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Truncal Adiposity, Relative Growth Hormone Deficiency, and Cardiovascular Risk

Neuroendocrine Unit (K.K.M., B.M.K.B., J.G.L., A.K.), Massachusetts General Hospital, and Department of Laboratory Medicine (G.B., N.R.), Children’s Hospital, and Harvard Medical School, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Karen K. Miller, M.D., Neuroendocrine Unit, BUL 457B, Massachusetts General Hospital, Boston, Massachusetts 02114. E-mail: KKMiller{at}Partners.org.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We hypothesized that endogenous GH would be reduced in healthy women with relative truncal adiposity despite lack of generalized obesity and that decreased GH would be associated with increased cardiovascular risk markers. Fifteen healthy female volunteers were divided into two groups, low truncal fat and high truncal fat, of comparable body mass index (BMI). Age and BMI (23.7 ± 2.1 vs. 25.8 ± 2.8 kg/m²) were similar in the two groups. Trunk fat was higher in the high-truncal-fat group, as designed. Twenty-four-hour mean GH, amplitude, and basal GH concentration were 41, 32, and 36% lower, respectively, in the high-truncal-fat group, but GH pulse frequency and IGF-I levels did not differ. In a stepwise regression model, trunk fat accounted for 38% of the variation of mean GH levels (P = 0.02), but neither total body fat nor BMI were significant determinants of mean GH in the model. There was a strong inverse association between mean 24-h GH and both truncal fat and cardiovascular risk markers, including high-sensitivity C-reactive protein. Our data suggest that visceral adiposity may be associated with reduced endogenous GH in healthy women, even in the absence of generalized obesity, and that decreased GH secretion may be associated with increased cardiovascular risk markers in this population.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
ABDOMINAL ADIPOSITY HAS been demonstrated to confer a 3-fold increased risk for heart disease in women compared with accumulation of body fat in the gluteal femoral region (1). This increase is thought to be caused by increases in visceral adipose depots. Although abdominal and truncal adipose tissue include both visceral and sc depots, measurements of truncal and abdominal adiposity have been demonstrated to be excellent, although imperfect, markers of visceral adiposity (2, 3, 4). Atherogenic abnormalities associated with visceral adiposity are many and include increases in inflammatory cardiovascular risk markers, dyslipidemia, and insulin resistance (5, 6, 7). An elevated risk of both abdominal and visceral adiposity as well as cardiovascular disease has been established in women with GH deficiency caused by hypopituitarism, and decreased GH secretion has been implicated as a risk factor for abdominal and visceral obesity and cardiovascular disease in such patients (8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18). Physiological GH replacement reduces truncal (17, 19) and visceral (20, 21) adiposity in men and women with GH deficiency caused by hypopituitarism. Moreover, inflammatory cardiovascular risk markers have been demonstrated to decrease with GH replacement compared with placebo in men with GH deficiency caused by hypopituitarism (19). This is consistent with the known function of GH as an important modulator of immune function and inflammation. GH is a cytokine and has been shown to enhance phagocytic activity, stimulate DNA synthesis by T lymphocytes, and reduce the production of cytokines in acute injury (22, 23, 24).

Endogenous GH secretion has been shown in small studies to be reduced in obese women and men without pituitary disease compared with age-matched controls and in obese women with visceral adiposity compared with body mass index (BMI)-matched controls with less abdominal fat (25, 26, 27). However, to our knowledge, the question of whether endogenous GH is reduced in nonobese women with truncal adiposity has not been addressed directly, nor has the relationship between endogenous GH and cardiovascular risk been investigated in this population. We hypothesized that endogenous GH would be reduced in a group of women with truncal adiposity but without generalized obesity, i.e. with mean BMI less than 30 kg/m², and that decreased GH would be associated with increased cardiovascular risk markers in this population.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

We studied a total of 15 healthy volunteers, recruited from the community through advertisements and referrals from healthcare providers. Subjects had no history of pituitary disorders and were not receiving medications known to affect lipids, lipoproteins, or other cardiovascular risk markers. Patients receiving estrogens were excluded. Eleven subjects were premenopausal and had regular periods. Four subjects were postmenopausal. All subjects were Caucasian.

Subjects were divided into two groups for comparison based on truncal fat, as determined by dual x-ray absorptiometry (DXA). The eight women with the least trunk fat were grouped into a low-truncal-fat group and the seven with the most trunk fat were grouped into the high-truncal-fat group. This division also resulted in the four postmenopausal women being divided evenly between the two groups. Similarly, for comparisons of GH parameters, subjects were also divided based on BMI and total body fat mass, as determined by DXA, into a group of seven with the highest values and eight with the lowest values.

Materials and methods

The study was approved by the Institutional Review Board at the Massachusetts General Hospital, and written informed consent was obtained from all subjects. All data were collected during one inpatient visit at the Massachusetts General Hospital General Clinical Research Center, which included frequent blood sampling every 10 min for 24 h, starting at 0800 h. Body composition was determined using total body DXA with a Hologic QDR-2000 densitometer (Hologic, Inc., Waltham, MA). This technique has a precision for measuring fat mass of 3% and fat-free mass of 1.5% (28). A nutritional evaluation, including weight in a gown, was performed in the morning by registered dietitians at the General Clinical Research Center for all study participants, who were required by the protocol to have fasted overnight. The insulin resistance index obtained from the homeostasis model (IR-HOMA) was calculated as glucose (millimoles per liter) x insulin (milliinternational units per liter)/22.5 (29).

GH levels were determined by immunochemiluminometric (Nichols Institute Diagnostics, San Juan Capistrano, CA), with an intraassay coefficient of variation (CV) of less than or equal to 5.4% and a sensitivity of 0.02 ng/ml. Leptin levels were determined by RIA (Linco Research Inc., St. Charles, MO) with an intraassay CV of less than or equal to 8.3% and a sensitivity of 0.5 ng/ml. Insulin levels were determined by RIA (Diagnostic Products Corp., Los Angeles, CA) with an intraassay CV of less than or equal to 9.3% and a sensitivity of 9.03 µmol/liter. High-sensitivity C-reactive protein (hsCRP) level was determined by using a Hitachi 917 analyzer (San Jose, CA) using reagents and calibrators from Equal Diagnostics (Exton, PA). The intraassay CV was less than or equal to 10% for hsCRP, and the sensitivity was 0.1 mg/liter. Total cholesterol and high-density lipoprotein (HDL) cholesterol were determined using the Hitachi 911 analyzer (San Jose, CA) using reagents and calibrators from Roche Diagnostics (Indianapolis, IN). The intraassay CV was less than or equal to 1.7% for total cholesterol and 3.3% for HDL. Triglycerides were measured enzymatically with correction for endogenous glycerol and with CVs less than or equal to 1.8%. Low-density lipoprotein (LDL) cholesterol was determined by a homogenous direct method from Roche Diagnostics. The interassay percent CV was less than 3.01%. Concentrations of fibrinogen were determined using immunoturbidimetric assays on the Hitachi 911 analyzer with reagents from Kamiya Biomedical (Seattle, WA). The interassay CV of the fibrinogen assay was 1.50%. Apolipoprotein B (ApoB) was measured using the Hitachi 911 analyzer with reagents from Wako Chemicals (Richmond, VA), and the interassay CVs were less than or equal to 5.1%. Tissue plasminogen activator (tPA) was determined using ELISA by American Diagnostica (Greenwich, CT). For tPA, the assay had an intraassay CV of less than or equal to 5.5%. Glucose was measured by previously described methods (30).

Cluster analysis to determine GH concentration parameters over 24 h was performed using the Pulsar-peak identification algorithm, edition 1983.1 (George R. Merriam and Kenneth W. Wachter, National Institute of Child Health and Human Development, Bethesda, MD, and University of California, Berkeley, CA).

Statistical analysis

JMP Statistical Discoveries, version IV (SAS Institute Inc., Cary, NC) was used for statistical analysis. Subject characteristics were compared by ANOVA for normally distributed variables. ANCOVA was used to control for total fat mass. All variables were tested for normality by the Shapiro-Wilk test. For all variables not normally distributed, the Wilcoxon rank-sums test was used to assess statistical significance. A forward stepwise regression model was used to determine predictors of GH; the following variables were included in the model: trunk fat, total body fat, and BMI. Other forward stepwise regression models used the following variables: model 1, truncal fat and total body fat; and model 2, truncal fat and total body fat minus truncal fat. Univariate regression analysis was performed for the association between GH parameters, body composition, and cardiovascular risk markers. Pearson correlation coefficients were calculated and are reported. All variables lacking a normal distribution underwent a natural logarithmic transformation before regression analysis was performed. Statistical significance was defined as a two-tailed P < 0.05. Results are reported as mean ± SD or median (25th percentile, 75th percentile).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Clinical characteristics of study subjects

Clinical characteristics of study subjects are shown in Table 1. Age and BMI were similar in the high- and low-truncal-fat groups, whereas trunk fat was higher in the high-truncal-fat group, as designed. Mean BMI was in the normal or overweight, not obese, range. Waist circumference, waist/hip ratio, and total body fat levels were also higher in the high-truncal-fat group.

GH results are shown in Table 2 and Fig. 1. Twenty-four-hour mean GH was 41% lower in the high-truncal-fat group compared with the low-truncal-fat group. Mean amplitude was 32% lower in the high-truncal-fat group than in the low-truncal-fat group. Basal concentration was 36% lower in the high-truncal-fat group. There was no difference between the groups in frequency of GH pulses or in serum IGF-I levels.

View larger version (16K): [in this window] [in a new window]   FIG. 1. GH concentration in two representative subjects with high truncal fat (A) and low truncal fat (B). Cluster analysis revealed reduced mean GH over 24 h, amplitude, and basal concentration in healthy women with high truncal fat compared with low truncal fat.

View larger version (12K): [in this window] [in a new window]   FIG. 2. Mean GH over 24 h was lower in the high-truncal-fat group compared with the low-truncal-fat group (A). However, when the group was divided based on BMI (B) or total body fat mass (C), there was no difference between the groups in mean GH concentration.

HsCRP, LDL, ApoB, ApoB/LDL, triglycerides, fibrinogen, and leptin were all markedly higher in the high-truncal-fat group compared with the low-truncal-fat group (Table 3). After controlling for total body fat, the following variables remained significantly different: hsCRP, LDL, ApoB, ApoB/LDL, and triglycerides.

Relationship between GH and body composition

Results of univariate regression analyses are shown in Table 4. There was a strong inverse association between both mean 24-h GH and basal GH concentration and 1) trunk fat, 2) total body fat (basal GH only), and 3) leptin. Stepwise regression analysis revealed that trunk fat accounted for 38% (r² = 0.38) of the variation of mean GH levels (P = 0.02) when the following variables were put into the model: BMI, total body fat (kg), and trunk fat (kg). BMI and total body fat were not significant determinants of mean GH in the model. The same results were obtained (truncal fat was the only significant determinant of mean GH; r² = 0.38; P = 0.02) when the following variables were put into a forward stepwise regression model: 1) truncal fat and total body fat and 2) truncal fat and total body fat minus truncal fat.

Results of univariate regression analyses between GH concentration parameters and cardiovascular risk markers are shown in Table 5. There were strong inverse correlations between measures of GH concentration and hsCRP, LDL, ApoB, ApoB/LDL, triglycerides, and fibrinogen (Table 5 and Fig. 3).

View larger version (22K): [in this window] [in a new window]   FIG. 3. Univariate regressions between mean GH over 24 h and hsCRP (A), LDL (B), ApoB (C), ApoB/LDL (D), triglycerides (E), and fibrinogen (F).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Our results are limited by lack of direct measurement of visceral adiposity and by the cross-sectional design of the study. We used DXA to measure truncal fat, which is composed of both visceral and sc adipose tissue. Truncal fat, as measured by DXA, and waist circumference have been demonstrated to be strong correlates of visceral adiposity (2, 4) and to estimate visceral adiposity with similar accuracy (2). In addition, change in waist circumference has been shown to correlate well with changes in visceral fat over a 7-yr period (3). However, it is important to note that DXA does not directly measure visceral adipose tissue. Therefore, additional studies are needed to determine whether 1) visceral adiposity is associated with reduced GH and increased cardiovascular risk markers in the absence of generalized obesity, 2) reductions in endogenous GH contribute to the increase in cardiovascular risk observed in otherwise healthy women with visceral adiposity, and 3) physiological GH replacement therapy would lead to reductions in cardiovascular risk in this population.

In a small number of male subjects, Veldhuis et al. (27) have reported that morbid obesity is associated with markedly decreased endogenous GH despite normal pituitary function. Kanaley et al. (33) showed decreased GH response to exercise in obese women compared with lean women but no difference between women with upper-body obesity and with lower-body obesity. In addition, Pijl et al. (25) have demonstrated that GH secretion is reduced in obese women with visceral adiposity compared with BMI-matched obese women without a predominantly central fat distribution and with lean normal controls. Weltman et al. (34) investigated GH secretion in women over 60 yr old and reported lower 24-h GH in women with visceral adiposity compared with lower-weight women with less visceral fat mass. In this study, inverse associations between GH and traditional cardiovascular risk markers, i.e. lipids and lipoproteins, were also observed. Buijs et al. (26) also demonstrated a greater than 50% lower mean GH in eight obese women with visceral adiposity (mean BMI, 32.1 ± 2.6 kg/m²) compared with six normal-weight women (mean BMI, 22.7 ± 1.5 kg/m²) and, in addition, showed that the change in lipolysis after a 20-h fast correlated with mean GH concentration. Data to suggest that visceral adiposity is associated with reduced GH levels in nonobese men and women without pituitary disease include studies in which abdominal visceral fat was an important predictor of 24-h GH concentrations in multivariate models (35, 36, 37). However, this is the first study to our knowledge to investigate endogenous GH levels in a group of women with increased truncal adiposity but not generalized obesity and to compare them with a group of women of comparable BMI but without a predominant central distribution of body fat. Our data demonstrate decreased serum concentration of GH as measured by frequent sampling in such women. Additional data from larger groups are needed to confirm these findings. Interestingly, when the group of healthy volunteers was divided based on BMI or total fat mass, women with increased BMI or total fat mass did not have reduced GH concentrations compared with subjects with lower BMI or lower fat mass. Moreover, in a stepwise regression model, truncal fat was a more important determinant of endogenous GH than BMI or total body fat. This suggests that truncal adiposity may be a stronger determinant of decreased GH than adiposity itself and that GH secretion and/or metabolism may be impaired in patients who are not obese but whose adipose tissue is predominantly distributed in visceral depots. In addition, we cannot rule out the converse, i.e. that low endogenous GH secretion is contributing to the development of truncal adiposity in these patients.

Our data demonstrate higher levels of hsCRP, triglycerides, LDL cholesterol, ApoB, ApoB/LDL, fibrinogen, insulin, and leptin in otherwise healthy generally nonobese women with truncal adiposity and decreased endogenous GH secretion. Of particular note, the hsCRP level of 2.4 mg/liter in the high-truncal-fat group has been shown by Ridker et al. (38) to confer a 2- to 3-fold risk of myocardial infarction in women. In contrast, hsCRP in the low-truncal-fat group was in the lowest quintile of cardiovascular risk as determined by Ridker et al. (38) and low cardiovascular risk as defined by the 2003 American Heart Association/Centers for Disease Control and Prevention guidelines. In these recently published guidelines, hsCRP levels less than 1 mg/liter are considered to reflect low cardiovascular risk, levels of 1–3 mg/liter average cardiovascular risk, and levels greater than 3 mg/liter high cardiovascular risk (39). Therefore, the median hsCRP in the high-truncal-fat/low-GH-secretion group was at a level that is known to be predictive of increased risk for cardiovascular events compared to that of the low-truncal-fat/high-GH-secretion group.

The possibility of an association between decreased endogenous GH and an increase in cardiovascular risk markers is plausible but not proven. GH deficiency in patients with hypopituitarism is associated with an increase in both central adiposity (17, 18) and cardiovascular risk (8, 9, 10, 11, 12, 13) as well as cardiovascular risk markers (15, 40). GH replacement in men and women with GH deficiency caused by hypopituitarism has been shown to markedly reduce truncal (17, 19) and visceral (20, 21) adiposity. Moreover, GH is a cytokine (22, 23, 24) and therefore has been posited to be a mediator of inflammatory mechanisms underlying atherogenesis (41). GH replacement in men with GH deficiency caused by pituitary disease has been shown to decrease the inflammatory cardiovascular risk marker hsCRP (19), a stronger predictor than LDL cholesterol of cardiovascular events (38). Other studies have demonstrated that GH replacement may result in decreases in carotid intima-media thickness and other cardiovascular risk markers in patients with GH deficiency caused by pituitary disease (31, 32, 42, 43). There are few data regarding the effects of GH administration on cardiovascular risk in populations without pituitary disease. However, a randomized, placebo-controlled study of the effects of GH administration in normal men with abdominal obesity and with BMI 25–35 kg/m² provides preliminary data suggesting efficacy in reducing total body fat, abdominal fat, total cholesterol, and triglycerides in patients without organic pituitary disease (44). In addition, a recently published paper suggests that a combination of GH administration and caloric restriction in obese patients may decrease weight and body fat and increase HDL cholesterol (45).

Our data suggest that additional studies are warranted to determine whether there is a causal link between reduced endogenous GH and increased cardiovascular risk in otherwise healthy women with truncal adiposity and whether GH administration would be efficacious in reducing cardiovascular risk in this population.

	Acknowledgments

 
We thank the staff of the Massachusetts General Hospital General Clinical Research Center for their dedicated patient care and the patients who participated in the study.

	Footnotes

 
This work was supported in part by the following grants: MO1-RR01066 (including Clinical Associate Physician Award supplements of B.M.K.B. and K.K.M.).

First Published Online November 30, 2004

Abbreviations: ApoB, Apolipoprotein B; BMI, body mass index; CV, coefficient of variation; DXA, dual x-ray absorptiometry; HDL, high-density lipoprotein; hsCRP, high-sensitivity C-reactive protein; IR-HOMA, insulin resistance index obtained from the homeostasis model; LDL, low-density lipoprotein; tPA, tissue plasminogen activator.

Received May 12, 2004.

Accepted November 16, 2004.

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