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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 3 1340-1344
Copyright © 2000 by The Endocrine Society

Special Articles

Hormone Replacement Therapy and Interrelation between Serum Interleukin-6 and Body Mass Index in Postmenopausal Women: A Population-Based Study

R. H. Straub, H. W. Hense, T. Andus, J. Schölmerich, G. A. J. Riegger and H. Schunkert

Departments of Internal Medicine I (R.H.S., T.A., J.S.) and II (G.A.J.R., H.S.), University Medical Center, Regensburg, 93042 Regensburg; and Institute of Epidemiology, University of Munster (H.W.H.), Munster, Germany

Address all correspondence and requests for reprints to: Rainer H. Straub, M.D., Laboratory of Neuroendocrinoimmunology, Department of Internal Medicine I, University Medical Center, 93042 Regensburg, Germany. E-mail: rainer.straub{at}klinik.uni-regensburg.de


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Postmenopausal women are at increased risk to develop osteoporosis, coronary artery disease, heart failure, and hypertension. Interleukin-6 (IL-6) may be a pathogenetic element in these disorders. Serum IL-6 levels increase during aging and seem to be related to increased body fat mass. In the present retrospective study we aimed to investigate the role of hormone replacement therapy (HRT) on serum IL-6 levels and the interrelation of IL-6 and body fat mass. Parameters were assessed in a population-based sample of postmenopausal women (n = 302) and, for comparison, 245 men of the same age. Women with HRT (n = 92) had significantly lower serum IL-6 levels compared to subjects without HRT, which was independent of age, antihypertensive therapy, smoking habits, and blood pressure (1.5 ± 0.1 vs. 2.9 ± 0.6 pg/mL; P = 0.017). In women without HRT, the body mass index (BMI) was correlated with serum IL-6 levels (P < 0.001). Multivariate analysis controlling simultaneously for the effects of blood pressure and heart rate confirmed the positive correlation (P = 0.001). However, in subjects with HRT no such correlation between IL-6 and BMI was demonstrated, which was confirmed after controlling covariates. In male subjects, BMI correlated with serum IL-6 (P = 0.009), which was, however, blunted after controlling for blood pressure and heart rate, probably indicating an influence of the sympathetic nervous system on this interrelation. In conclusion, women receiving HRT display lower serum IL-6 levels and a blunted interrelation of IL-6 and BMI. As IL-6 may be a pathogenetic factor in age-related diseases, HRT-related inhibition of IL-6 secretion could be an important element for the favorable effects of HRT in postmenopausal women.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
INTERLEUKIN-6 (IL-6) is associated with age-related diseases such as osteopenia (1, 2), atherosclerosis (3, 4), coronary heart disease (5, 6, 7), and heart failure (8, 9, 10). At least in osteopenia, IL-6 was found to be a causal factor, as this cytokine has osteoclastogenic properties (1). IL-6 is able to increase hepatic de novo fatty acid synthesis (11) and triglyceride synthesis (12), which may be harmful in atherosclerosis and coronary heart disease. Furthermore, IL-6 stimulates the central nervous system (13), leading to activation of the hypothalamus-pituitary-adrenal axis and the sympathetic nervous system, which may result in hypertension. All of these mechanisms may contribute to age-related disorders, a risk that is further enhanced by an age-associated increase in body fat mass.

In recent years, evidence accumulated that IL-6 is released from sc adipose tissue (14, 15, 16) and visceral fat deposits (15). The positive correlation between serum levels of IL-6 and body mass index (BMI) was demonstrated in two recent studies (14, 17). During aging, increased fat mass may lead to elevated serum IL-6 levels, and it was recently shown that IL-6 increased during aging (18). Increases in both body fat mass and serum IL-6, may be interrelated, and such a potential interaction could be relevant for the above-mentioned age-related diseases. In postmenopausal women, the association between IL-6 and body fat mass may be further complicated by the decrease in estrogen production, because estrogens were shown to inhibit IL-6 secretion from different cell types (19, 20, 21, 22, 23). Another indication of the interplay of IL-6, estrogens, and body fat mass may be increased serum estrogen levels in postmenopausal women with elevated BMI (24). However, in postmenopausal women with elevated BMI, production of estrogens by adipose tissue does not lead to serum estrogen levels comparable to those in premenopausal women. Thus, in postmenopausal women with elevated BMI, adipose tissue-derived estrogens would not be sufficient to reduce IL-6 in a similar way as endogenous estrogens in premenopausal women.

It was the aim of this retrospective study to investigate the interrelation of BMI and serum IL-6 levels in postmenopausal women of a population-based sample. Furthermore, we investigated the role of hormone replacement therapy (HRT) on the interrelation of BMI and IL-6. As the sympathetic nervous system with elevated norepinephrine levels may be a significant covariable (25, 26), we controlled for the influence of blood pressure and heart rate as clinical variables that reflect to some extent the activity of the sympathetic nervous system. For comparison, 245 healthy age-matched male subjects were included.


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

The subjects of this retrospective study had initially participated in the MONICA (Multinational Monitoring of Trends and Determinants in Cardiovascular Disease, Augsburg), baseline survey of 1984/85 and 1987/88. Subjects originate from a sex- and age-stratified random sample of all German residents of the Augsburg study area. In 1994, a second follow-up examination was offered to a total of 1010 men and women, aged 50–67 yr, of whom 646 subjects attended (27). We do not know why only 646 of 1010 attended the reexamination, which might lead to bias in the initial random selection. Body height and weight were recorded in light clothing, and BMI was computed as weight in kilograms divided by height in meters squared. We used the BMI because it is best correlated with total fat mass (28). Resting blood pressure was measured after subjects had been in a sitting position for a minimum of 30 min. Using a mercury sphygmomanometer, blood pressure was read three times in the right arm by two investigators. The mean of three measurements was used for this study. The characteristics of the study group are demonstrated in Table 1Go.


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  		Table 1. Characteristics of study subjects

 
Blood was drawn from nonfasting subjects who were in a supine resting position for at least 30 min. Serum was immediately stored on -80 C. The analysis was limited to subjects in whom samples were available that had not been thawed previously (302 postmenopausal women and 245 age-matched men). IL-6 was measured by immunometric enzyme immunoassay (high sensitivity Quantikine, R&D Systems, Minneapolis, MN; sensitivity: 0.2 pg/mL). Inter- and intraassay coefficients of variation were below 10%.

Statistical analysis

To assess the statistical significance of differences in mean values between women with different types of HRT, the nonparametrical Kruskal-Wallis analysis was performed (SPSS/PC for Windows, version 8.0.0, SPSS, Inc., Chicago, IL). Group means in two different groups were compared by Mann-Whitney rank test (SPSS/PC for Windows, version 8.0.0, SPSS, Inc.). Correlation analyses between IL-6 and BMI were demonstrated by linear regression lines, and significance was tested by Spearman rank correlation analysis (SPSS, Inc.). Multiple linear regression analysis was run to demonstrate the interrelation between BMI and serum IL-6 while controlling for additional variables (SPSS, Inc.). P < 0.05 were considered to be significant, and the mean ± SEM are given. P in multiple comparisons were adjusted according to Bonferroni.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
BMI and serum IL-6

The mean serum IL-6 in all postmenopausal female subjects was 2.4 ± 0.4 pg/mL, which was similar to the mean of 2.3 ± 0.2 pg/mL in all male subjects. In postmenopausal women without HRT, BMI correlated with serum IL-6 (P < 0.001; Fig. 1AGo). However, in female subjects receiving HRT (n = 92), BMI did not correlate with serum IL-6 (Fig. 1BGo).



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  		Figure 1. Correlation of BMI and serum IL-6 in postmenopausal women without (A) and with (B) HRT. The regression line was calculated by linear regression analysis, and the correlation coefficient and its P were calculated by Spearman rank correlation analysis. Broken lines indicate the 95% confidence interval of the linear regression line.

 
As epinephrine and norepinephrine are able to increase IL-6 secretion via ß-adrenergic ligation (29, 30, 31, 32, 33), activation of the sympathetic nervous system may lead to elevated serum levels of IL-6. To control for possible influences of the sympathetic nervous system we included systolic and diastolic blood pressures and heart rate in a multiple linear regression analysis that yielded the following results. 1) The correlation between BMI and serum IL-6 remained constant in women without HRT (P < 0.001). 2) After exclusion of 36 subjects with ß-blocker therapy, the positive interrelation between BMI and serum IL-6 in women without HRT remained stable. The ß-adrenergic blocker itself was not associated with decreased serum IL-6 levels (data not shown). 3) After exclusion of female subjects with antihypertensive treatment, the correlation between BMI and serum IL-6 remained constant in women without HRT (P = 0.002). 4) After exclusion of all smoking female subjects and female subjects with antihypertensive treatment, the correlation between BMI and serum IL-6 remained constant in women without HRT (P < 0.001). 5) In women with HRT, again no correlation was found between BMI and serum IL-6 (P = 0.151). 6) In women with HRT, after exclusion of subjects with antihypertensive treatment (plus smokers), there was no correlation between BMI and serum IL-6 (P = 0.113; plus smokers, P = 0.818).

In male subjects, BMI was significantly correlated with serum IL-6 (RRank = 0.167; P = 0.009) as well as with heart rate (RRank = 0.153; P = 0.016), diastolic blood pressure (RRank = 0.146; P = 0.021), and systolic blood pressure (RRank = 0.239; P < 0.001). This indicates a significant interrelation between hemodynamic parameters that reflect to some extent the sympathetic nervous tone and serum IL-6 in male subjects. In a multiple linear regression analysis with serum IL-6 as the dependent parameter and BMI as the independent parameter controlling for the influence of systolic and diastolic blood pressures and heart rate, the correlation between BMI and serum IL-6 was blunted (P = 0.559). After exclusion of male subjects with antihypertensive treatment (plus smokers), the correlation between BMI and serum IL-6 was blunted, too (P = 0.807; plus smokers, P = 0.608).

Serum HRT and IL-6 levels

In the comparison of women with HRT vs. women without HRT (all types of HRT included), serum IL-6 was significantly higher in subjects without HRT (P = 0.017; Fig. 2AGo), which remained stable after exclusion of subjects with antihypertensive therapy. Furthermore, BMI tended to be lower in the group with HRT vs. the group without HRT (Fig. 2BGo).



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  		Figure 2. Serum levels of IL-6 (A) and BMI (B) in postmenopausal women with (+HRT) and without (-HRT) HRT. The P for the comparison of -HRT vs. +HRT and the mean of the demonstrated parameters are given.

 
In the subanalysis of the different types of HRT, serum IL-6 was highest in subjects without HRT (2.9 ± 0.6 pg/mL) followed by women taking unconjugated estrogens (1.6 ± 0.2 pg/mL), mixed estrogen and progesterone (1.5 ± 0.2 pg/mL), and conjugated estrogens (1.3 ± 0.5 pg/mL), which was statistically significant (by Kruskal-Wallis test, P = 0.019 for the entire comparison). In the different HRT subgroups, age, antihypertensive therapy, smoking habits, diastolic and systolic blood pressures, and BMI were not different.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study demonstrates a positive interrelation between BMI and serum levels of IL-6 in postmenopausal women without HRT and male subjects of similar age. In postmenopausal women receiving HRT, serum IL-6 was lower than that in women without HRT, and the interrelation of BMI and serum IL-6 was blunted. The positive interrelation between BMI and serum IL-6 in postmenopausal women without HRT was still present after controlling for blood pressure and heart rate. In contrast, in male subjects the correlation between BMI and serum IL-6 was blunted after controlling for clinical parameters reflecting the activity of the sympathetic nervous system.

Using the population-based sample, we confirm data from two investigations with a smaller number of subjects that demonstrated the positive correlation between serum levels of IL-6 and BMI (14, 17). However, the previous study did not control for the influence of the sympathetic nervous system, which is an important covariate because epinephrine and norepinephrine are able to increase IL-6 from different cell types via stimulation through the ß-adrenergic pathway (29, 30, 31, 32, 33). In addition to the above-mentioned study (14), it was demonstrated that BMI and serum IL-6 remain to be interrelated in postmenopausal women without HRT even after controlling for variables that reflect the activity of the sympathetic nervous system. This indicates that in postmenopausal females the positive interrelation between BMI and serum IL-6 may be largely independent of the sympathetic nervous tone. The interrelation remained constant in women without HRT after exclusion of smokers and subjects with antihypertensive treatment. In male subjects, this interrelation was blunted after adjusting for heart rate and blood pressure levels. At least in female subjects without HRT, the interrelation of BMI and serum IL-6 may be explained by the observed release of IL-6 from fat tissue (14, 15, 16). In male subjects, however, the interrelation of BMI and IL-6 seems to dependent on the influence of the sympathetic nervous tone, which was found to be increased in male obese subjects (34). As it is known that fat tissue produces IL-6 (14, 15, 16), and IL-6 production is partly under ß-adrenergic control (29, 30, 31, 32, 33), we speculate that testosterone and estradiol differentially modify the adrenergic regulation of IL-6 production at the local tissue level or via the hypothalamus and the downstream axes.

As estrogens inhibit IL-6 secretion from different cell types (19, 20, 21, 22, 23), the drop in estrogen levels after menopause may be a factor for elevated IL-6 concentrations in aging female subjects (18). This prompted us to investigate the influence of HRT on serum IL-6 levels in postmenopausal women. Postmenopausal women receiving HRT had lower serum IL-6 levels than women without HRT. The type of HRT, whether unconjugated estrogens, conjugated estrogens, or mixed estrogen/progesterone therapy, influenced the IL-6-lowering effect of HRT. Furthermore, women receiving HRT had a blunted interrelation of BMI and serum IL-6 and tended to have lower BMI than women without HRT. This indicates that HRT has a favorable influence on serum IL-6 concentrations.

As IL-6 is a pleiotropic cytokine that may be involved in age-related diseases, reduction of this cytokine may be favorable. The question remains whether the HRT-related reduction of serum IL-6 from about 3.0 to 1.5 pg/mL has a physiological or a pathophysiological meaning. Much higher serum IL-6 levels appear to be necessary to stimulate the hypothalamus (35). Moreover, the present study cannot provide data on IL-6 tissue concentrations where this cytokine exerts its actions. We can only speculate that a low cytokine concentration in serum may reflect reduced production of IL-6 in the tissue. Relevant tissues for IL-6 action include fat, bone, adrenal glands (36), liver, spleen, or lymph nodes. Hence, at these local sites, it remains to be demonstrated whether HRT may reduce IL-6 production.

In conclusion, aging, increased body fat mass during aging, immobility, and elevation of the sympathetic nervous tone (hypertension) are critical elements for atherosclerosis and osteopenia. Furthermore, in women, the decrease in endogenous estrogens after the menopause increases the risk for the development of atherosclerosis (37), coronary heart disease (38), and osteopenia (39). As IL-6 may be one of the pathophysiologically relevant factors for the induction or progression of the mentioned age-related diseases, HRT-related inhibition of IL-6 secretion may be an important element of the favorable effects of HRT in postmenopausal women.

Received July 16, 1999.

Revised October 5, 1999.

Accepted October 27, 1999.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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