Endogenous Sex Hormones and Incident Cardiovascular Disease in Post-Menopausal Women

Abstract

Background: Higher androgen and lower estrogen levels are associated with cardiovascular disease (CVD) risk factors in women. However, studies on sex hormones and incident CVD events in women have yielded conflicting results.

Objectives: The authors assessed the associations of sex hormone levels with incident CVD, coronary heart disease (CHD), and heart failure (HF) events among women without CVD at baseline.

Methods: The authors studied 2,834 post-menopausal women participating in the MESA (Multi-Ethnic Study of Atherosclerosis) with testosterone, estradiol, dehydroepiandrosterone, and sex hormone binding globulin (SHBG) levels measured at baseline (2000 to 2002). They used Cox hazard models to evaluate associations of sex hormones with each outcome, adjusting for demographics, CVD risk factors, and hormone therapy use.

Results: The mean age was 64.9 ± 8.9 years. During 12.1 years of follow-up, 283 CVD, 171 CHD, and 103 HF incident events occurred. In multivariable-adjusted models, the hazard ratio (95% confidence interval [CI]) associated with 1 SD greater log-transformed sex hormone level for the respective outcomes of CVD, CHD, and HF were as follows: total testosterone: 1.14 (95% CI: 1.01 to 1.29), 1.20 (95% CI: 1.03 to 1.40), 1.09 (95% CI: 0.90 to 1.34); estradiol: 0.94 (95% CI: 0.80 to 1.11), 0.77 (95% CI: 0.63 to 0.95), 0.78 (95% CI: 0.60 to 1.02); and testosterone/estradiol ratio: 1.19 (95% CI: 1.02 to 1.40), 1.45 (95% CI: 1.19 to 1.78), 1.31 (95% CI: 1.01 to 1.70). Dehydroepiandrosterone and SHBG levels were not associated with these outcomes.

Conclusions: Among post-menopausal women, a higher testosterone/estradiol ratio was associated with an elevated risk for incident CVD, CHD, and HF events, higher levels of testosterone associated with increased CVD and CHD, whereas higher estradiol levels were associated with a lower CHD risk. Sex hormone levels after menopause are associated with women's increased CVD risk later in life.

Keywords: cardiovascular disease; coronary heart disease; estradiol; heart failure; sex hormone binding globulin; sex hormones; testosterone.

Figure 1. Flow chart of study participants

The present analysis included all post-menopausal women who attended the baseline exam (N=3,087). After exclusions shown in Figure, the final sample size was 2,834 women.

Figure 2. Hazard Ratios (HR) for incident CVD, CHD and HF by sex hormone levels*,^†,‡

*Abbreviations: CVD, cardiovascular disease; CHD, coronary heart disease; HF, Heart Failure. ^†The curves represent the adjusted HR of CVD/CHD/HF by log sex hormone levels. The dose response association was estimated by using a linear and a cubic spline term for each sex hormone in the multivariable cox regression. Curves represent adjusted HR (solid line) and 95% CI (dashed lines) based on restricted cubic splines for sex hormones with knots at the 5th, 35th, 65th and 95th percentiles of their sample distributions. The reference values (diamond dots) were set at 10th percentile. ^‡The model was adjusted for age, race/ethnicity, study center, education, waist to hip ratio, physical activity, smoking, systolic blood pressure, use of antihypertensive medications, total cholesterol, HDL-cholesterol, use of lipid lowering medications, diabetes, eGFR, use of hormone therapy, log(CRP), log(IL6), log(fibrinogen), and log(D-dimer). Panel A: total testosterone (nmol/L) Panel B: estradiol (nmol/L) Panel C: testosterone-estradiol ratio

Figure 2. Hazard Ratios (HR) for incident CVD, CHD and HF by sex hormone levels*,^†,‡

*Abbreviations: CVD, cardiovascular disease; CHD, coronary heart disease; HF, Heart Failure. ^†The curves represent the adjusted HR of CVD/CHD/HF by log sex hormone levels. The dose response association was estimated by using a linear and a cubic spline term for each sex hormone in the multivariable cox regression. Curves represent adjusted HR (solid line) and 95% CI (dashed lines) based on restricted cubic splines for sex hormones with knots at the 5th, 35th, 65th and 95th percentiles of their sample distributions. The reference values (diamond dots) were set at 10th percentile. ^‡The model was adjusted for age, race/ethnicity, study center, education, waist to hip ratio, physical activity, smoking, systolic blood pressure, use of antihypertensive medications, total cholesterol, HDL-cholesterol, use of lipid lowering medications, diabetes, eGFR, use of hormone therapy, log(CRP), log(IL6), log(fibrinogen), and log(D-dimer). Panel A: total testosterone (nmol/L) Panel B: estradiol (nmol/L) Panel C: testosterone-estradiol ratio

Figure 2. Hazard Ratios (HR) for incident CVD, CHD and HF by sex hormone levels*,^†,‡

*Abbreviations: CVD, cardiovascular disease; CHD, coronary heart disease; HF, Heart Failure. ^†The curves represent the adjusted HR of CVD/CHD/HF by log sex hormone levels. The dose response association was estimated by using a linear and a cubic spline term for each sex hormone in the multivariable cox regression. Curves represent adjusted HR (solid line) and 95% CI (dashed lines) based on restricted cubic splines for sex hormones with knots at the 5th, 35th, 65th and 95th percentiles of their sample distributions. The reference values (diamond dots) were set at 10th percentile. ^‡The model was adjusted for age, race/ethnicity, study center, education, waist to hip ratio, physical activity, smoking, systolic blood pressure, use of antihypertensive medications, total cholesterol, HDL-cholesterol, use of lipid lowering medications, diabetes, eGFR, use of hormone therapy, log(CRP), log(IL6), log(fibrinogen), and log(D-dimer). Panel A: total testosterone (nmol/L) Panel B: estradiol (nmol/L) Panel C: testosterone-estradiol ratio

Figure 3. Associations between sex hormone levels with incident CVD, CHD and HF by age and race/ethnic subgroups

Panel A: Hazard Ratio for CVD; Panel B: Hazard Ratio for CHD; Panel C: Hazard Ratio for HF. *Hazard Ratios are associated with 1 SD increase in log sex hormones. The model was adjusted for the covariates listed in footnote for Figure 2.

Figure 3. Associations between sex hormone levels with incident CVD, CHD and HF by age and race/ethnic subgroups

Panel A: Hazard Ratio for CVD; Panel B: Hazard Ratio for CHD; Panel C: Hazard Ratio for HF. *Hazard Ratios are associated with 1 SD increase in log sex hormones. The model was adjusted for the covariates listed in footnote for Figure 2.

Figure 3. Associations between sex hormone levels with incident CVD, CHD and HF by age and race/ethnic subgroups

Panel A: Hazard Ratio for CVD; Panel B: Hazard Ratio for CHD; Panel C: Hazard Ratio for HF. *Hazard Ratios are associated with 1 SD increase in log sex hormones. The model was adjusted for the covariates listed in footnote for Figure 2.

Central Illustration. Testosterone/Estradiol Ratio and the Risk of Incident CVD, CHD, and HF in post-menopausal women: the Multi-Ethnic Study of Atherosclerosis*,^†,‡

*Abbreviations: CVD, cardiovascular disease; CHD, coronary heart disease; HF, Heart Failure. ^†Left panel: Boxplot distribution of the testosterone/estradiol ratio by outcome status (unadjusted). The bottom and top of the box are the first and third quartiles, and the band inside the box is the second quartile (the median). The whiskers represent the 1st quartile −1.5*IQR and 3rd quartile +1.5*IQR. ^‡Right panel: Adjusted Hazard Ratio of CVD/CHD/HF for testosterone/estradiol ratio using restricted cubic spline with knots at the 5th, 35th, 65th and 95th percentiles of the sample distribution. The reference value (diamond dot) was set at 10th percentile. The model was adjusted for age, race/ethnicity, study center, use of hormone therapy, education, waist to hip ratio, physical activity, smoking, systolic blood pressure, use of antihypertensive medications, total cholesterol, HDL-cholesterol, use of lipid lowering medications, diabetes, eGFR,, log(CRP), log(IL6), log(fibrinogen), and log(D-dimer).