels did not differ between the groups; however, one subject in the GHRH group experienced a 12-wk blood glucose level greater than 126 g/dl. No other toxicities were observed (20).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
HIV-infected patients treated with highly active antiretroviral therapy demonstrate changes in fat distribution, including increased visceral adiposity and reduced sc fat. In such patients, bone density is reduced in inverse association with increased visceral adiposity (31), whereas bone turnover is abnormal (3, 4, 5). The increase in visceral adiposity is associated with reduced GH secretion (10, 11). We hypothesized that increasing GH secretion would increase bone turnover in HIV-infected subjects with central fat accumulation. We chose GHRH as a physiological approach to increase GH levels without altering GH pulse frequency (32). GHRH has been shown to avoid the deleterious effects of high-dose GH on glucose and other metabolic abnormalities in this population (20).

GHRH is a potentially appealing strategy to increase bone turnover in HIV-infected patients. GHRH increases GH secretion and may increase bone turnover via this mechanism. GH administration increases bone turnover (16, 17, 18) and bone density in non-HIV-infected patients with low GH (19). Additionally, strategies that increase GH are known to be lipolytic in GH-deficient patients (33). Indeed, our recent study with GHRH achieved a physiological increase in IGF-I with simultaneous reductions in visceral fat and the ratio of VAT to SAT in HIV-infected patients with visceral adiposity with no deleterious effects on glucose or insulin (20). However, the effects of GHRH on bone turnover in HIV infected subjects with abdominal fat accumulation are not known, and the relationship among detailed parameters of GH secretion, bone turnover, fat distribution, and bone density has not been investigated in this population.

Our study population demonstrated reduced bone density. Using CT volumetric bone density and a gender- and age-matched reference population (23, 25), bone density was, on average, 0.70 SD below the expected bone density for healthy controls. Thirty-two percent of our subjects (n = 10) demonstrated a bone density Z score less than –1.0 and greater than or equal to –2.5 SD and 3% (n = 1) demonstrated a Z score of less than –2.5 SD. There was a trend toward decreased bone density in association with increased visceral adiposity (P = 0.07). In previous studies we have shown that wasting and weight loss are associated with reduced bone density in the HIV population (34), but the current study population was normal to slightly overweight (BMI 26.2 ± 0.6). Total testosterone levels were within normal limits.

The mechanism by which bone density is reduced in HIV-infected patients is unclear. HIV infection itself might be a contributing factor to the development of bone disease. Serrano et al. (35) reported that several parameters of formation, such as surface-based bone formation rate or turnover, such as activation frequency, were lower in patients with greater HIV disease severity. Similarly, in our study bone turnover tended to be lowest among patients with the highest viral load.

Highly active antiretroviral therapy (HAART), including protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs), may be associated with reduced bone density (35, 36, 37, 38, 39, 40, 41) and abnormal bone turnover (4, 42) in HIV-infected patients. However, the effects of HAART on bone density have not been fully clarified (3, 43). PIs may affect vitamin D synthesis through suppression of 1{alpha}-hydroxylase (44), but levels of 25 hydroxyvitamin D, 1,25 dihydroxyvitamin D, calcium, phosphorus, and PTH were normal in our study population.

Additionally, HAART is associated with an increased risk of developing osteoporosis and central obesity in HIV-infected men with lipodystrophy (36). Our group has previously shown that visceral adiposity is inversely related to decreased bone density in HIV-infected men with fat redistribution receiving HAART (31). A similar observation was recently made by Brown et al. (6) relating increased truncal adiposity and postload hyperglycemia to reduced bone mineral density.

Another potential explanation for abnormal bone turnover and reduced bone density in HIV-infected patients may be relative reductions in GH secretion. GH secretion is reduced in viscerally obese HIV-infected patients, and such patients have the most severe reductions in bone density (6, 31). Indeed, in the present study, we show for the first time that GH pulse area during overnight frequent sampling is positively related to bone density, suggesting that relative reductions in GH area with visceral adiposity may have an impact on bone density and bone turnover. After 3 months, GHRH treatment increased IGF-I and IGFBP-3, reduced VAT, and increased lean body mass (20). In response to GHRH, CTx and PINP increased significantly, whereas NTx and osteocalcin tended to increase as well. Change in IGF-I correlated significantly with changes in markers of bone turnover including NTx, CTx, and osteocalcin in all subjects. No significant changes were seen in calcium, phosphorus, or other calciotropic hormones in response to GHRH.

In humans, GH secretagogue treatment affects biochemical markers of bone turnover and increases growth velocity in selected short children with or without GH deficiency (45). In rodents, GH secretagogue treatment increase bone mineral content, but it has not yet been shown that GH secretagogue treatment can affect bone mass in adult humans (46). In this study we show significant and near significant effects on multiple markers of bone turnover, including indices of bone formation and also serum markers of bone resorption.

Skeletal integrity is maintained by a dynamic process of cellular events, with bone resorption by osteoclasts and subsequent formation of new bone by osteoblasts (47). During normal bone turnover these processes are closely regulated and synchronized. GH is implicated in the regulation of both osteoblast and osteoclast formation and activity, both directly and via IGF-I. Our findings of increased PINP and CTx suggest that GHRH increases bone turnover. There was a strong correlation between changes in the markers of formation and resorption, suggesting a global increase in bone turnover and coupling between formation and resorption indices in response to GHRH.

Prior studies show a significant increase in bone mineral density and bone mass after 6 months of GH treatment in GH-deficient adults (48). Prolonged treatment with GH results in increased BMD in GH-deficient patients (49, 50). The study duration, 3 months, was too short to see an effect of GHRH on bone density. Further studies are needed to assess the effects of GHRH on bone density and see whether changes in bone density are predicted by baseline bone turnover or change in bone turnover in response to GHRH. Furthermore, the effects of GHRH on fracture risk should be assessed in HIV patients.

In our study we used spinal CT to evaluate bone density. Quantitative CT is an established method for the assessment of bone mineral density (21, 22, 23). The strengths of quantitative CT as compared with DXA are its ability to precisely locate the region of interest in three dimensions and provide a direct bone density measurement as well as its ability to spatially separate cancellous bone from cortical bone (24).

Our findings indicate increased bone turnover in response to short-term GHRH in an HIV-infected population with increased visceral adiposity and relative reductions in bone density. In this population, reduced GH secretion correlated with reduced bone density and inversely with visceral adiposity, suggesting a possible connection between increased visceral adiposity, reduced GH, and low bone density. Long-term studies are needed to determine whether the stimulatory effects of GHRH on bone turnover will translate into increased bone density in this population. Because of its stimulatory effects on bone turnover and reduction of visceral adiposity in HIV-infected patients with fat accumulation, GHRH may be a useful therapy in this population.


   Acknowledgments
 
We acknowledge the nursing and bionutrition staffs of the General Clinical Research Center of the Massachusetts General Hospital and Massachusetts Institute of Technology for their dedicated patient care. Study medication was provided by Serono, Inc. Serono had no role in the conduct or analysis of the study.


   Footnotes
 
This work was supported in part by National Institutes of Health Grants R01 DK063639 and M01-RR01066.

First Published Online December 28, 2004

Abbreviations: BMI, Body mass index; BSAP, bone-specific alkaline phosphatase; CT, computerized tomography; CTx, C-terminal telopeptide; CV, coefficient of variation; DXA, dual-energy x-ray absorptiometry; HAART, highly active antiretroviral therapy; IGFBP, IGF binding protein; NRTI, nucleoside reverse transcriptase inhibitor; NTx, N-terminal telopeptide; PI, protease inhibitor; PINP, N-terminal propeptide of type 1 procollagen; VAT, visceral adipose tissue.

Received July 23, 2004.

Accepted December 16, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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