Endogenous hormones and coronary heart disease in postmenopausal women

doi:10.1016/j.atherosclerosis.2011.01.053

Atherosclerosis

Volume 216, Issue 2, June 2011, Pages 414-419

https://doi.org/10.1016/j.atherosclerosis.2011.01.053 Get rights and content

Abstract

The association between serum levels of endogenous estrogens in postmenopausal women and the subsequent risk of coronary heart disease (CHD) was examined in a prospective case–control study nested within the New York University Women's Health Study (NYUWHS). The NYUWHS is a prospective cohort study of 14,274 healthy women enrolled between 1985 and 1991. A total of 99 women who were postmenopausal and free of cardiovascular disease at enrollment and who subsequently experienced CHD, defined as non-fatal myocardial infarction (MI), fatal CHD, percutaneous transluminal coronary angioplasty (PTCA), or coronary artery bypass grafting (CABG), were matched 1:2 by baseline age, blood sampling date, and postmenopausal status to controls who remained free of CHD as of the date of diagnosis of the matching case. Biochemical analyses for total estradiol, estrone, percent free estradiol, percent estradiol bound to sex hormone-binding globulin (SHBG), and SHBG were performed on pre-diagnostic stored serum samples. Participants had not used any hormone medications in the 6 months prior to blood collection. In the model adjusting only for matching factors, the risk of CHD in the top tertile of calculated bioavailable estradiol was elevated compared with the bottom tertile (OR = 2.10; 95% CI = 1.13–3.90, P for trend = 0.03), and the risk in the top tertile of SHBG was reduced (OR = 0.50, 95% CI = 0.28–0.92, P for trend < 0.01). However, these associations disappeared after adjusting for baseline hypertension status, body mass index, and serum cholesterol levels. These findings suggest that circulating estradiol and SHBG are not associated with CHD risk in postmenopausal women beyond what can be explained by the variation in hypertension status, BMI, and cholesterol.

Section snippets

Background

The role of endogenous sex hormones in coronary heart disease (CHD) among postmenopausal women has not been extensively studied. Many studies have indicated that among postmenopausal women, sex hormone binding globulin (SHBG) levels are positively associated with a more favorable lipid profile, including lower levels of total cholesterol, LDL-cholesterol, and triglycerides, and higher levels of HDL-cholesterol [1], [2], [3], [4], [5]. More recent data have suggested that SHBG may influence

New York University Women's Health Study

Detailed information about the NYUWHS has been presented elsewhere [14]. Briefly, the NYUWHS is a prospective cohort study of women enrolled at a mammography screening center in New York City. From March 1985 to June 1991, 14,274 women between the ages of 34 and 65 were enrolled in the study. Participants in the cohort are well educated, with 44% of the women having a college degree; health conscious, with only 19% of the women smoking and 49% taking multivitamins at the time of enrollment; and

Results

Compared with their age-matched controls, incident cases of CHD were more likely at baseline (time of entry to the study and blood draw) to have higher BMI, lower levels of physical activity, higher levels of total and LDL-cholesterol, a lower level of HDL-cholesterol, and a family history of MI (Table 1). Cases also had a higher level of bioavailable estradiol and a lower level of serum SHBG and percent of estradiol bound to SHBG at baseline in comparison to controls. The median time from

Discussion

Among postmenopausal women, we found a positive association between bioavailable estradiol and risk of CHD and an inverse association between SHBG levels and CHD risk. However, the associations disappeared after adjustment for hypertension status, BMI and serum cholesterol profile.

In the model adjusted only for matching variables, although levels of bioavailable estradiol and SHBG were both associated with CHD risk, the associations of total estradiol and estrone with CHD risk were not as

Acknowledgments

This research was supported by U.S. grants HL52123, NIEHS ES000260, American Heart Association grant 0835569D, and NCI CA016087. The contributions of the authors were as follows—YC, OPW, AAA, AZJ, PT, RS, ML, KLK contributed to the conception, revision and editing of the manuscript. The authors had no conflict of interest. The authors thank Aileen McGinn for carrying out the cardiovascular follow up.

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Cardiovascular Implications of the Menopause Transition: Endogenous Sex Hormones and Vasomotor Symptoms
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Citation Excerpt :
The impact and molecular mechanisms of FSH in different cell types of the cardiovascular system should be further explored. Studies assessing associations between endogenous estrogen and CVD events109–119 show conflicting results, with some reporting null findings109,112,114,115,119 and others showing inconsistent associations.110,111,113,116–118 None have assessed repeated measures of E2 over the MT. Understanding how the dynamic changes in E2 level or the declining pattern of E2 trajectories58 over the MT are related to CVD events later in life is urgently needed.
Simultaneous determination of three estrogens in human saliva without derivatization or liquid-liquid extraction for routine testing via miniaturized solid phase extraction with LC-MS/MS detection
2018, Talanta
Citation Excerpt :
These sex steroid hormones not only play a central role in the development of the female reproductive system and secondary sex characteristics [1,2], but they also regulate numerous physiological processes in female and male growth, including bone formation, nervous system maturation and fat deposition [3–5]. Additionally, compelling evidence implicates alterations in estrogen levels in several pathological conditions such as breast cancer [6,7], coronary artery disease [8] and cognitive dysfunction [9]. Moreover, estrogen concentrations are utilized to assess fertility [10] and fracture risk [11] as well as monitor hormone replacement therapy [12].
Accurate quantitation of estrogens (i.e, estrone (E1), estradiol (E2) and estriol (E3)) is valuable for clinical assessment of human health and disease. Alterations in estrogen levels have been implicated in numerous pathological conditions. However, inadequacies in sensitivity and specificity, cumbersome sample preparation and invasive specimen collection hamper the usability of available methods for clinical applications. Herein, a simple, rapid, highly sensitive and specific LC-MS/MS method was developed and validated for the simultaneous determination of three estrogens in human saliva providing a non-invasive alternative to conventional blood samples. For the first time, a 96-well hydrophilic-lipophilic-balanced (HLB) microplate was employed for clean-up and enrichment of estrogens in a single extraction without the requirements of derivatization, evaporation, liquid-liquid extraction and online extraction. A rapid LC chromatographic separation with a turnaround time of 5.0 min was achieved on a BEH C18 XP column. The use of 0.1 mM ammonium fluoride (NH₄F) as LC additive, and integration of summated and scheduled multiple reaction monitoring (MRM) transitions substantially improved the sensitivity to 1 pg/mL, allowing the accurate quantitation of trace levels of three estrogens in one run. The assay was fully validated with good performance for extraction efficiency (67.0–85.6%), matrix effect (89.6–100.2%), linearity (from 1.0 pg/mL up to 1000 pg/mL), accuracy (98.9–112.4%) and precision (≤7.4%). Additionally, the assay was unaffected by 34 structurally-similar, potentially interfering substances tested at high clinical concentrations. The applicability of the assay was demonstrated by assessing the reference intervals of authentic saliva samples from healthy adult males, pre- and post-menopausal females. The easy sample preparation, fast LC and multi-analyte MS/MS detection utilizing noninvasive saliva as a specimen delivers a simple, practical, sensitive and accurate tool suitable for the high throughput measurement of E1, E2 and E3 in clinical laboratories.
Gaps, limitations and new insights on endogenous estrogen and follicle stimulating hormone as related to risk of cardiovascular disease in women traversing the menopause: A narrative review
2017, Maturitas
Citation Excerpt :
As can be seen in Fig. 2A, not all postmenopausal women may have similar E2 levels after FMP. Interestingly, previous studies which only included postmenopausal women used single measure of E2 after FMP as a surrogate measure of postmenopausal E2 levels irrespective of the time elapsed since FMP or possibility that E2 trajectories of women included in the study may not be the same [91,92–106]. Although speculative, it is interesting to note that the majority of the studies which included postmenopausal women who were ≥60 years old at the time of estradiol measurement reported positive associations between levels of postmenopausal E2 and CVD risk (e.g. incident ischemic arterial disease, stroke, CVD events: myocardial infarction, angina, heart failure, and coronary bypass, or incident hypertension) [91,92,100,102–105] that remained significant even after adjusting for potential risk factors in some of the studies [91,92,103,105].
While it is known that estrogen protects heart health in women prior to menopause, its role after menopause and during the menopause transition is far less apparent. Previous reviews summarizing the literature on the impact of endogenous estrogen on risk of cardiovascular disease (CVD) have focused on postmenopausal women and have not come to a clear conclusion. No previous review has summarized the associations between follicle stimulating hormone (FSH), a proxy measure of the menopause transition, and CVD risk. The main purpose of this narrative review is to highlight gaps and limitations in the literature on endogenous estrogen and FSH as related to CVD risk. Future directions are addressed in light of recent findings in the field. When studying the relationship of estrogen to cardiovascular risk, it is critical to separate endogenously produced estrogen from exogenously administered estrogen. Moreover, other reproductive hormones such as FSH should be assessed, since growing evidence suggests a potential contribution of this hormone. Evaluation of estrogen changes over time allows a separation of women based on their hormone trajectories. These individual trajectories correlate with subclinical CVD and thus indicate that it is much more important to observe a woman over time rather than ascribe risk to a single determination at a single time point. As women progress through menopause and the ovary stops producing estradiol, the nature of the relationship between estrogens and subclinical CVD markers also appears to undergo a switch. Studies are needed to examine the midlife course of endogenous estradiol, FSH and CVD risk. These studies should also consider other hormones, including androgens, with an eye towards helping women modify their cardiovascular risk in midlife, when prevention is most likely possible.
Fertile lifespan characteristics and all-cause and cause-specific mortality among postmenopausal women: the Rotterdam Study
2017, Fertility and Sterility
To characterize the relation between established and previously unexplored characteristics of the fertile life with all-cause and cause-specific mortality.
Prospective cohort study.
Not applicable.
A total of 4,076 postmenopausal women.
Women's fertile lifespan (age at menarche to menopause), number of children, maternal age at first and last child, maternal lifespan (interval between maternal age at first and last child), postmaternal fertile lifespan (interval between age at last child and menopause), lifetime cumulative number of menstrual cycles, and unopposed cumulative endogenous estrogen (E) exposure.
Registry-based all-cause and cause-specific mortality.
A total of 2,754 women died during 14.8 years of follow-up. Compared with women with 2–3 children, a 12% higher hazard of dying was found for women having 1 child (hazard ratio [HR], 1.12; 95% confidence interval [CI] 1.01–1.24), which became nonsignificant in models adjusted for confounders (HR, 1.08; 95% CI 0.96–1.21). Late age at first and last birth were associated with a 1% lower hazard of dying (HR, 0.99; 95% CI 0.98–1.00). Longer maternal and postmaternal fertile lifespan (HR 1.01; 95% CI 1.00–1.02), longer fertile lifespan (HR 1.02; 95% CI 1.00–1.05), and unopposed cumulative E exposure (HR, 1.02; 95% CI 1.00–1.04) were significantly harmful for all-cause mortality. Findings differed with regard to direction, size, and statistical significance when stratifying for cardiovascular disease, cancer, and other mortality.
Overall, we found that late first and last reproduction were protective for all-cause mortality, whereas a longer maternal lifespan, postmaternal fertile lifespan, and E exposure were harmful for all-cause mortality. More research is needed in contemporary cohorts with larger sample sizes and more extreme ages of birth.
High variability in serum estradiol measurements in men and women
2014, Steroids
Citation Excerpt :
Epidemiological studies found that the relative risk for breast cancer in postmenopausal women with high E2 levels ranges from 1.5 to 3.0 [1–5]. Other research reported associations of serum E2 levels with chronic diseases such as cardiovascular disease [6,7], cognitive function [8], and fracture risk [9]. The use of estradiol as a drug, as well as the association of the effects of estradiol levels in blood on human health, is subject to extensive research [10].
To reduce the variability in estradiol (E2) testing and to assure better patient care, standardization of E2 measurements has been recommended. This study aims to assess the accuracy and variability of E2 measurements performed by 11 routine immunological methods and 6 mass spectrometry methods using single donor serum materials and to compare the results to a reference method. The contribution of calibration bias, specificity or matrix effects, and imprecision on the overall variability of individual assays was evaluated.
This study showed substantial variability in serum E2 measurements in samples from men and pre- and post-menopausal women. The mean bias across all samples, for each participant, ranged between −2.4% and 235%, with 3 participants having a mean bias of over 100%. The data suggest that calibration bias is the major contributor to the overall variability for nine assays.
The analytical performances of most assays measuring E2 concentrations do not meet current needs in research and patient care. Three out of 17 assays would meet performance criteria derived from biological variability of ±12.5% bias at concentrations ⩾20 pg/mL, and a maximum allowable bias of ±2.5 pg/mL at concentrations <20 pg/mL. The sensitivity differs highly between assays. Most assays are not able to measure E2 levels below 10 pg/mL. Standardization, specifically calibration to a common standard by using panels of individual patient samples, can reduce the observed variability and improve the utility of E2 levels in clinical settings.
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Endogenous hormones and coronary heart disease in postmenopausal women

Abstract

Section snippets

Background

New York University Women's Health Study

Results

Discussion

Acknowledgments

Fertil Steril

Ann Epidemiol

Ann Epidemiol

Biochem Med

Endogenous androgen levels and cardiovascular risk profile in women across the adult life span

Menopause

Endogenous postmenopausal hormones and serum lipids: the atherosclerosis risk in communities study

J Clin Endocrinol Metab

Relation of sex hormones and dehydroepiandrosterone sulfate (DHEA-SO4) to cardiovascular risk factors in postmenopausal women

Am J Epidemiol

Sex-hormone-binding globulin and the free androgen index are related to cardiovascular risk factors in multiethnic premenopausal and perimenopausal women enrolled in the Study of Women Across the Nation (SWAN)

Circulation

The relation of endogenous sex steroid hormone concentrations to serum lipid and lipoprotein levels in postmenopausal women

Am J Epidemiol

Endogenous sex hormones and C-reactive protein in healthy postmenopausal women

J Intern Med

Endogenous sex hormones and risk factors for atherosclerosis in healthy Greek postmenopausal women

Eur J Endocrinol

Prospective study of endogenous sex hormones and fatal cardiovascular disease in postmenopausal women

BMJ

Sex hormones and DHEA-SO4 in relation to ischemic heart disease mortality in diabetic subjects. The Wisconsin Epidemiologic Study of Diabetic Retinopathy

Diabetes Care

Sex hormone levels and risk of cardiovascular events in postmenopausal women

Circulation

Endogenous hormones and breast cancer: a prospective cohort study

Breast Cancer Res Treat