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Endogenous Postmenopausal Hormones and Serum Lipids: The Atherosclerosis Risk in Communities Study

Department of Medicine (S.M., A.S.D., S.H.G.), Johns Hopkins University School of Medicine and the Department of Epidemiology (M.S., S.H.G.), Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland 21287; Department of Medicine (J.D.), Wake Forest University Medical Center, Winston-Salem, North Carolina 27157; and Department of Epidemiology (J.A.C.), University of Pittsburgh School of Public Health, Pittsburgh, Pennsylvania 15261

Address all correspondence and requests for reprints to: Dr. Sherita Hill Golden, Johns Hopkins University School of Medicine, Division of Endocrinology and Metabolism, 2024 East Monument Street, Suite 2–600, Baltimore, Maryland 21205. E-mail: sahill{at}jhmi.edu.

	Abstract

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Previous studies have revealed that exogenous estrogen has a beneficial effect on the lipid profile; however, studies examining the relation between endogenous hormones and lipid profiles in postmenopausal women have yielded conflicting results. We sought to characterize the cross-sectional relationship between endogenous hormones and lipid parameters in postmenopausal women with significant (cases, n = 156) and minimal (controls, n = 172) carotid atherosclerosis not taking hormone therapy in the Atherosclerosis Risk in Communities Study. Endogenous hormone status was assessed by measuring levels of estrone, total testosterone, androstenedione, dehydroepiandrosterone sulfate, and SHBG. Free testosterone was estimated using the free androgen index (total testosterone/SHBG). Lipid parameters assessed included total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol. We found that SHBG was significantly associated with a more favorable lipid profile, including lower total and LDL cholesterol and triglycerides and higher HDL cholesterol among controls. This association was less prominent among cases where SHBG was only associated with higher triglycerides and lower HDL cholesterol. The free androgen index was associated with a more atherogenic lipid profile, including increased LDL cholesterol among controls and increased total and LDL cholesterol and triglycerides among cases. These relations were independent of demographic and metabolic factors and health behaviors. In contrast to controls, estrone was associated with higher total cholesterol and triglycerides among cases in multivariate analyses. Our data suggest that endogenous sex hormones may play a role in regulating lipid metabolism in postmenopausal women.

	Introduction

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TWO RECENTLY CONDUCTED large, randomized clinical trials of hormone therapy (HT) for the prevention of cardiovascular disease in postmenopausal women have yielded negative results (1, 2, 3). In fact, the Women’s Health Initiative (WHI) demonstrated that women randomized to the estrogen plus progestin group had an increased risk of coronary heart disease compared with women in the placebo group (3). In addition, previous studies failed to demonstrate a beneficial effect of estrogen plus progestin or estrogen alone in preventing the progression of coronary atherosclerosis assessed by angiography (4, 5). In the Heart and Estrogen/Progestin Replacement Study (HERS) for the secondary prevention of heart disease, there appeared to be an increased risk of cardiovascular events during the first year of therapy, with a reduction in risk during the subsequent years of the study; however, in the HERS II follow-up study, there was a failure of lower rates of coronary heart disease in the final years of HERS to persist during an additional 2.7 yr of follow-up (6). Most recently, results from the estrogen-only arm of the WHI among women with a prior hysterectomy did not show a reduction of coronary heart disease and, in fact, showed an increased risk of stroke (7). Consequently, HT is no longer recommended for the primary and secondary prevention of cardiovascular disease in postmenopausal women (8, 9). The underlying mechanisms that mediate these cardiovascular effects are unknown. In the WHI, there was no evidence that lipids or markers of inflammation influenced the outcomes of the study. Effects may be mediated by endogenous estrogen levels, but little is known of the relation between endogenous postmenopausal sex hormones and cardiovascular disease and its risk factors.

Prior observational studies revealed that exogenous estrogen had a beneficial effect on the lipid profile, including increased high-density lipoprotein (HDL) cholesterol and lower low-density lipoprotein (LDL) cholesterol (10, 11, 12, 13). However, in studies examining endogenous estrogen and lipid profiles of peri- and postmenopausal women, the results are more conflicting. Several studies have found a positive correlation between estradiol and HDL cholesterol (14, 15) and a negative correlation between estradiol and total cholesterol (16). Another cross-sectional study has shown a positive association between estrone and HDL cholesterol and a negative association between estrone and LDL cholesterol (17). In contrast, several studies found no significant correlation between estrogens and cholesterol levels (18, 19).

The relative androgen excess, which occurs as estrogen levels decline during menopause, may be more predictive of the increased risk of cardiovascular disease after menopause (20). In evidence of this hypothesis, Kumagi et al. found that free testosterone was the single independent predictor of total cholesterol and LDL cholesterol. Shelley et al. (14) also reported a positive association between free androgen index (FAI) and LDL cholesterol in women with a normal body mass index. In contrast, other studies did not observe a correlation between testosterone levels and lipid parameters (16, 17). Also in keeping with the theory of androgen excess, high levels of SHBG, which decrease free testosterone, have been consistently associated with favorable lipid profiles (16, 17, 19, 22). Data on the association between weaker androgens, such as dehydroepiandrosterone (DHEA) and androstenedione, and cardiovascular disease risk are limited, however.

With this in mind, we sought to characterize the relationship between endogenous postmenopausal hormone levels and lipid parameters in a subgroup of postmenopausal women not taking hormone replacement therapy in the Atherosclerosis Risk in Communities (ARIC) Study.

	Subjects and Methods

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Study population

The ARIC cohort is a probability sample of 15,792 men and women, between ages 45 and 64 yr, from four United States communities (selected Minneapolis suburbs, MN; Washington County, MD; Forsyth County, NC; and Jackson, MS). Details of the sampling frames and methods and the cohort examination procedures have been described previously (24).

Participants in this study were previously selected for a case-control study examining the association between endogenous postmenopausal sex hormones and carotid atherosclerosis in women who were not current or ever users of HT (25). In that study, carotid atherosclerosis was assessed using B-mode ultrasound measurements of the average carotid artery intimal-medial thickness (IMT) from visits 1 and 2, conducted 3 yr apart (26). Cases were defined as: postmenopausal women with no history of HT use who had an average of all carotid IMT measurements at each of six sites visualized for visits 1 and 2 equal to or above the 95th percentile. Controls were postmenopausal women with no history of HT, frequency matched to cases on five-year age groups and ARIC center, whose IMT was less than the 75th percentile at each of six sites visualized (25).

Postmenopausal women in the ARIC cohort who were not current or ever users of HT in the form of pills, dermal patches, shots, or implants were eligible for the present analysis. Menopause was defined based on visit 1 interview data. A woman was considered postmenopausal if she had not menstruated in the last 2 yr. Postmenopausal women were further classified as having undergone a surgical menopause if they had had a bilateral oophorectomy. Natural menopause also included nonmenstruating women 55 yr of age or older who had had a hysterectomy and had at least one intact ovary (27). Women were excluded from the present analysis if they were using cholesterol-lowering medications (25 cases and 10 controls), leaving 156 cases and 172 controls available for the present analysis. The ARIC Study was approved by the Institutional Review Board of each participating center, and written informed consent was obtained from each subject.

Sex hormone measurements

Endogenous postmenopausal hormone status was assessed by measuring levels of estrone, androgens [androstenedione, DHEA-sulfate (DHEA-S), and total testosterone], and SHBG performed by Yerkes Laboratory on blood collected during visit 2 (3 yr after visit 1), because visit 1 serum was not available (Assay Services Laboratory, Yerkes Regional Primate Research Center of Emory University, Atlanta, GA). Estrone was measured instead of estradiol because of concern that small differences in levels of estradiol in postmenopausal women might not be detectable by the assay. Serum androstenedione, DHEA-S, and testosterone were measured by RIA using a Diagnostics Products Corporation Kit (Los Angeles, CA). Serum estrone and SHBG were measured by RIA using a Diagnostic Systems Lab Assay Kit (Webster, TX). The intraassay coefficient of variation for each hormone was less than 10%. The interassay coefficients of variation were 9% for DHEA-S and total testosterone, 13% for estrone, 16% for androstenedione, and 18.5% for SHBG. The lower limits of detection for estrone, androstenedione, DHEA-S, total testosterone, and SHBG were 7.5 pg/ml, 0.1 ng/ml, 2.5 µg/dl, 5 ng/dl, and 5 nmol/liter, respectively. We also calculated the total testosterone/SHBG ratio as a marker of free testosterone (28). All assays were performed in the same batch for cases and controls.

Covariates

Venipunctures were performed in the morning after participants had fasted for 12 h. A minimally traumatic venipuncture was performed, using a 21-gauge butterfly needle, with the participant seated. Fasting times were recorded. After standardized processing at the clinical site, samples were aliquoted into 2-ml tubes, frozen at –70 C, and shipped on dry ice to the appropriate ARIC Central Laboratory. Total cholesterol and triglycerides were measured using enzymatic methods (26). HDL cholesterol was measured using Dextran and magnesium precipitation (26), and LDL cholesterol was calculated using the Friedewald formula (29). Insulin was measured by RIA (125-I Insulin 100 test kit, Cambridge Medical Diagnostics, Billerica, MA). Glucose was measured using the hexokinase method, and insulin was measured by RIA (125-I Insulin 100 test kit).

Information on variables from visit 1 was used. Anthropometry was performed in the fasting state, with the urinary bladder empty. Participants wore light-weight, nonconstricting underwear. Measurements were taken by teams of two certified technicians to ensure optimal placement of measuring instruments. Height (without shoes) was measured using a wall-mounted ruler. Weight was measured using a balance scale (Detecto, model no. 437; Detecto Scale Co., Webb City, MO), which was zeroed daily (26).

Blood pressure was measured in the right arm after the participant had been seated for 5 min, using a random-zero sphygmomanometer and an appropriate sized cuff. Three measurements were taken; the mean of the second and third measurements was used to characterize blood pressure at the visit (26). Individuals were classified as having diabetes mellitus if they met any of the following criteria: fasting serum glucose levels of 126 mg/dl, nonfasting serum glucose of at least 200 mg/dl, current self-reported use of medications prescribed to treat diabetes (e.g. insulin or sulfonylureas), or a positive response to the question "Has a doctor ever told you that you had diabetes?"

Active smoking was assessed by a 12-item questionnaire. For the present analysis, smoking history was summarized as pack-years of smoking (26).

Current and past alcohol intake were assessed using a dietary intake questionnaire and expressed as the number of drinks/week (26).

Physical activity was assessed by interview using a questionnaire developed by Baecke, including 16 items about usual exertion (30). Three indices ranging from 1 (low) to 5 (high) were derived for physical activity at work, during leisure time, and in sports. Sports index was used in our analysis.

Analysis

In univariate analysis, mean levels of total cholesterol, triglycerides, LDL cholesterol, and HDL cholesterol were calculated for cases and controls for each sex hormone quartile (estrone, androstenedione, DHEA-S, total testosterone, SHBG, and FAI). A P-value for trend was calculated in comparing mean lipid levels in moving from the lowest to the highest quartile of each sex hormone.

For multivariate analyses, multiple linear regression models were used to determine the relation between the endogenous hormone levels and each lipid parameter for cases and controls. In these models, the ß-coefficient represented the mean difference in a given lipid level for an individual with a 1-unit difference in a given sex hormone level. ß-coefficients were standardized per 1 SD increase for each hormone to allow comparable comparisons across each hormone parameter. Because body mass index might be in the causal pathway in the relationship between sex hormones and lipid levels, exploratory analyses were conducted stratified by body mass index (<25 kg/m² vs. 25 kg/m²). Because there were no statistically significant interactions of sex hormones on lipid levels by body mass index categories, pooled analyses were conducted. However, because there was a statistically significant interaction of sex hormones on lipid levels by carotid atherosclerosis case-control status, univariate and multivariate analyses were conducted separately for cases and controls.

To determine whether the relation between sex hormones and lipids was independent of adiposity: in one set of models, body mass index was excluded; and in another set of models, adjustment was done for body mass index as a continuous variable. Additional variables included in the multivariate analyses were: smoking status, alcohol intake, physical activity, fasting insulin, fasting glucose, and systolic blood pressure. A two-tailed P-value < 0.05 was used to determine statistical significance. Statistical analyses were carried out using SAS 8.0 statistical software (Cary, NC, 2003).

	Results

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Baseline characteristics

Demographic and metabolic variables. Table 1 displays the demographic, behavioral, and physiological characteristics of the study participants with minimal (controls) and significant (cases) carotid atherosclerosis. Compared with controls, cases were more likely to be current smokers and more likely to have diabetes and the metabolic syndrome. Cases also had significantly higher pack-years of cigarette smoking, waist circumference, total and LDL cholesterol, triglycerides, and fasting glucose and significantly lower HDL cholesterol. Although cases had higher fasting insulin levels than controls, this difference did not reach statistical significance.

Univariate analysis. Estrone showed significant associations with triglycerides among cases and controls and with HDL cholesterol among controls only (Table 2). There was a significant increase in triglycerides in moving from the lowest to the highest quartiles of estrone. Controls in quartile 4 had an average triglyceride level of 147 mg/dl compared with an average of 108 mg/dl in quartile 1 (P-value for trend = 0.006). Similarly, cases in quartile 4 had an average triglyceride level of 224 mg/dl compared with an average of 117 mg/dl in quartile 1 (P-value for trend = 0.047). In contrast to the association with oral estrogen, HDL cholesterol was inversely related to estrone levels in controls only, with a significant decline in HDL cholesterol in moving from the highest to lowest quartile of estrone. Women in quartile 1 had an HDL cholesterol level of 56.6 mg/dl compared with 46.0 mg/dl in quartile 4 (P-value for trend = 0.006).

FAI, a marker of free testosterone, was positively related to LDL cholesterol among the controls. Compared with individuals in quartile 1, individuals in quartile 4 had a significantly higher mean LDL cholesterol (126 vs. 148 mg/dl; P-value for trend = 0.007). FAI was also inversely related to HDL cholesterol, with individuals in quartile 1 having a mean HDL cholesterol of 58.9 mg/dl compared with a mean of 46.6 mg/dl for individuals in quartile 4 (P-value for trend = 0.0039). In contrast, FAI showed a strong, positive association with triglycerides among cases but not controls. Individuals in quartile 1 had mean triglycerides of 133 mg/dl compared with a mean of 241 mg/dl in quartile 4 (P-value for trend = 0.01). Androstenedione, DHEA-S, and total testosterone were not related to lipid levels in cases or controls.

Multivariate analysis

Controls. Linear regression analyses of the relation between endogenous hormone levels and lipid levels for controls are displayed in Table 3. After minimal adjustment for age, race, and ARIC center, SHBG showed strong and significant inverse associations with total and LDL cholesterol and triglycerides and showed a strong positive association with HDL cholesterol (model 1). These relations persisted after further adjustment for other variables such as health behaviors (smoking status, ethanol intake, physical activity) and metabolic factors (fasting insulin, fasting glucose, and systolic blood pressure) (model 2) and additional adjustment for body mass index (model 3).

Cases. Table 4 summarizes linear regression analyses of the relation between endogenous hormone levels and lipid levels among cases of carotid atherosclerosis. Estrone showed a strong, positive association with total cholesterol and triglycerides after minimal adjustment for age, race, and ARIC center (model 1). In contrast to the associations in controls, these persisted after adjustment for health behaviors and metabolic factors (model 2) and additional adjustment for body mass index (model 3). Although androstenedione was positively associated with triglycerides in the minimally adjusted model (model 1), this association was no longer significant after additional multivariate adjustment (models 2 and 3).

As in the controls, SHBG showed a significant inverse association with triglycerides and a positive association with HDL cholesterol that persisted after multivariate adjustment; however, in contrast to what was observed in the cases, there was no association between SHBG and total cholesterol and LDL cholesterol (Table 4). When waist circumference was substituted for body mass index in all of the models and when it was added to the models that included body mass index, the associations were unchanged.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In the present examination of endogenous sex hormones and lipid levels in postmenopausal women, SHBG was associated with a more favorable lipid profile, including lower total and LDL cholesterol and triglycerides and higher HDL cholesterol among controls with minimal atherosclerosis. This association of SHBG with a more favorable lipid profile was not as prominent among cases with significant atherosclerosis. Although SHBG was associated with lower triglycerides and higher HDL cholesterol, there was no association with total and LDL cholesterol in cases. FAI, a marker of free testosterone, was associated with a more atherogenic lipid profile, primarily increased LDL cholesterol, in controls. In contrast, the association of androgens with a more atherogenic lipid profile was much stronger among cases, where both total testosterone and FAI were associated with increased total and LDL cholesterol and triglycerides. These relations were independent of demographic factors, health behaviors, and metabolic factors, including adiposity. Estrone, the principle estrogen in postmenopausal women, was associated with higher triglyceride and lower HDL cholesterol levels among the controls, although this relation did not persist after multivariate adjustment. As in controls, estrone was associated with increased triglycerides among the cases; however, it was also strongly associated with increased total cholesterol, and both associations persisted after multivariate adjustment.

One explanation for the associations that we observed between sex hormones and lipid parameters is that there is confounding related to the effects of obesity and insulin resistance on both sex hormone levels and lipids. Central obesity and insulin resistance are associated with several metabolic abnormalities, including: 1) increased triglycerides and reduced HDL cholesterol (31); 2) reduced SHBG, leading to a higher FAI (32, 33); and 3) increased estrone due to peripheral conversion from androstenedione (34). Thus, this might explain the associations of estrone with increased triglycerides in controls and univariate analyses and why these associations were no longer significant after adjustment for adiposity and markers of insulin resistance. However, the associations of SHBG and FAI with lipid parameters persisted in controls after adjustment for adiposity; and in cases, all associations of sex hormones with lipid parameters persisted despite adjustment for adiposity and markers of insulin resistance.

SHBG may mediate its positive effect on the lipid profile by regulating bioavailable androgen levels. SHBG binds testosterone with high affinity, regulating its free concentration (32). Haffner et al. (35) hypothesized that SHBG may reflect intracellular bioavailable testosterone better than total testosterone, with reduced SHBG reflecting greater androgenicity. Hyperandrogenism in the polycystic ovary syndrome has been associated with a more unfavorable lipid profile (36). FAI, a marker of free testoterone, was associated with higher LDL cholesterol among controls and higher total and LDL cholesterol and triglycerides among cases, indicating that greater androgenicity is associated with a more atherogenic lipid profile.

In our population, FAI was positively associated with LDL cholesterol among controls and with total and LDL cholesterol and triglycerides among cases, which persisted after multivariate analyses. Our results are similar to those of Shelley et al. (14) who have demonstrated a significant positive association between LDL cholesterol and FAI in lean women. Kumagai et al. (19) found free testosterone to be independently and positively associated with total cholesterol and LDL cholesterol, as well as the ratio of total cholesterol/HDL cholesterol and LDL cholesterol/HDL cholesterol. Androgens may play a role in lipid metabolism. In men, androgens stimulate hormone-sensitive lipase, which increases lipolysis and fat mobilization and inhibits lipoprotein lipase (37). Less is known, however, about the androgen regulation of the enzymes involved in lipid metabolism in postmenopausal women. Iverius et al. (38) found a positive correlation between postprandial lipoprotein lipase activity and total and free testosterone in obese women. Stimulation of lipoprotein lipase activity ultimately leads to conversion of very-low-density lipoprotein cholesterol to LDL cholesterol, which might explain the association we found between LDL cholesterol and FAI in our study.

Although previous studies have found no significant association between estrone and lipid levels (14, 15, 18, 19) and markers of atherosclerosis (18, 25), we did find a strong positive association between estrone and total cholesterol and triglycerides among the women with significant carotid atherosclerosis. Exogenous estrogen therapy has been associated with an increase in triglyceride levels, and this is likely due to its effects on the enzymes that control lipid metabolism (39). Hormonal inhibition of lipoprotein lipase activity might result in raised triglyceride levels, which might explain the positive association we observed between estrone and triglyceride levels. Studies of exogenous exposure of female human adipose tissue to 17-ß estradiol has demonstrated that lipoprotein lipase activity is reduced (40, 41). One prior study examining the association of endogenous hormones in postmenopausal women with lipoprotein lipase activity has shown a negative correlation between estrone levels and plasma lipoprotein lipase activity (42), although another study that included both pre- and postmenopausal women failed to find an association between estrone levels and lipoprotein lipase activity (38).

The present study has several strengths. We were able to examine the association of lipid parameters with multiple sex hormones in a community-based (as opposed to clinic-based) sample. Because ARIC has data on multiple metabolic and cardiovascular risk factors, we were able to determine the independent association between endogenous hormones and lipid parameters in multivariate analyses. In addition, we were able to take advantage of a prevalent case-control study of subclinical carotid atherosclerosis to compare the associations between endogenous hormones and lipids in women with minimal and significant atherosclerosis.

Certain limitations should be kept in mind in interpreting our data. First, we did not measure free testosterone directly, as was done in more recent studies. However, our estimation of the total testosterone/SHBG ratio is a valid estimation of free testosterone and androgenicity (28). Second, we did not measure estradiol, which is a more potent estrogen than estrone; however, estrone is the predominant form of estrogen circulating in postmenopausal women. Third, because estradiol was not directly measured, we cannot be certain that the differences in lipid profile attributed to SHBG are not due to differences in bioavailable estradiol. Finally, although this was a community-based sample, it was still a highly selected group of postmenopausal women based on carotid atherosclerosis status, and our results may not be fully generalizable.

Our study has several implications. Our data suggest that endogenous sex hormones may play a role in regulating lipid metabolism in postmenopausal women; however, more research is needed to elucidate the effects of endogenous sex hormones, particularly the ovarian and adrenal androgens, on the enzymes that regulate lipid metabolism, namely lipoprotein lipase, hepatic lipase, and hormone-sensitive lipase. Also, it has been suggested that androgen deficiency in postmenopausal women may be a risk factor for cardiovascular disease (43). Recent studies of testosterone replacement therapy in postmenopausal women have demonstrated beneficial effects, including improved sexual function (44, 45), improved endothelial function (23), decreased plasma viscosity (21), and increased lean body mass with decreased fat mass (45). We have described the association between endogenous testosterone and lipids, and the effects of exogenous oral testosterone on lipids may differ due to the effects of first-pass hepatic metabolism. Testosterone replacement in postmenopausal women, however, may have a negative impact on lipid parameters, and its long-term cardiovascular disease risk deserves further study.

	Acknowledgments

 
The authors thank the staff and participants in the ARIC study for their important contributions.

	Footnotes

 
First Published Online November 16, 2004

Abbreviations: ARIC, Atherosclerosis Risk In Communities; DHEA, dehydroepiandrosterone; DHEA-S, DHEA sulfate; FAI, free androgen index; HDL, high-density lipoprotein; HERS, Heart and Estrogen/Progestin Replacement Study; HT, hormone therapy; IMT, intimal-medial thickness; LDL, low-density lipoprotein; WHI, Women’s Health Initiative.

This work was supported under contracts NO1 HC55015, NO1 HC55016, NO1 HC55018, NO1 HC55019, NO1 HC55020, NO1 HC55021, and NO1 HC55022 with the National Heart, Lung, and Blood Institute. S.H.G. was supported by a Minority Medical Faculty Development Program Award from the Robert Wood Johnson Foundation (Princeton, NJ).

Received April 26, 2004.

Accepted November 8, 2004.

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