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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2008-1333
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 11 4254-4260
Copyright © 2008 by The Endocrine Society

The Effects of Central Adiposity on Growth Hormone (GH) Response to GH-Releasing Hormone-Arginine Stimulation Testing in Men

Hideo Makimura, Takara Stanley, David Mun, Sung Min You and Steven Grinspoon

Program in Nutritional Metabolism and Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Hideo Makimura, M.D., Ph.D., Program in Nutritional Metabolism, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, LON 211, Boston, Massachusetts 02114. E-mail: hmakimura{at}partners.org.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: The relative contribution of central adiposity vs. weight on GH response to stimulation testing in obesity is not known.

Objective: We aimed to assess the contribution of weight and specific measures of central and peripheral adiposity to GH response to GHRH-arginine testing in lean, overweight, and obese men.

Design: A total of 75 men [mean age, 44.3 ± 1.1 yr; body mass index (BMI), 28.8 ± 0.7 kg/m2] were investigated. Subjects were classified as lean (BMI < 25 kg/m2; n = 23), overweight (BMI ≥ 25 and <30 kg/m2; n = 28), or obese (BMI ≥ 30 kg/m2; n = 24). Subjects were also stratified by waist circumference (WC) (<102 cm, n = 47; ≥102 cm, n = 28). Body composition and regional adiposity were assessed by anthropometrics, dual-energy x-ray absorptiometry (DEXA), and abdominal computed tomography (CT) scans.

Results: Peak stimulated GH was 36.4 ± 5.4, 16.6 ± 2.9, and 7.6 ± 0.9 µg/liter among lean, overweight, and obese subjects, respectively (P < 0.001 for all comparisons). Peak stimulated GH was 26.9 ± 3.4 µg/liter among subjects with WC less than 102 cm compared to 7.9 ± 0.9 µg/liter among subjects with WC of 102 cm or greater (P < 0.0001). Separate multivariate models using anthropometric, DEXA, and CT-derived measures of central adiposity demonstrated strong associations between peak stimulated GH and measures of central adiposity including WC, trunk fat by DEXA, and visceral adiposity by CT, controlling for age, BMI, and more general measures of adiposity. WC was independently associated with peak GH response to GHRH-arginine in a model including age, BMI, and hip circumference. In this model, BMI was no longer significant, and peak GH was reduced 1.02 µg/liter for each 1 cm increase in WC (P = 0.02).

Conclusions: GH response to GHRH-arginine testing is reduced in both overweight and obese subjects and negatively associated with indices of central abdominal obesity including WC, trunk fat, and visceral adipose tissue. The use of waist circumference, as a surrogate for central adiposity, adds predictive information to the determination of GH response, independent of BMI.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
Obesity is associated with decreased basal and pulsatile release of GH (1, 2, 3) as well as decreased stimulated GH release (4, 5, 6, 7, 8, 9). This GH deficiency associated with obesity is relative or functional, because weight loss restores 24-h GH pulse characteristics (10). Previous reports have suggested a potential relationship between relative GH deficiency of obesity and visceral adiposity. In a small study (n = 16) of obese premenopausal women, Pijl et al. (11) demonstrated decreased 24-h GH secretion in women with large visceral fat area compared with body mass index (BMI)-matched women with small visceral fat area, as determined by magnetic resonance imaging. In a study of 20 postmenopausal women, Franco et al. (12) demonstrated a negative association between basal and pulsatile GH secretion and visceral adiposity as determined by abdominal computed tomography (CT). In addition, trunk fat as assessed by dual-energy x-ray absorptiometry (DEXA) was inversely associated with mean 24-h GH pulse in a small study (n = 15) of nonobese women (13). Furthermore, Vahl et al. also demonstrated a negative association between mean 24-h GH levels and intraabdominal fat as measured by CT in 42 healthy men and women (14).

However, the contribution of central adiposity vs. body weight to the GH response to GHRH-arginine testing, a stimulation test commonly used in clinical practice, remains unknown in men and has not been assessed in relationship to specific measures of regional adiposity. More recently, the GH deficiency of obesity has been associated with increased carotid intima-media thickness (15). Taken together, these data suggest that reduced GH secretion in obesity may have cardiovascular consequences and may be mediated in part by central adiposity. These data also suggest the importance of determining the relative contribution of overall weight and central adiposity to GH response to standardized stimulation algorithms. We hypothesized that peak stimulated GH levels on GHRH-arginine test would be specifically associated with measures of central adiposity in men.


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

Seventy-five men from the Boston community were recruited between October 1999 and January 2008 using local print advertisement. Data from a subset (n = 43) were previously published in a study comparing GH secretion in non-HIV men to HIV-infected men (16, 17). Male subjects with a range of BMI, between the ages of 20 and 60 yr, and who were otherwise healthy without known pituitary dysfunction including dysfunction of the adrenal, GH, thyroid or gonadal axes were selected. Subjects receiving GH, anabolic hormones, glucocorticoids, testosterone, or any medication known to affect GH were excluded. Subjects with known diabetes mellitus, hemoglobin level less than 11 g/dl, creatinine above 1.5 mg/dl, aspartate aminotransferase above 2.5-fold upper limit of normal, and chronic illness such as HIV were also excluded. Subjects with a history and physical exam suggestive of pituitary dysfunction were also excluded. Written informed consent was obtained from each subject before testing, in accordance with the Committee on the use of Humans as Experimental Subjects of the Massachusetts Institute of Technology and the Subcommittee on Human Studies at the Massachusetts General Hospital.

Biochemical assessment

GH stimulation testing was performed using standard GHRH-arginine stimulation. After an overnight fast, sermorelin acetate (GHRH 1–29) (Geref; Serono Laboratories, Inc., Rockland, MA) was administered iv at a dose of 1 µg/kg. Subsequently, arginine hydrochloride (30 g/300 ml) was administered at a dose of 0.5 g/kg (maximum 30 g) via iv pump at 600 ml/h over 30 min. GH levels were assessed at 0, 30, 45, 60, 90, and 120 min after sermorelin administration. The 30-min time point coincides with the completion of the arginine infusion. Serum GH was measured by an immunoradiometric assay using kits from Nichols Institute (San Juan Capistrano, CA) [n = 43; intraassay coefficient of variation (CV), 4.4%; interassay CV, 6.6%] and Diagnostic Systems Laboratories (Webster, TX) (n = 32; intraassay CV ranging from 3.1 to 5.4%; interassay CV ranging from 5.9 to 11.5%). The World Health Organization First International Standard code 80/505 was used as GH standard with both kits. Results were recapitulated in separate analyses using data from each assay (data not shown) and combined to increase power because no obvious differences were seen by assay.

Anthropometric assessment

Height and body weight were obtained after an overnight fast. Measurement of waist circumference was performed in triplicate at the iliac crest in a standardized fashion with the subject in an upright position. Measurement of hip circumference was performed at the widest point, also with the subject in an upright position. Fat and fat-free mass were determined by DEXA testing using a Hologic-4500 densitometer (Hologic, Inc., Waltham, MA). Measurements of regional adiposity using DEXA were standardized (1995 User’s Guide Hologic Inc). Lower extremity fat represents the arithmetic sum of fat mass in each leg. The technique has a precision error (1 SD) of 3% for fat and 1.5% for lean body mass (18). In addition, 1-cm cross-sectional abdominal CT scans were performed at the level of L4 to assess the distribution of total abdominal adipose tissue (TAT), abdominal sc adipose tissue (SAT), and abdominal visceral adipose tissue (VAT) as previously described (16).

Statistical analysis

Continuous variables were tested for normality of distribution with the use of the Wilk-Shapiro test and examination of the histogram distribution. Variables that were normally distributed were compared using the Student’s t test, and variables that were not normally distributed were compared using the nonparametric Wilcoxon rank sum test. Nominal variables were compared using the {chi}2 test. GH area under the curve (AUC) response to GHRH-arginine testing was determined using the trapezoid method. For comparison between groups, subjects were stratified by BMI into lean (BMI < 25 kg/m2), overweight (BMI ≥ 25 and < 30 kg/m2), and obese (BMI ≥ 30 kg/m2), as well as by waist circumference using 102 cm as a cutoff as per the National Cholesterol Education Program (NCEP) guidelines of the Adult Treatment Panel III (19). Univariate regression analysis was performed comparing peak stimulated GH levels with measures of overall and regional adiposity using the Pearson correlation coefficient. Multivariate regression analysis with standard least squares modeling was also performed using age, BMI, and various measures of regional adiposity as covariates and peak stimulated GH as the dependent variable. Specific anthropometric, DEXA, and CT models were constructed. Combined models were not constructed due to the colinearity of measures of central adiposity by the various techniques and so that clear information would be provided on the specific utility of measures using each technique independently. Statistical analysis was performed using JMP Statistical Database Software (SAS Institute, Inc., Cary, NC). Statistical significance was determined as P < 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Clinical characteristics of study subjects

The subjects ranged in age from 20 to 60 yr. The BMI ranged from 20.0 to 47.3 kg/m2. Of the 75 subjects, 23 were lean (BMI < 25 kg/m2), 28 were overweight (BMI between 25 and 29.9 kg/m2), and 24 were obese (BMI ≥ 30 kg/m2) (Table 1Go). The subjects in each group were similar in age and ethnicity as well as height. Body composition variables including measures of both total and regional adiposity differed significantly across the strata. In addition, both systolic and diastolic blood pressure differed across BMI categories (Table 1Go).


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  		TABLE 1. Baseline characteristics of study subjects stratified by BMI (n = 75)

 
In a separate analysis, subjects were stratified according to waist circumference using 102 cm as the cutoff value as per NCEP guidelines (19). Forty-seven subjects had waist circumference less than 102 cm, whereas 28 subjects had waist circumference of at least 102 cm. The two groups had similar age, ethnicity, and height. BMI and measures of both total and regional adiposity differed significantly between groups stratified by waist circumference (Table 2Go).


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  		TABLE 2. Baseline characteristics of study subjects stratified by waist circumference (n = 75)

 
GHRH-arginine stimulation testing

The response to GHRH-arginine stimulation clearly segregated by BMI status (Fig. 1AGo). The peak stimulated GH occurred at 45 min and progressively declined over the remainder of the test. The peak stimulated GH levels were lower in the overweight subjects and lower still in the obese subjects (Fig. 1Go, B and C). The lean subjects had peak stimulated GH of 36.4 ± 5.4 µg/liter. In comparison, the overweight subjects had a peak stimulated GH level of 16.6 ± 2.9 µg/liter (P = 0.0001 in comparison with lean), and the obese subjects had a peak stimulated GH level of 7.6 ± 0.9 µg/liter (P < 0.0001 in comparison with lean; P = 0.0004 in comparison with overweight). Similarly, the AUC for GH during the GHRH-arginine stimulation test also differed by BMI (data not shown).


Figure 1
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  		FIG. 1. A, GHRH-arginine stimulation tests in lean (n = 23), overweight (n = 28), and obese (n = 24) subjects. The results are presented as mean ± SEM. P < 0.01 in all time points in lean vs. overweight subjects; P < 0.001 in all time points in lean vs. obese subjects; P < 0.05 in all time points except 90 min where P = 0.08 in overweight vs. obese subjects. B, Peak stimulated GH levels from GHRH-arginine stimulation tests in lean (n = 23), overweight (n = 28), and obese (n = 24) subjects. The results are presented as mean ± SEM. P = 0.0001 in lean vs. overweight subjects; P < 0.0001 in lean vs. obese subjects; P = 0.0004 in overweight vs. obese subjects. C, Scatter plot for peak stimulated GH levels from the GHRH-arginine stimulation tests in lean (n = 23), overweight (n = 28), and obese (n = 24) subjects. D, GHRH-arginine stimulation tests in subjects with waist circumference less than 102 cm (n = 47) and subjects with waist circumference of 102 cm or greater (n = 28). The results are presented as mean ± SEM. All time points are significant by P < 0.01. E, Peak stimulated GH levels from GHRH-arginine stimulation tests in subjects with waist circumference less than 102 cm (n = 47) and subjects with waist circumference of at least 102 cm (n = 28). The results are presented as mean ± SEM. P < 0.0001. F, Scatter plot for peak stimulated GH levels from the GHRH-arginine stimulation tests in subjects with waist circumference less than 102 cm (n = 47) and subjects with waist circumference of at least 102 cm (n = 28).

 
The response to GHRH-arginine stimulation also segregated by waist circumference (Fig. 1DGo). Subjects with waist circumference less than 102 cm had higher peak stimulated GH levels compared with subjects with waist circumference of at least 102 cm (26.9 ± 3.4 vs. 7.9 ± 0.9 µg/liter; P < 0.0001) (Fig. 1Go, E and F). Similarly, the GH AUC was also significantly higher in subjects with waist circumference less than 102 cm compared with subjects with waist circumference of 102 cm or more (data not shown).

Relationship of peak stimulated GH to measures of total and regional adiposity

Univariate analysis was performed among all subjects (including lean, overweight, and obese subjects; n = 75). Peak stimulated GH was negatively related to body weight, BMI, and various anthropometric measurements including waist circumference, hip circumference, waist-to-hip ratio, and measures of adiposity including TAT, VAT, SAT, lower extremity fat, trunk fat, total fat mass, and percentage fat mass. The peak stimulated GH levels were positively related to percentage lean body mass (Table 3Go). Similar results were seen for GH AUC (data not shown).


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  		TABLE 3. Univariate analysis of peak stimulated GH levels to various parameters in all subjects (n = 75)

 
Multivariate regression analysis was performed using standard least squares modeling among all subjects (n = 75). In a simple model consisting solely of age and BMI, BMI was significantly and inversely associated with peak stimulated GH levels (P < 0.0001; r2 = 0.26) (Table 4AGo). Subsequently, three distinct models were created to assess the significance of generalized and regional adiposity using: 1) anthropometric, 2) DEXA, and 3) abdominal CT scan measurements of overall adiposity, central, and regional fat depots.


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  		TABLE 4. Multivariate analyses of peak stimulated GH level and parameters of regional fat distribution (n = 75)

 
In the anthropometric model, waist circumference was significantly and inversely related to peak stimulated GH levels controlling for age, BMI, and hip circumference (P = 0.02; r2 = 0.32) (Table 4BGo). With the inclusion of waist circumference, BMI was no longer significantly associated with peak stimulated GH in the model. The effect size was –1.02, suggesting a 1 µg/liter decrease in peak stimulated GH for each 1 cm increase in waist circumference, controlling for age and BMI.

In the DEXA model, trunk fat was significantly inversely related to peak stimulated GH levels controlling for age, BMI, and lower extremity fat (P = 0.006; r2 = 0.35). With the inclusion of trunk fat, BMI and lower extremity fat were no longer significantly associated with peak stimulated GH in the model (Table 4CGo). The significant relationship between trunk fat and peak stimulated GH held with the addition of total lean mass to the model (P = 0.006; r2 = 0.36).

In the third model using CT measurements of specific depots of abdominal fat, a significant inverse relationship between VAT and peak stimulated GH was identified controlling for age, BMI, TAT, and SAT (P = 0.02; r2 = 0.34). With the inclusion of VAT, neither BMI, TAT, nor SAT was significantly associated with peak stimulated GH (Table 4DGo). The multivariate regression model was reanalyzed without TAT because this covariate is colinear with VAT; however, no significant changes were noted in the relationship between VAT and peak stimulated GH while controlling for age, BMI, and SAT (P = 0.02; r2 = 0.33).

Similar results were obtained for GH AUC in all three models (data not shown).

Correlation between anthropometric measurements, DEXA, and VAT

Both waist circumference (r = +0.84; P < 0.0001) and trunk fat (r = +0.86; P < 0.0001) were significantly and strongly associated with VAT in univariate regression analysis.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Previous studies have demonstrated an association between peak stimulated GH levels and BMI (9, 20). Furthermore, Pijl et al. (11) demonstrated an association between 24-h GH secretion and visceral fat as assessed by magnetic resonance imaging in obese premenopausal women, whereas Franco et al. (12) demonstrated an association between basal and pulsatile GH secretion on 24-h frequent sampling and visceral fat as assessed by CT in postmenopausal subjects. In addition, Miller et al. (13) demonstrated an association between 24-h GH secretion and truncal adiposity in nonobese women. However, prior studies have not investigated the relationship between GH response to GHRH-arginine and specific measures of regional adiposity in men. Our data demonstrate that peak stimulated GH levels on GHRH-arginine testing are most strongly associated with measures of central adiposity such as waist circumference, trunk fat, and VAT when controlling for age, BMI, and peripheral fat. These data highlight the importance of central adiposity, independent of weight per se, as a strong predictor of GH response to standardized testing.

Visceral adiposity is thought to confer increased risk for metabolic complications of obesity including dyslipidemia, insulin resistance, and increased cardiovascular disease risk (21, 22, 23). The data in this study suggest that increased visceral adiposity may contribute to reduced GH secretion, which may be a further mechanism for increased cardiovascular disease risk in men with central adiposity. Among women, Utz et al. (15) recently demonstrated that relative GH deficiency of obesity is associated with increased carotid intima-media thickness, analogous to the cardiovascular disease risk seen with GH deficiency of hypopituitarism (24). Similar studies investigating the independent effects of reduced GH secretion on cardiovascular disease risk among obese but otherwise healthy men are currently under way.

Although VAT was significantly associated with GH response, abdominal CT scanning to assess specific fat depot remains an investigational tool. It is therefore of clinical interest to note that in this study, a simple surrogate of central adiposity, waist circumference, was also significantly associated with peak stimulated GH independent of BMI. Given the strong association between VAT and waist circumference that we demonstrate, waist circumference may be a simple but effective surrogate for visceral adiposity among overweight and obese patients. Moreover, the use of waist circumference may be useful to predict GH response to standardized GH testing and may provide information beyond that of BMI in assessing the anticipated reduction in GH response with increasing weight. Indeed, the effect size suggests that a 1-cm increase in waist circumference is associated with a decrease in peak stimulated GH of 1 µg/liter. The importance of measuring waist circumference for assessment of metabolic and cardiovascular consequences was recently highlighted in the position statement of the North American Society for Obesity (25).

There are several limitations to our study. First of all, causality cannot be determined in a cross-sectional study, and therefore low GH could also be contributing to increased central adiposity. However, this possibility does not negate our findings that measures of central adiposity provide useful information in predicting GH response to stimulation testing. Moreover, the finding that weight loss can restore the GH pulsatility associated with obesity (10) suggests that weight gain and central adiposity are the proximal causes in this relationship. Nonetheless, exogenous GH clearly reduces VAT (26, 27), so this relationship is dynamic and may be bidirectional. Interventions to block the feedback loop at either point may interrupt a vicious cycle and result in functional improvement of both central adiposity and GH levels. This study was limited to men, but significant gender differences exist with respect to GH secretion (28) and body fat distribution (29) in men and women, and gender-specific analyses are therefore necessary. Physical activity data were not available in our study, but all subjects were healthy and ambulatory. Our data complement smaller studies demonstrating similar relationships of central fat to endogenous GH secretion in women by DEXA (13) and use highly specific body composition methods to assess this relationship, including CT scanning.

In summary, our study confirms a significant inverse relationship between BMI and GH response to standard stimulation testing (20). In addition, data from this study demonstrate a strong independent relationship between measures of central adiposity and peak stimulated GH levels, controlling for BMI. These data therefore suggest that measures of central adiposity, in addition to BMI, should be considered in the determination of appropriate cutoffs to define GH deficiency. Consideration should be given to adjusting cutoffs on GH stimulation testing for waist circumference, a standardized and easy to obtain measure of central adiposity. Furthermore, our data suggest the potential utility of simple anthropometric measurements as an aid in the determination of normal GH response in overweight and obese men. Further research is needed to develop optimal cutoffs for GH deficiency using waist circumference in men and women.


   Footnotes
 
This work was supported by National Institutes of Health Grant 1 R01 HL085268-01A1 (to S.G.). The studies were conducted at the General Clinical Research Center at the Massachusetts Institute of Technology and funded by a grant (M01 RR-01066) from the National Center for Research Resources, National Institutes of Health.

Disclosure Statement: The authors have nothing to disclose.

First Published Online September 2, 2008

For editorial see page 4221

Abbreviations: AUC, Area under the curve; BMI, body mass index; CT, computed tomography; CV, coefficient of variation; DEXA, dual-energy x-ray absorptiometry; SAT, sc adipose tissue; TAT, total abdominal adipose tissue; VAT, visceral adipose tissue.

Received June 20, 2008.

Accepted August 22, 2008.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals