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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-1694
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 3 1093-1098
Copyright © 2006 by The Endocrine Society

Growth Hormone (GH) Substitution in GH-Deficient Patients Inhibits 11ß-Hydroxysteroid Dehydrogenase Type 1 Messenger Ribonucleic Acid Expression in Adipose Tissue

Søren Kildeberg Paulsen, Steen Bønløkke Pedersen, Jens Otto Lunde Jørgensen, Sanne Fisker, Jens Sandahl Christiansen, Allan Flyvbjerg and Bjørn Richelsen

Department of Endocrinology and Metabolism C (S.K.P., S.B.P., S.F., B.R.), Medical Department M (Diabetes and Endocrinology) (J.O.L.J., J.S.C.), and The Medical Research Laboratories (A.F.), Clinical Institute and Medical Department M (Diabetes and Endocrinology), Aarhus University Hospital, Aarhus Sygehus, DK-8000 Aarhus C, Denmark

Address all correspondence and requests for reprints to: Søren K. Paulsen, Department of Endocrinology and Metabolism C, Aarhus University Hospital, Aarhus Sygehus, Tage Hansensgade 2, DK-8000 Aarhus C, Denmark. E-mail: skpaulsen{at}dadlnet.dk.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: Local tissue activity of glucocorticoids is in part determined by the isoenzymes 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) and 11ß-HSD2, interconverting inert cortisone and active cortisol. Increased tissue activity of cortisol may play a central role in the features of GH deficiency and the metabolic syndrome.

Objective: We investigated the effects of GH treatment on adipose tissue 11ß-HSD mRNA.

Subjects and Methods: A randomized placebo-controlled double-blind study design was used. Twenty-three GH-deficient patients (16 males and seven females) were randomized to 4 months of GH treatment (2 IU/m2) (n = 11) or placebo treatment (n = 12). Adipose tissue biopsies and blood samples were obtained before and after treatment. Biopsies were obtained from the abdominal sc depot at the level of the umbilicus and do not necessarily reflect the metabolically more important visceral adipose tissue. Gene expressions were determined by real-time RT-PCR.

Results: GH treatment decreased 11ß-HSD1 mRNA 66% [95% confidence interval (CI), 23–107%; P < 0.01] and increased 11ß-HSD2 mRNA 167% (95% CI, 33–297%; P < 0.05) in adipose tissue. Serum IGF-I and IGF-I mRNA increased in the GH-treated group by 187% (95% CI, 122–250%; P < 0.001) and 470% (95% CI, 88–846%; P < 0.01). The change in 11ß-HSD1 mRNA expression was negatively correlated with the change in serum IGF-I (R = –0.434; P < 0.05). In contrast, the change in 11ß-HSD2 mRNA expression was positively correlated with the change in serum IGF-I (R = 0.487; P < 0.05), and even stronger with the change in IGF-I mRNA expression (R = 0.798; P < 0.0001).

Conclusion: GH treatment is able to decrease 11ß-HSD1 mRNA and increase 11ß-HSD2 and accordingly may be able to reduce the amount of locally produced cortisol in adipose tissue.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
IT IS WIDELY accepted that the distribution of fat is important for the morbidity and mortality associated with obesity. Central obesity, in particular, is associated with insulin resistance, development of type 2 diabetes, dyslipidemia, cardiovascular morbidity and the metabolic syndrome (1, 2, 3). The morphological and metabolic features of the metabolic syndrome have apparent similarities with the features of Cushing’s syndrome, which has led to the assumption that cortisol excess, or increased tissue activity of cortisol, is a contributor to the metabolic syndrome (4). Although serum cortisol levels are not elevated in simple obesity or in the metabolic syndrome (5), recent studies suggest that peripheral cortisol production is increased (6) and that the hypothalamic-pituitary-adrenal axis is abnormally regulated (7, 8).

Patients suffering from GH deficiency (GHD) share some of the clinical features of the metabolic syndrome and of Cushing’s disease, particularly central obesity, insulin resistance, type 2 diabetes, cardiovascular morbidity, and mortality, some of which are improved during replacement therapy (9, 10, 11, 12). Furthermore, obesity is associated with a decrease in GH secretion and an inadequate response to stimuli (13, 14, 15). GH concentrations are negatively correlated with both intraabdominal fat mass and waist-to-hip ratio (16), and weight loss results in improved or normalized GH secretion (13), indicating that the relative GHD is secondary to the central obesity. Furthermore, GH treatment in obesity causes loss of both intraabdominal fat and sc fat (17). Thus, GHD, central obesity and the associated metabolic syndrome, and glucocorticoid excess or activity seem evidently coherent.

Because serum cortisol levels in central obesity and GHD are normal, recent focus has been on altered tissue activity of cortisol or autocrine conversion of inactive cortisone to active cortisol. The tissue activity of cortisol is mainly determined by the 11ß-hydroxysteroid dehydrogenases (11ß-HSDs), of which two isoenzymes exist. 11ß-HSD2 protects mineralocorticoid receptors from the influence of cortisol by converting this to the inert cortisone. It is therefore primarily expressed in the distal nephron of the kidney and in sweat and salivary glands (5). Its presence and importance in adipose tissue are undetermined. 11ß-HSD1 is bidirectional, thus interconverting active cortisol and inert cortisone. However, in intact cells and organs, it catalyzes the conversion of cortisone to cortisol (5, 18, 19). Because inert free cortisone is abundant in circulation, the expression and activity of the enzyme is considered a major determent for local cortisol action. 11ß-HSD1 is widely expressed, notably in liver, adipose tissue, lung, and gonads. The mechanisms regulating the 11ß-HSD isoenzymes are complex and still, to a great extent, unsettled. In vitro studies show that 11ß-HSD1 is inhibited by GH and/or IGF-I (20). Furthermore, in primary GHD and in the relative GHD associated with obesity, treatment with GH has been shown to reduce urinary tetra-metabolite ratio of cortisol and cortisone (tetrahydrocortisol plus {alpha}-tetrahydrocortisol/tetrahydrocortisone), an indicator of whole-body activity of 11ß-HSD1 (21, 22, 23). The specific changes of the expression and activity of the 11ß-HSDs in adipose tissue during GH treatment are still unidentified.

We investigated the effect of 4 months of GH treatment on the expression of 11ß-HSD1 and 11ß-HSD2 mRNA in adipose tissue in GHD adults.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Twenty-three patients (seven females and 16 males) participated in the study. Seventeen patients had adult-onset hypopituitarism secondary to a pituitary mass lesion or its surgical treatment; none of these patients had received GH substitution before the study. Six patients were diagnosed with GHD in childhood, of whom three had idiopathic hypopituitarism. Twenty-one patients had additional pituitary deficits for which they had received stable replacement for at least 1 yr before the study; this included 18 patients receiving hydrocortisone (seven in the placebo group and 11 in the GH group). GHD was ultimately diagnosed or reconfirmed by at least two of the following stimulation tests using a cutoff of 5 µg/liter: insulin-induced hypoglycemia test [blood glucose < 0.4 g/liter (2.2 mmol/liter)], a clonidine test, arginine test, or the heat test. Additional clinical data of the patients are given in Table 1Go, some of which have previously been published (10, 24, 25, 26, 27). All participants were included in the study after giving written informed consent in accordance with Helsinki Declaration II. The study was approved by the national and the local ethical committees. The study was double blinded and placebo controlled, and patients were randomized to 4 months of GH treatment (Norditropin; Novo Nordisk A/S, Copenhagen, Denmark) in a dose of 2 IU/m2 (0.67 mg/m2) (n = 11) or 4 months of placebo treatment (n = 12). Full GH doses were reached during a 6-wk period.


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  		TABLE 1. Patient characteristics before and after 4 months of placebo or GH treatment

 
Adipose tissue biopsies

Adipose tissue biopsies were obtained by liposuction from the sc abdominal region (periumbilically) after an overnight fast. After local anesthesia with lidocaine (10 g/liter), isotonic NaCl was injected through the liposuction cannula, and biopsies were obtained by applying vacuum. The adipose tissue was washed with isotonic saline to remove blood and then frozen in liquid nitrogen for later RNA extraction. Biopsies were obtained before and after 4 months of GH or placebo treatment.

To compare isolated adipocytes and stroma-vascular cells, adipose tissue was obtained from 10 healthy individuals undergoing liposuction for cosmetic reasons.

Isolation of RNA

Total RNA was isolated from the biopsies using the TriZol reagent (Life Technologies, Inc., Life Technologies, Roskilde, Denmark), RNA was quantified by measuring absorbency at 260 and 280 nm, and the ratio should be 1.8 or higher. Finally, the integrity of the RNA was checked by visual inspection of the two ribosomal RNAs 18S and 28S on an agarose gel.

Real-time RT-PCR measurement of IGF-I, 11ß-HSD1, and 11ß-HSD2 mRNA

For real-time RT-PCR, cDNA was constructed using random hexamer primers as described by the manufacturer (GeneAmp RNA PCR kit from Perkin-Elmer Cetus, Norwalk, CT). PCR Mastermix, containing the specific primers, Hot star Taq DNA polymerase, and SYBR-Green PCR buffer was then added. The following primer pairs were used: IGF-I sense primer 5'-GACAGGGGCTTTTATTTCACC-3' and antisense primer 5'-CTCCAGCCTCCTTAGATCAC-3' [threshold cycle (CT) baseline, 24.41 ± 0.21); 11ß-HSD1 sense primer 5'-GACCATGACCTTCGCAGAGCAATTTGT-3' and antisense primer 5'-GACGCCAAGAACACAGAGAGTGATTGA-3' (CT baseline, 27.60 ± 0.31); 11ß-HSD2 sense primer 5'-CTTATGGAACCTCCAAAGCG-3' and antisense primer 5'-CAGGGAAGGAGTTCACAGC-3' (CT baseline, 31.17 ± 0.16). As a housekeeping gene, ß-actin was amplified using sense primer 5'-GTGCCCATCTACGAGGGGTATGC-3' and antisense primer 5'-GGTACATGGTGGTGCCGCCAGACA-3' (CT baseline, 21.79 ± 0.26). Real-time quantification of genes was performed with SYBR-Green real-time RT-PCR assay (QIAGEN, Inc., Chatsworth, CA) using an ICycler from Bio-Rad (Bio-Rad Laboratories, Hercules, CA). Gene mRNA was amplified in separate tubes, and the increase in fluorescence was measured in real time. The CT was calculated, and the relative gene expression was calculated essentially as described in the User Bulletin no. 2, 1997, from Perkin-Elmer. All samples were amplified in duplicate. A similar set-up was used for negative controls except that the reverse transcriptase was omitted and no PCR products were detected under these conditions.

Preparation of isolated adipocytes and stroma-vascular cells

The adipose tissue was washed with isotonic saline to remove blood and thereafter isolated by collagenase digestion (0.15 mg/g adipose tissue) of adipose tissue fragments in 10 mmol/liter HEPES buffer for 45–60 min at 37 C. The isolated adipocytes were washed in medium three times. Finally, the cell suspension containing 10% adipose cells was snap-frozen in liquid nitrogen and kept at –80 C for later RNA extraction. The remaining stroma-vascular fraction was centrifuged, resuspended in buffer, and filtered through a nylon mesh three times, after which the supernatant was removed and the stroma-vascular fraction was snap-frozen in liquid nitrogen and kept at –80 C for later RNA extraction.

Analysis of blood samples

Serum IGF-I was measured using an in-house RIA after extraction of serum.

Statistical analysis

Mann-Whitney rank sum test was used to compare groups. When necessary, data were logarithmically transformed to achieve normality. Correlation between variables was tested by Pearson’s correlation coefficient. The level of significance chosen was 0.05. Data represent mean ± SEM unless otherwise stated. All analyses were performed with SigmaStat (Systat Software, Inc., Richmond, CA) statistical software.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
No significant difference in age or serum IGF-I between the placebo-treated group and the GH-treated group at baseline was found, nor did we find any significant differences in the mRNA expression of IGF-I, 11ß-HSD1, or 11ß-HSD2. We found a tendency to a difference in body mass index (BMI), the placebo-treated group having the higher BMI (P = 0.083). Because expression and activity of 11ß-HSD1 in some studies has been linked to BMI (28, 29, 30, 31, 32) and has been shown to correlate positively with BMI (30), a test for correlation between BMI and 11ß-HSD1 mRNA expression was performed. In this study, we found no correlation between BMI and 11ß-HSD1 mRNA expression (R = 0.034; P = 0.881).

Substitution with GH for 4 months in GHD patients resulted in a 66% [95% confidence interval (CI), 23–107%] decrease in mRNA expression of 11ß-HSD1 (P < 0.01) compared with baseline. Furthermore, the mRNA expression of 11ß-HSD1 was significantly (P < 0.01) decreased in the GH-treated group compared with the placebo-treated group, where no change in 11ß-HSD1 mRNA expression was found (Fig. 1Go). Because the regulation and metabolism of fat tissue differs between sexes, we compared the mRNA expression of 11ß-HSD1 between men and women and found that in this study, 11ß-HSD1 mRNA expression was significantly higher in men compared with women (P < 0.05). A gender-specific analysis of the mRNA expression was consequently performed. We found that in both men and women, GH treatment resulted in a decrease in 11ß-HSD1 mRNA expression of 66% (males) and 64% (females), respectively (Fig. 1Go, insets), although this was significant only in the male group (P < 0.05). No difference in 11ß-HSD2 mRNA expression between men and women was detected in this study. Thus it seems that GH/IGF-I exerts its effects on 11ß-HSD1 mRNA expression in human adipose tissue irrespective of gender.


Figure 1
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  		FIG. 1. Effects of GH/placebo treatment on 11ß-HSD1 mRNA in adipose tissue. 11ß-HSD1 mRNA is shown relative to ß-actin mRNA before (black bars) and after (white bars) treatment for 4 months with GH or placebo. Insets represent results for men exclusively (top) and women (bottom). Data represent mean ± SEM; *, P < 0.01 (before vs. after treatment); **, P < 0.05 (before vs. after treatment).

 
Treatment with GH was associated with about 3-fold increase (95% CI, 2.22- to 3.50-fold increase) in serum IGF-I (P < 0.001) as well as a 5-fold increase (95% CI, 1.88- to 9.46-fold increase) in the mRNA expression of IGF-I in adipose tissue (P < 0.01).

Adipose tissue 11ß-HSD2 mRNA expression was increased 1.7-fold (95% CI, 1.33–3.97; P < 0.05) in the GH-treated group (Fig. 2Go), whereas no change in mRNA was found in the placebo-treated group.


Figure 2
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  		FIG. 2. Effects of GH/placebo treatment on 11ß-HSD2 mRNA in adipose tissue. 11ß-HSD 2 mRNA is shown relative to ß-actin mRNA before (black bars) and after (white bars) treatment for 4 months with GH or placebo. Data represent mean ± SEM; *, P < 0.05 (before vs. after treatment).

 
The change in serum IGF-I levels and in adipose tissue IGF-I mRNA expression was positive correlated (R = 0.545; P < 0.01). The change in 11ß-HSD1 expression was negatively correlated with the change in serum IGF-I (R = –0.434; P < 0.05) (Fig. 3Go). In contrast, the change in the expression of 11ß-HSD2 was found to be positively correlated with the change in serum IGF-I (R = 0.487; P < 0.05) (Fig. 3Go) and even more strongly correlated with the change in mRNA expression of IGF-I (R = 0.798; P < 0.0001).


Figure 3
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  		FIG. 3. Correlation between the change in serum IGF-I and in mRNA expression of 11ß-HSD1 (A) (R = –0.434; P < 0.05) and serum IGF-I and mRNA expression of 11ß-HSD2 (B) (R = 0.487; P < 0.05). Data represent logged values.

 
To determine which cell types in the adipose tissue may be of importance for the expression of 11ß-HSDs, we investigated isolated adipocytes and the stroma-vascular cells from human adipose tissue. 11ß-HSD1 mRNA was equally expressed in adipocytes and in the stroma-vascular cells, whereas 11ß-HSD2 mRNA was primarily expressed in the stroma-vascular fraction (P < 0.005) (Fig. 4Go).


Figure 4
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  		FIG. 4. 11ß-HSD1 mRNA and 11ß-HSD2 mRNA relative to ß-actin mRNA in stroma-vascular cells (black bars) and isolated adipocytes (white bars). Data represent mean ± SEM; *, P < 0.005 (stroma-vascular fraction vs. isolated adipocytes).

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
In the present study, we demonstrated that GH treatment in GHD patients markedly decrease the gene expression of 11-ß HSD1 in sc abdominal tissue. Previous studies have shown that GH treatment in GHD as well as in simple obesity reduces the urinary tetra-metabolite ratio of cortisol and cortisone (21, 22), indicating a reduced activity of 11ß-HSD1. These studies reflect whole-body changes in the metabolism of cortisol and cortisone rather than the sole changes in the activity of the 11ß-HSDs, and the results have been somewhat conflicting (5, 18). This study is the first to describe the tissue-specific changes in the expression of 11ß-HSD1 in human adipose tissue during GH treatment. Adipose tissue 11ß-HSD1 expression is of particular interest because studies of transgenic mice have shown that increased adipose 11ß-HSD1 expression resembles the metabolic syndrome and GHD (33), which may be a consequence of increased local production of cortisol in adipose tissue. Furthermore, a recent study has shown that increased inactivation of cortisol in adipocytes, by making transgenic mice overexpressing 11ß-HSD2 in adipocytes, protects against obesity and improves insulin sensitivity, glucose tolerance, and adipokine profile (34). In humans, obesity is associated with an increased expression and activity of 11ß-HSD1 in adipose tissue (28, 29, 30, 32), irrespective of the presence of insulin resistance, whereas hepatic 11ß-HSD1 seems to be compensatorily reduced (6, 28, 29).

The metabolic complications of central obesity are often attributed to visceral fat rather than sc fat. In this study, we examine changes in sc adipose tissue from the umbilical region, which cannot be assumed to reflect changes in visceral adipose tissue, because metabolic regulation and enzyme expression in sc and visceral adipose tissue generally is uneven. Because intraabdominal adipose tissue is unobtainable from our patient cohort, using sc adipose tissue biopsies from the umbilical region, as used in our study, seems prudent, because previous studies have shown that the metabolic characteristics of visceral adipose tissue and abdominal sc adipose tissue correspond better than visceral and sc adipose tissue from the lower body, e.g. gluteal adipose tissue (35). The mRNA expression of 11ß-HSD1 in visceral and in sc abdominal adipose tissue has previously been reported not to differ (36).

The effects of GH on the activity and expression of 11ß-HSD1 are thought to be mediated through IGF-I, rather than GH, because in vitro studies have shown a dose-dependent inhibition of 11ß-HSD1 by IGF-I but not GH (20, 23). We find that IGF-I in serum as well as the mRNA expression of IGF-I in the sc abdominal adipose tissue, as expected, is significantly increased by GH treatment. Additionally, we find that the mRNA expression of 11ß-HSD1 is negatively correlated with serum IGF-I, suggesting that in human adipose tissue, 11ß-HSD1 is also down-regulated by IGF-I.

Whereas 11ß-HSD1 is a bidirectional enzyme, 11ß-HSD2 is a unidirectional enzyme converting the active cortisol to inert cortisone. It is NAD+ dependent and has a high affinity (Km, approximately 15 nM) (37) for cortisol compared with 11ß-HSD1 (Km, approximately 2 µM) (38). It is primarily expressed in the target tissues for mineralocorticoids, excluding cortisol from exerting an effect on the mineralocorticoid receptor. Deficiency or inhibition of 11ß-HSD2 results in a syndrome of apparent mineralocorticoid excess, characterized by hypertension, hypokalemia, and sodium retention (39). It is, however, expressed in other tissues including lung (40), gonads (38), and endothelium (41). 11ß-HSD2 has not previously been reported in adipose tissue. The function of 11ß-HSD2 in non-mineralocorticoid target tissues is still to a great extent undisclosed, although some recent studies suggest that it may play a role, limiting glucocorticoid action in these tissues (38, 42).

We show that 11ß-HSD2 is indeed expressed in sc adipose tissue, the expression levels being approximately 17 times lower than 11ß-HSD1 at baseline. 11ß-HSD1 is equally expressed in isolated adipocytes and stroma-vascular cells, whereas 11ß-HSD2 is mainly expressed in the stroma-vascular fraction of the adipose tissue. Because adipocytes and cells in the stroma-vascular fraction of adipose tissue are known to cross-talk, it is indeed possible that 11ß-HSD2 exerts an effect on adipocytes and the adipose tissue as a whole. We found an increase of 11ß-HSD2 mRNA in the GH-treated group. Furthermore, we found that adipose tissue mRNA expression of 11ß-HSD2 was strongly correlated with adipose tissue IGF-I mRNA as well as with serum IGF-I. It can be argued that this low expression of 11ß-HSD2 might not have any physiological significance, although a recent study by Ge et al. (38) showed that despite very low 11ß-HSD2 expression level, at approximately 1/1000 of 11ß-HSD1 in Leydig cells, 11ß-HSD2 accounted for 50% of oxidase activity, concluding that 11ß-HSD2 may affect levels of active glucocorticoids even in tissues where the expression is low. In the present study, we found that adipose tissue 11ß-HSD2 expression levels were many times higher than in the latter study, because the 11ß-HSD1/11ß-HSD2 ratio in the GH-treated group was 2.4. The fact that the expression of 11ß-HSD2 found in our study is considerably higher, and that 11ß-HSD2 expression is closely correlated with IGF-I, suggests that it may perhaps play a part in the increased local cortisol activity associated with GHD and the relative GHD of simple obesity.

Thus, based on these findings, we propose that some of the effects of GH on adipose tissue distribution, adipose lipoprotein lipase activity and changes in adipose tissue cytokine production are caused by GH inducing either systemically or locally in adipose tissue an increase in IGF-I. This increase in IGF-I subsequently diminishes adipose tissue 11ß-HSD1 expression and stimulates 11ß-HSD2 expression, which results in lower levels of active cortisol. The lower level of active glucocorticoids may then result in lower lipoprotein lipase activity (18, 43) and lower differentiation of preadipocytes to mature adipocytes (44) and may change the production of adipokines that are known to be affected by cortisol (45, 46, 47).

GH treatment in GHD results in a favorable change in body composition, with increased lean body mass and loss of fat mass, particularly intraabdominal (9, 10), as well as improved cardiovascular risk factors (9). However, GH exerts an insulin-antagonistic effect as well, and GHD patients develop insulin resistance and decreased glucose tolerance during treatment with GH despite beneficial changes in body distribution (9, 10). The insulin-antagonistic effects of GH are not fully disclosed but are in part caused by stimulation of lipolysis (9, 27).

In conclusion, GH treatment increases serum IGF-I levels as well as increases adipose tissue IGF-I mRNA. Furthermore, a close positive association between IGF-I and 11ß-HSD1 in concert with a marked negative association between IGF-I and 11ß-HSD2 indicate that IGF-I might control adipose tissue expression of the 11ß-HSDs. The decrease in 11ß-HSD1 reduces adipose tissue activation of cortisone, and the up-regulation of 11ß-HSD2 may possibly increase the deactivation of cortisol. These changes are likely to result in lower adipose tissue levels of cortisol, which results in improved insulin sensitivity and glucose tolerance as well as an improved adipokine profile and reduced fat mass, especially visceral fat mass, because the density of the glucocorticoid receptor is higher in visceral adipose tissue (48). IGF-I and the 11ß-HSDs seem inevitably coherent, and the relative insufficiency of GH seen in truncal obesity (15, 16) may play a role in the development of the metabolic syndrome. Thus, inhibition of adipose 11ß-HSD1 or activation of adipose 11ß-HSD2 are obvious targets for preventing complications to obesity and the metabolic syndrome.


   Acknowledgments
 
We thank Lenette Pedersen and Pia Hornbæk for their excellent technical assistance.


   Footnotes
 
First Published Online December 20, 2005

Abbreviations: BMI, Body mass index; CI, confidence interval; CT, threshold cycle; GHD, GH deficiency; 11ß-HSD, 11ß-hydroxysteroid dehydrogenase.

This work was supported by the Danish Medical Research Council, The Clinical Institute, Aarhus University, and the Novo Nordisk Foundation.

Received July 29, 2005.

Accepted December 12, 2005.


   References
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 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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