Published online before print September 15, 2003, doi: 10.1161/01.CIR.0000091114.36254.F3
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(Circulation. 2003;108:1688.)
© 2003 American Heart Association, Inc.
Clinical Investigations |
Sex Hormone Levels and Risk of Cardiovascular Events in Postmenopausal Women
From the Department of Medicine, Division of Preventive Medicine (K.M.R., J.E.M., I.-M.L., P.M.R., N.R.C., J.E.B.), Brigham and Women’s Hospital and Harvard Medical School; Department of Epidemiology (J.E.M., I.-M.L., J.E.B.), Harvard School of Public Health; Reproductive Endocrine Unit Assay Laboratory (P.M.S.), Massachusetts General Hospital; and Department of Ambulatory Care and Prevention (J.E.M., J.E.B.), Harvard Medical School, Boston, Mass.
Correspondence to Dr Kathryn M. Rexrode, Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, 900 Commonwealth Ave E, Boston, MA 02215. E-mail krexrode{at}partners.org
Received September 23, 2002; de novo received May 20, 2003; revision received July 24, 2003; accepted July 26, 2003.
Abstract
Background— Despite diffuse effects of sex hormones on the cardiovascular system, few prospective studies have examined the relationship of plasma androgens and estrogens with risk of cardiovascular disease (CVD) in postmenopausal women.
Methods and Results— A nested case-control study was performed among women in the Women’s Health Study. Two hundred women who developed CVD were matched 1:1 by age, smoking, and postmenopausal hormone therapy (HT) to controls who remained free of CVD. We measured testosterone, estradiol, and sex hormone binding globulin (SHBG) levels and calculated free androgen index (FAI), free estradiol index, and the FAI/free estradiol index ratio. Results were stratified by HT use. Among HT nonusers, cases had significantly higher androgen profiles (higher median FAI and lower SHBG levels) than controls. After adjustment for age, smoking, use of aspirin, vitamin E, and alcohol, family history of myocardial infarction, and physical activity, nonusers in the lowest SHBG quartile had an OR of 2.25 (95% CI, 1.03 to 4.91) for CVD, and there were significant trends across FAI quartiles (P for trend=0.03). Additional adjustment for body mass index, hypertension, diabetes, and elevated cholesterol eliminated associations with SHBG and FAI. Among women using HT, no significant differences in hormones or SHBG were observed among women who developed CVD and controls.
Conclusions— Among HT nonusers, lower SHBG and higher FAI levels were noted among postmenopausal women who developed CVD events, but this was not independent of body mass index and other cardiovascular risk factors. Estradiol levels were not associated with risk of CVD in HT users or nonusers.
Key Words: hormones • women • cardiovascular diseases • risk factors
Several lines of indirect evidence suggest that sex hormone levels may be associated with risk of cardiovascular disease (CVD) in women. In biologic studies, estrogen has diffuse effects on the cardiovascular system, including favorable effects on lipid profiles and fibrinolytic proteins,1 as well as adverse effects on inflammatory and thrombotic markers.2 Although exogenous hormones have recently been documented to increase risk of CVD,3 the role of endogenous estrogen levels as a risk factor for CVD in postmenopausal women has not been well studied. Whether estradiol levels influence risk of CVD among women undergoing hormone therapy (HT) has not been determined.
High androgen levels may increase cardiovascular risk in women through adverse effects on lipids, blood pressure, and glucose metabolism.4,5 In one cross-sectional study, testosterone levels correlated with the degree of coronary atherosclerosis measured on angiography.6 Although endogenous sex hormone levels have been associated with risk of osteoporosis7 and breast cancer,8 only 2 small prospective studies9–11 have investigated the relationship of sex hormone levels and risk of CVD in postmenopausal women. The higher androgen/estrogen ratio in postmenopausal than premenopausal women has been posited as 1 mechanism for increased cardiovascular risk after menopause,4 yet no prospective studies have looked at this as a predictor of cardiovascular events in postmenopausal women.
The Women’s Health Study provided a large cohort in which to analyze the relationship of plasma sex hormone levels (testosterone and estradiol) as well as sex hormone binding globulin (SHBG) and risk of cardiovascular events among postmenopausal women. Our primary hypothesis at the time the study was designed was to test whether lower estrogen levels (low total estradiol and low free estrogen index [FEI]), lower SHBG levels, and higher androgen levels (high total testosterone, high free androgen index [FAI], and high FAI/FEI ratio) predict risk of CVD in postmenopausal women.
Methods
The Women’s Health Study (WHS) is an ongoing, randomized, double-blind, placebo-controlled study of low-dose aspirin and vitamin E in the prevention of cardiovascular events and cancer among 39 786 female health professionals age 45 years or older at baseline.12 Women complete yearly questionnaires on demographic, behavioral, and lifestyle factors as well as the occurrence of any medical illnesses. Data on traditional cardiovascular risk factors were gathered at baseline. Blood samples were collected in citrate tubes from 28 345 women (71%) before randomization (in years 1993 to 1996) and were stored in liquid nitrogen freezers at -170°C until the time of analysis.
Annually, WHS participants report the occurrence of any cardiovascular outcome and consent to release of relevant medical records, which are reviewed by an end points committee of physicians. Myocardial infarction (MI) is the presence of characteristic symptoms and either elevated cardiac enzymes or ECG changes. Coronary revascularization (percutaneous transluminal coronary angioplasty or coronary artery bypass grafting) is confirmed by documentation in the medical record. Deaths attributable to coronary disease are confirmed on the basis of autopsy reports, symptoms, circumstances of death, and prior history of coronary disease. Stroke is confirmed by documentation of a typical neurologic deficit of sudden or rapid onset that persists for 
24 hours or until death. A composite end point of CVD, defined as the first occurrence of nonfatal MI, coronary revascularization, nonfatal stroke, coronary disease, or stroke death, was used.
All women in the WHS were free from known prior coronary heart disease, stroke, or cancer (except for nonmelanoma skin cancer) at study entry. Two hundred cases occurred among WHS participants who (1) were postmenopausal, (2) had citrated plasma samples available, and (3) suffered a confirmed CVD event. For each case, a control subject was selected from the WHS who met the same criteria but remained free from CVD during follow-up and was matched to the index case by age, smoking status, and use of HT (never, past, and current).
All assays were conducted without knowledge of the case/control status. Matched case-control pairs were handled identically and assayed in the same analytical run. Twenty quality-control specimens (n=20) were interspersed among the study samples. Over a 3-year period, intraclass correlation coefficients were 0.73 for free estradiol, 0.92 for SHBG, and 0.88 for testosterone in postmenopausal female nurses.13
Estradiol levels were measured at Quest Diagnostic in 2000 by radioimmunoassay preceded by extraction and purification by Celite column chromatography.14 The lower limit of detection for the assay was 5 pg/mL; the coefficient of variation was 9.5%. Estradiol levels from citrated plasma were slightly lower than from EDTA, with a correlation of 0.89. The linear regression formula was (plasma citrate estradiol level)=0.74 (EDTA plasma estradiol)+8.6.
Testosterone and SHBG levels were assayed at the Massachusetts General Hospital Reproductive Endocrine Laboratory in 2000. Total testosterone was measured using a solid-phase radioimmunoassay (Diagnostic Products Corporation). The lower limit of sensitivity was 4.0 ng/dL. SHBG was measured using a fully automated system (Immulite; Diagnostic Products Corporation), which used a solid-phase, 2-site immunometric assay. Coefficients of variation were 4.5% for SHBG and 4.8% for total testosterone.
To estimate free (non–protein-bound) testosterone, we calculated the free androgen index (FAI), the molar ratio of total testosterone/SHBG, which is highly correlated with free testosterone15 (to convert testosterone to nanomolar, the nanogram per deciliter value is multiplied by 0.0347). Similarly, to estimate the free estradiol concentration, the free estradiol index (FEI), the molar ratio of estradiol/SHBG was calculated (to convert estradiol to picomolar, the picogram per milliliter value is multiplied by 3.67).
Because of skewed distributions, hormone medians were compared using the Wilcoxon rank-sum test. Quartiles were created based on the distribution of values in the control population. Because of the a priori hypothesis that low estrogen levels and high androgen levels were associated with increased risk of CVD, referent categories were defined as high estrogen quartiles (high estradiol and FEI) and low androgen quartiles (high SHBG and low testosterone, FAI, and FAI/FEI ratio). Because the distribution of hormonal values differed significantly for present HT users and past/never users, analyses were stratified by HT status and separate quartiles were created. Values for past users and never users were similar; thus, these 2 groups were combined into nonusers.
Logistic regression was performed to adjust for matching factors, traditional risk factors, and potential confounders. Data on age, body mass index (BMI), physical activity (rarely or never, 1 to 3 times per month, 1 time per week), smoking (never, past, current), alcohol consumption (rarely or never, 1 to 3 times per month, 1 time per week), HT history, parental history of MI before age 60 years, as well as medical history of diabetes, elevated cholesterol, and hypertension were obtained from the WHS questionnaires. Models were also adjusted for randomized aspirin and vitamin E treatment assignment. Test for trend across quartiles was performed using ordinal variables. Conditional and unconditional logistic regression analyses yielded nearly identical results; thus, the unconditional logistic regression results are presented.
Results
Of the 200 women who developed cardiovascular events during a median follow-up of 2.9 years, there were 88 nonfatal MIs, 23 coronary revascularizations, 62 nonfatal ischemic strokes, and 27 cardiovascular deaths (5 fatal strokes and 22 coronary heart disease deaths). The average age was 63.1 years, and 42.5% were current HT users, 24.5% past users, and 33.0% never users. In the total population, median levels of SHBG, testosterone, FAI, estradiol, FEI, FAI/FEI, and testosterone/estradiol did not significantly differ among women with cardiovascular events and those who remained free of cardiovascular events (data not shown).
Because of substantial effect modification by HT, all analyses were stratified by HT status. Among nonusers, women who developed cardiovascular events had higher BMI, tended to be less physically active, and were more likely to have a history of diabetes, hypertension, or elevated cholesterol than women without cardiovascular events (Table 1). Among current HT users, cases were more likely to have a history of hypertension. As expected, hormone levels differed according to HT use (Table 2). Although total testosterone levels and FEI were similar among users and nonusers, SHBG and estradiol were higher and FAI levels and FAI/FEI were lower. Therefore, separate quartiles were created for HT users and nonusers.
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Among women not using hormones, median SHBG levels were significantly lower (P=0.03) and FAI was significantly higher (P=0.008) among the 115 women who developed CVD events than controls (Table 3). No other hormones differed significantly. Among current HT users, there were no differences between the 85 women with subsequent cardiovascular events and those women who remained free from CVD.
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Logistic regression was performed to control for matching factors, as well as randomized aspirin and vitamin E assignment (Table 4). Among HT nonusers, higher androgens were associated with significant trends for CVD, with increasing risk associated with lower SHBG levels (P=0.03) and higher FAI (P=0.02). Women in the lowest SHBG quartile had an OR of 2.45 (1.14 to 5.23), whereas those in the highest FAI quartile had an OR of 1.94 (95% CI, 0.91 to 4.14) compared with women in the lowest quartile. Low estradiol levels were not associated with increased risk (OR, 1.09; 95% CI, 0.50 to 2.35).
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After adjustment for parental history of MI, alcohol use, and physical activity, significant associations remained for women in the lowest SHBG quartile, with an OR of 2.25 (95% CI, 1.03 to 4.91) with a significant trend across quartiles (P for trend=0.05). Trends were also significant across FAI quartiles (P for trend=0.03). Additional adjustment for BMI, which is strongly and inversely associated with SHBG, as well as history of elevated cholesterol, diabetes, and hypertension eliminated independent associations for both SHBG and FAI. Trends for FAI/FEI were of borderline significance, with highest risk observed among those in the highest quartile.
We hypothesized that hormone levels attained among HT users might be also associated with cardiovascular risk. However, among current HT users, no significant trends or associations were seen.
Discussion
Among postmenopausal women not taking HT, we found that women with low SHBG or high FAI were at increased risk of CVD events. In age-adjusted analyses, low SHBG levels conferred a 2-fold increased risk of cardiovascular events; however, this was mediated primarily by BMI and other cardiovascular risk factors and was eliminated after multivariate adjustment. By contrast, for current HT users, there were no clear associations between estrogen, androgen, or SHBG levels and risk of cardiovascular events.
Low estrogen levels had been proposed as an explanation for the dramatic rise in cardiovascular risk associated with menopause. Recent randomized trial evidence3 demonstrated increased risk of CVD with HT, raising concern that higher estrogen levels might increase risk. The relationship of endogenous estrogen levels to risk of CVD in postmenopausal women has not been frequently examined. We also found no relationship between estradiol levels and risk of CVD in HT users or nonusers.
Higher testosterone levels in women have been associated with dyslipidemia5 as well as type 2 diabetes mellitus16 and hypertension.17 During menopause, a greater decline in estrogen levels than androgen levels results in a higher androgen/estrogen ratio in postmenopausal than premenopausal women. There were weak trends toward increased risk of CVD among women with higher androgen/estrogen (FAI/FEI) ratios.
Prior direct data on endogenous hormone levels and risk of CVD are limited. In a case-control study, women with polycystic ovary syndrome, a condition associated with elevated androgen levels, had more extensive atherosclerosis on angiography than women with normal ovaries.18 In another angiographic case-control study, free testosterone was a stronger predictor of the degree of atherosclerosis than was total cholesterol. Estradiol was inversely but nonsignificantly related to degree of atherosclerosis.6 In contrast, atherosclerosis as measured by carotid intimal-medial thickness was inversely associated with testosterone in 2 cross-sectional studies.19,20
Before our study, only 2 small prospective studies had examined the relationship between endogenous hormones and CVD, and neither found significant relationships between endogenous hormones and CVD. In the Rancho Bernardo Study of 651 women, age-adjusted mean levels of bioavailable testosterone and estradiol9 did not predict CVD deaths during 19 years of follow-up. In a small prospective study, both estradiol and testosterone levels were nonsignificantly lower among 40 postmenopausal diabetic women who died of coronary heart disease than diabetic women who remained free of coronary heart disease.11 Our results support a lack of association between estradiol and risk of cardiovascular events.
Data for the relationship between SBHG and CVD have been mixed. Low SHBG levels, which are sometimes considered an androgenic marker in women, have been associated with low HDL cholesterol11 as well as increased risk of diabetes.21 In case-control studies, low plasma levels of SHBG were associated with higher likelihood of atherosclerosis on angiography22 and carotid intimal-medial thickness20; however, another angiographic case-control study failed to find an association.23 Two prospective studies have examined the relationships between SHBG and cardiovascular outcomes. In the Gothenburg Study, low SHBG concentrations were associated with increased overall mortality and MI during 12 years of follow-up but were not adjusted for BMI.24 In the Rancho Bernardo Study, which did adjust for BMI, SHBG levels were not associated with cardiovascular mortality.10 In our study, low SHBG was associated with significantly higher risk of CVD events among women who did not use HT; however, this relationship was not independent of BMI.
This study has several strengths and limitations. To our knowledge, it is the largest prospective study of endogenous hormone levels and risk of CVD in postmenopausal women. In addition, because of the differences in hormone levels between HT users and nonusers, analyses were stratified by HT use; however, we had limited power to find an association in these separate HT strata. Although only 1 measure of hormones was available, levels have been shown to be quite stable in postmenopausal women.13 Additionally, we measured only total hormone levels, but the calculated free index has been shown to be a good estimate of free levels.
The role of exogenous hormones on cardiovascular risk has been recently reported, but whether endogenous hormones also have an effect on this risk has not been well tested. The present study found that among women who were not using HT, low SHBG levels were a marker of cardiovascular risk, but this risk was not independent of BMI, hypertension, and diabetes. There were weak trends toward increased risk among women with higher FAI/FEI ratios. We did not find any association between estradiol levels and risk of CVD either among HT users or nonusers. Larger studies of the relationship between hormone levels and risk of CVD in women who are not using exogenous hormones are necessary to determine whether androgenicity is an independent cardiovascular risk factor in postmenopausal women.
Acknowledgments
This study was supported by grants CA47988 and HL43851 from the National Institutes of Health and by the Doris Duke Charitable Foundation. The authors would like to acknowledge the crucial contributions of the entire staff of the WHS, under the leadership of David Gordon, Susan Burt, Mary Breen, Marilyn Chown, Rose Ungarelli, Lisa Fields-Johnson, Georgina Friedenberg, Jean MacFadyen, Geneva McNair, David Potter, Claire Ridge, and Harriet Samuelson, as well as Natasha Gomelskaya for her assistance with data analysis. Finally, the authors are deeply indebted to the dedicated and committed participants of the WHS.
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