The totality of data indicate that the “window of opportunity” for reducing coronary heart disease (CHD) and overall mortality is initiation of hormone therapy (HT) within 6 years of menopause and/or before 60 years of age. Reduction of CHD risk and overall mortality with prolonged HT use in this subgroup of women is consistent across randomized controlled trials and observational studies. As such, HT use for 5 to 30 years in postmenopausal women who initiate HT in their 50s substantially increases quality-adjusted life-years (QALYs) by 1.5 QALYs and is highly cost-effective at $2,438 per QALY gained. Cumulated randomized controlled trial results indicate a consistency along with observational data that young postmenopausal women with menopausal symptoms who use HT for long periods of time have lower rates of CHD and overall mortality than comparable postmenopausal women who do not use HT.
To investigate the effect of surgical menopause due to bilateral oophorectomy on mortality, in light of evidence that bilateral oophorectomy among premenopausal women rapidly reduces endogenous hormone levels thereby modifying risks of cardiovascular disease and breast cancer.
The California Teachers Study (CTS) is a prospective cohort study of 133,479 women initiated in 1995–1996 through a mailed, self-administered questionnaire. Relative risks (RR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards regression.
CTS participants who, at baseline, reported having surgical menopause due to bilateral oophorectomy (n=9,785), were compared to participants with natural menopause (n=32,219).
Main outcome measures
We investigated whether bilateral oophorectomy was associated with all-cause, cardiovascular, or cancer mortality, overall and by menopausal hormone therapy (HT) use status.
Among participants younger than 45 years of age at menopause, multivariable relative risks were 0.86 (95% CI, 0.74–1.00), 0.85 (95% CI, 0.66–1.11) and 0.91 (95% CI, 0.67–1.23) for all-cause mortality, cardiovascular mortality and cancer mortality, respectively. Among participants with an age at menopause of 45 years or later, multivariable relative risks were 0.87 (95% CI, 0.80–0.94), 0.83 (95% CI, 0.71–0.96) and 0.84 (95% CI, 0.72–0.98) for all-cause, cardiovascular and cancer mortality, respectively. The association between bilateral oophorectomy and mortality did not differ by baseline status of HT use.
Surgical menopause due to bilateral oophorectomy vs. natural menopause does not increase all-cause, cardiovascular, or cancer mortality.
surgical menopause and mortality; bilateral oophorectomy; mortality; California Teachers Study
The totality of data indicate that the window of opportunity for reducing mortality and coronary heart disease (CHD) is initiation of hormone therapy (HT) within 6 years of menopause and/or by 60 years of age and continued for 6 years or more. Additionally, the risks of HT are rare (<1/1,000) especially in younger postmenopausal women and comparable to other primary prevention therapies. In fact, as randomized controlled trial results accumulate, the more they look like the consistent observational data that young postmenopausal women with menopausal symptoms who use HT for long periods of time have lower rates of mortality and CHD than comparable postmenopausal women who do not use HT.
Although women have a lower incidence of stroke than men in most age groups, women have an overall increased lifetime risk of stroke. Women also have unique risk factors for stroke, including the menopausal transition, the existence of debilitating vasomotor symptoms for some women, and the issues related to hormonal treatment for those symptoms. Although the initial studies of hormone therapy (HT) use in postmenopausal women suggested significant protection against heart disease, there was no obvious protection against stroke. Randomized trials of HT for secondary prevention showed a lack of benefit for both heart disease and stroke, and the suggestion of some early risk after initiation. However, the Women’s Health Initiative (WHI), a primary prevention study of the impact of HT on women aged 50 to 79 years, showed an increased risk of stroke, whether the HT was estrogen alone or estrogen combined with progestin. Therefore, HT is not recommended for stroke prevention, and it appears to cause harm. The reason for this increased stroke risk is not understood, but some have suggested that the initiation of HT closest to the time of menopausal transition should decrease the risk. Although there was a lower risk of heart disease when HT was initiated earlier, the risk appeared to be the same for stroke regardless of the timing. This was shown in both the WHI and the Nurses’ Health Study cohorts. Therefore, more research is needed to understand the mechanisms for the increased stroke risk and to identify those who may be at risk because of HT for vasomotor symptoms, atrophic vaginitis, or osteoporosis, the three remaining indications for HT use in women. Trials are under way to assess the intermediate outcomes of HT on subclinical vascular disease in perimenopausal/early postmenopausal women.
Largely on the basis of the first publication of findings of net harm with menopausal hormone treatment in the Women’s Health Initiative (WHI) hormone trials, current Food and Drug Administration recommendations limit menopausal hormone treatment to the “… shortest duration consistent with treatment goals …,” with goals generally taken to mean relief of menopausal symptoms and maximal duration as approximately 5 years. The WHI finding of net harm was due largely to the absence of beneficial effects on coronary heart disease incidence rates. Published analyses of WHI data by age or time since menopause find that excess coronary heart disease risk with menopausal hormone treatment is confined to more remotely menopausal or older women, with younger women showing nonsignificant trends toward benefit (the “timing hypothesis”). Moreover, a recently published reexamination of data from the WHI Estrogen plus Progestin trial suggests that reduced coronary heart disease risk may appear only after 5 to 6 years of treatment. Consistent with this finding, risk ratios for coronary heart disease were calculated as 1.08 (95% confidence interval, 0.86–1.36) in years 1 to 6 and as 0.46 (confidence interval, 0.28–0.78) in years 7 to 8+ in the WHI Estrogen Alone trial. Previous studies also support the beneficial effects of menopausal hormone treatment after prolonged exposure. Thus, current analyses do not support a generalized recommendation for short duration of menopausal hormone treatment. Rather, they suggest that current Food and Drug Administration practice guidelines should be reconsidered to allow individualized care based on risk:benefit considerations. New research is urgently needed evaluating influences of timing, duration, dose, route of administration, and agents on menopausal hormone treatment-related risks and benefits to better understand how to optimize recommendations for individual patients.
Cardiovascular disease; Estrogen; Hormones; Menopause; Women’s health
Over the past decade two informative events in primary prevention of coronary heart disease (CHD) have occurred for women’s health. The first concerns hormone therapy (HT) where data have come full circle from presumed harm to consistency with observational data that HT initiation in close proximity to menopause significantly reduces CHD and overall mortality. The other concerns sex-specific efficacy of CHD primary prevention therapies where lipid-lowering and aspirin therapy have not been conclusively shown to significantly reduce CHD and more importantly where there is lack of evidence that either therapy reduces overall mortality in women. Cumulated data supports a “window-of-opportunity” for maximal reduction of CHD and overall mortality and minimization of risks with HT initiation before 60 years of age and/or within 10 years of menopause and continued for 6 years or more. There is a substantial increase in quality-adjusted life-years over a 5–30 year period in women who initiate HT in close proximity to menopause supporting HT as a highly cost-effective strategy for improving quality-adjusted life. Although primary prevention therapies and HT contrast in their efficacy to significantly reduce CHD and especially overall mortality in postmenopausal women, the magnitude and types of risks associated with HT are similar to those associated with other medications commonly used in women’s health. The cumulated data highlight the importance of studying the HT cardioprotective hypothesis in women representative of those from whom the hypothesis was generated.
Hormone Therapy; Estrogen; Menopause; Women; Coronary Heart Disease; Randomized Controlled Trials; Mortality; Meta-Analysis
Principle findings on stroke from the Women’s Health Initiative (WHI) clinical trials of hormone therapy indicate that estrogen, alone or with a progestogen, increases a woman’s risk of stroke. These results were not unexpected, and research during the past decade has tended to support these findings. Consistent evidence from clinical trials and observational research indicates that standard dose hormone therapy increases stroke risk for postmenopausal women by about a third; increased risk may be limited to ischemic stroke. Risk is not modified by age of hormone initiation or use, or by temporal proximity to menopause, and risk is similar for estrogen plus progestogen and for unopposed estrogen. Limited evidence implies that lower doses of transdermal estradiol (≤50μg/d) may not alter stroke risk. For women less than 60 years of age, the absolute risk of stroke from standard dose hormone therapy is rare, about 2 additional strokes per 10,000 person-years of use; the absolute risk is considerably greater for older women. Other hormonally active compounds — including raloxifene, tamoxifen, and tibolone — can also affect stroke risk.
estrogen; progestogen; hormone therapy; raloxifene; tamoxifen; tibolone; review; stroke; women’s health initiative
There has been an overall decrease in incident ischaemic heart disease (IHD), but the reduction in IHD risk factors has been greater among those with higher social position. Increased social inequalities in IHD mortality in Scandinavian countries is often referred to as the Scandinavian “public health puzzle”. The objective of this study was to examine trends in absolute and relative educational inequalities in four modifiable ischaemic heart disease risk factors (smoking, diabetes, hypertension and high total cholesterol) over the last three decades among Norwegian middle-aged women and men.
Population-based, cross-sectional data from The Nord-Trøndelag Health Study (HUNT): HUNT 1 (1984–1986), HUNT 2 (1995–1997) and HUNT 3 (2006–2008), women and men 40–59 years old. Educational inequalities were assessed using the Slope Index of Inequality (SII) and The Relative Index of Inequality (RII).
Smoking prevalence increased for all education groups among women and decreased in men. Relative and absolute educational inequalities in smoking widened in both genders, with significantly higher absolute inequalities among women than men in the two last surveys. Diabetes prevalence increased in all groups. Relative inequalities in diabetes were stable, while absolute inequalities increased both among women (p = 0.05) and among men (p = 0.01). Hypertension prevalence decreased in all groups. Relative inequalities in hypertension widened over time in both genders. However, absolute inequalities in hypertension decreased among women (p = 0.05) and were stable among men (p = 0.33). For high total cholesterol relative and absolute inequalities remained stable in both genders.
Widening absolute educational inequalities in smoking and diabetes over the last three decades gives rise to concern. The mechanisms behind these results are less clear, and future studies are needed to assess if educational inequalities in secondary prevention of IHD are larger compared to educational inequalities in primary prevention of IHD. Continued monitoring of IHD risk factors at the population level is therefore warranted. The results emphasise the need for public health efforts to prevent future burdens of life-style-related diseases and to avoid further widening in socioeconomic inequalities in IHD mortality in Norway, especially among women.
Trends; Socioeconomic inequalities; Gender differences; Ischaemic heart disease risk factors; Smoking; Diabetes; Hypertension; High total cholesterol
The authors further analyzed results from the Women's Health Initiative randomized trials (1993–2004) of conjugated equine estrogens, with or without medroxyprogesterone acetate, focusing on health benefits versus risks among women who initiated hormone therapy soon after menopause. Data from the Women's Health Initiative observational study (1993–2004) were included in some analyses for additional precision. Results are presented here for incident coronary heart disease, stroke, venous thromboembolism, breast cancer, colorectal cancer, endometrial cancer, or hip fracture; death from other causes; a summary global index; total cancer; and total mortality. Hazard ratios for breast cancer and total cancer were comparatively higher (P < 0.05) among women who initiated hormone therapy soon after menopause, for both regimens. Among these women, use of conjugated equine estrogens appeared to produce elevations in venous thromboembolism and stroke and a reduction in hip fracture. Estrogen plus progestin results among women who initiated use soon after menopause were similar for venous thromboembolism, stroke, and hip fracture but also included evidence of longer-term elevations in breast cancer, total cancer, and the global index. These analyses provide little support for the hypothesis of favorable effects among women who initiate postmenopausal estrogen use soon after menopause, either for coronary heart disease or for health benefits versus risk indices considered.
clinical trial; cohort studies; estrogens; estrogen replacement therapy; hormone replacement therapy; medroxyprogesterone 17-acetate; postmenopause; progestins
The male excess risk of premature ischemic heart disease (IHD) mortality may be partially due to an unknown macro-environmental influence associated with economic development. We examined whether excess male risk of IHD mortality was higher with birth in an economically developed environment.
We used multivariable logistic regression in a population-based case-control study of all adult deaths in Hong Kong Chinese in 1998 to compare sex differences in IHD mortality (1,189 deaths in men, 1,035 deaths in women and 20,842 controls) between Hong Kong residents born in economically developed Hong Kong or in contemporaneously undeveloped Guangdong province in China.
Younger (35–64 years) native-born Hong Kong men had a higher risk of IHD death than such women (odds ratio 2.91, 95% confidence interval 1.66 to 5.13), adjusted for age, socio-economic status and lifestyle. There was no such sex difference in Hong Kong residents who had migrated from Guangdong. There were no sex differences in pneumonia deaths by birth place.
Most of these people migrated as young adults; we speculate that environmentally mediated differences in pubertal maturation (when the male disadvantage in lipids and fat patterning emerges) may contribute to excess male premature IHD mortality in developed environments.
Emerging evidence suggests that women with menopausal vasomotor symptoms (VMS) have increased cardiovascular disease (CVD) risk as measured by surrogate markers. We investigated the relationships between VMS and clinical CVD events and all-cause mortality in the Women's Health Initiative Observational Study (WHI-OS).
We compared the risk of incident CVD events and all-cause mortality between four groups of women (total N=60,027): (1) No VMS at menopause onset and no VMS at WHI-OS enrollment (no VMS [referent group]); (2) VMS at menopause onset, but not at WHI-OS enrollment (early VMS); (3) VMS at both menopause onset and WHI-OS enrollment (persistent VMS [early and late]); and (4) VMS at WHI-OS enrollment, but not at menopause onset (late VMS).
For women with early VMS (N=24,753), compared to no VMS (N=18,799), hazard ratios (HRs) and 95% confidence intervals (CIs) in fully-adjusted models were: major CHD, 0.94 (0.84, 1.06); stroke, 0.83 (0.72, 0.96); total CVD, 0.89 (0.81, 0.97); and all-cause mortality, 0.92 (0.85, 0.99). For women with persistent VMS (N=15,084), there was no significant association with clinical events. For women with late VMS (N=1,391) compared to no VMS, HRs and 95% CIs were: major CHD, 1.32 (1.01, 1.71); stroke, 1.14 (0.82, 1.59); total CVD, 1.23 (1.00, 1.52); and all-cause mortality, 1.29 (1.08, 1.54).
Early VMS were not associated with increased CVD risk. Rather, early VMS were associated with decreased risk of stroke, total CVD events, and all-cause mortality. Late VMS were associated with increased CHD risk and all-cause mortality. The predictive value of VMS for clinical CVD events may vary with onset of VMS at different stages of menopause. Further research examining the mechanisms underlying these associations is needed. Future studies will also be necessary to investigate whether VMS that develop for the first time in the later postmenopausal years represent a pathophysiologic process distinct from classical perimenopausal VMS.
Vasomotor symptoms; Hot flashes; Cardiovascular disease; Women's health
Hormone therapy is still used by millions of women for menopausal symptoms. Concerns regarding hormone therapy and breast cancer were initially based on case reports and retrospective case–control studies. However, recent results from large prospective cohort studies and the Women’s Health Initiative (WHI) randomized placebo-controlled hormone therapy trials have substantially changed concepts regarding how estrogen alone and estrogen plus progestin influence breast cancer. The preponderance of observational studies suggested that estrogen alone and estrogen plus progestin both increased the risk of breast cancer, with cancers commonly diagnosed at an early stage. However, substantially different results emerged from the WHI randomized hormone therapy trials. In the WHI trial evaluating estrogen plus progestin in postmenopausal women with an intact uterus, combined hormone therapy statistically significantly increased the risk of breast cancer and hindered breast cancer detection, leading to delayed diagnosis and a statistically significant increase in breast cancer mortality. By contrast, estrogen alone use by postmenopausal women with prior hysterectomy in the WHI trial did not substantially interfere with breast cancer detection and statistically significantly decreased the risk of breast cancer. Differential mammography usage patterns may explain differences between observational study and randomized trial results. In clinical practice, hormone therapy users have mammograms more frequently than nonusers, leading to more and earlier stage cancer detection. By contrast, in the WHI randomized trials, mammogram frequency was protocol mandated and balanced between comparison groups. Currently, the different effects of estrogen plus progestin vs estrogen alone on breast cancer are not completely understood.
Peripheral arterial disease (PAD), like coronary heart disease, is a clinical manifestation of atherosclerosis and is associated with increased mortality. Although atherosclerotic cardiovascular disease is the leading cause of death for women as well as for men, PAD in women has received less attention than coronary heart disease or stroke. This paper reviews the prevalence of PAD, its risk factors, clinical significance, and management in women. One gender-specific therapeutic issue of particular interest to practitioners and the lay public is the role of postmenopausal hormone therapy. Prior to completion of the Heart and Estrogen/Progestin Replacement Study and the Women's Health Initiative Hormone Trials, postmenopausal hormone therapy was believed to exert antiatherosclerotic effects and to thereby reduce coronary heart disease risk in women on the basis of case-control and cohort studies. This review particularly focuses on the role, if any, of postmenopausal hormone therapy for prevention or treatment of PAD, which was a pre-specified secondary outcome for these three randomized trials.
women; estrogen; peripheral arterial disease
To investigate whether hormone therapy (HT) and obesity are associated with endometrial cancer risk among postmenopausal women in the California Teachers Study cohort.
Of 28,418 postmenopausal women, 395 developed type 1 endometrial cancer between 1995 and 2006. Multivariate Cox regression was performed to estimate relative risks (RR), stratified by HT use (never used, ever estrogen-alone (ET), or exclusively estrogen-plus-progestin (EPT)).
Among women who never used HT, overall and abdominal adiposity were associated with increased risk; when evaluated simultaneously, abdominal adiposity was more strongly associated (RR 2.2, 95% confidence interval (CI): 1.1–4.5 for waist ≥35 vs. <35 inches). Among women who ever used ET, risk was increased in women with BMI ≥25 kg/m2 (RR 1.6, 95% CI: 1.1–2.3 vs. <25 kg/m2). Neither overall nor abdominal obesity was associated with risk in women who exclusively used EPT (P-interaction<0.001 for BMI by HT use).
Among women who never used HT, risk was strongly positively related to obesity and may have been influenced more by abdominal than overall adiposity; however, due to small numbers, this latter finding requires replication. Among women who ever used ET, being overweight at baseline predicted higher risk, whereas use of EPT mitigated any effect of obesity.
endometrial cancer; obesity; abdominal adiposity; hormone therapy
Clinical trials of postmenopausal hormone therapy have shown increased risk of coronary heart disease (CHD) in the first few years after initiation of therapy, and no overall benefit.
To evaluate a range of inflammatory, lipid, thrombotic, and genetic markers for their association with CHD and to assess whether any of these markers modified or mediated the initially increased risk associated with hormone therapy
Nested case-control study of biomarkers and genetic variants in the Women’s Health Initiative randomized, controlled trials of hormone therapy in postmenopausal women aged 50–79 years at baseline.
Conjugated equine estrogens 0.625 mg daily or placebo in 10,739 hysterectomized women, and the same estrogen plus medroxy-progesterone acetate 2.5 mg daily in 16,608 women with an intact uterus.
Main outcome measures
Associations between putative biomarkers and genetic markers, hormone treatment, and CHD events during the first 4 years after randomization.
In multivariable-adjusted analyses of 359 cases and 820 controls, in the combined trials baseline levels of 12 of the 23 biomarkers studied were associated with CHD events: interleukin-6, matrix metalloproteinase-9, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol, triglycerides, d-dimer, factor VIII, von Willebrand factor, leukocyte count, homocysteine, and fasting insulin. Biomarkers tended to be more strongly associated with CHD in the initial 2 years after randomization. The genetic polymorphism glycoprotein IIIa leu33pro was significantly associated with CHD. Baseline low-density lipoprotein cholesterol interacted significantly with hormone treatment (particularly with CEE+MPA), so that women with higher levels were at higher risk of CHD when given hormone therapy (p for interaction = 0.03). There was a non-significant interaction of baseline high-density lipoprotein cholesterol with hormone therapy on CHD (p = 0.08). The levels of several biomarkers were changed by hormone therapy, but these changes did not appear to be associated with future CHD events.
The study confirmed that several thrombotic, inflammatory, and lipid biomarkers were associated with CHD events in postmenopausal women, however only low-density cholesterol (an established risk factor) modified the effect of hormone therapy. Further research is needed to identify the mechanisms by which hormone therapy increases the risk of CHD.
biomarkers; risk prediction; hormone therapy; estrogen; medroxy-progesterone; coronary heart disease; stroke; mortality; clinical trials; age; menopause
Objective. The aim of the present study was to estimate the premature ischemic heart disease (IHD) mortality attributable to alcohol abuse in Russia on the basis of aggregate-level data of mortality and alcohol consumption. Method. Age-standardized sex-specific male and female IHD mortality data for the period 1980–2005 and data on overall alcohol consumption were analyzed by means of autoregressive integrated moving average (ARIMA) time series analysis. Results. The results of the analysis suggest that 41.1% of all male deaths and 30.7% of female deaths from IHD in Russia could be attributed to alcohol. The estimated alcohol-attributable fraction for men ranged from 24.0% (75+ age group) to 62.0% (15–29 age group) and for women from 20.0% (75+ age group) to 64.0% (30–44 age group). Conclusions. The outcomes of this study provide indirect support for the hypothesis that the high rate of IHD mortality in Russia may be related to alcohol, as indicated by a close aggregate-level association between number of deaths from IHD and overall alcohol consumption per capita.
Evolving knowledge regarding sex differences in coronary heart disease (CHD) is emerging. Given the lower burden of obstructive coronary artery disease (CAD) and preserved systolic function in women contrasted by higher rates of myocardial ischemia and near-term mortality compared to men, we propose the term ischemic heart disease (IHD) as appropriate for this discussion specific to women, rather than CAD or CHD. This paradoxical difference where women have lower rates of anatomical CAD but more symptoms, ischemia, and outcomes appear linked to coronary reactivity which includes microvascular dysfunction. Novel risk factors can improve the Framingham risk score, including inflammatory markers and reproductive hormones, as well as noninvasive imaging and functional capacity measurements. Risk for women with obstructive CAD is elevated compared to men, yet women are less likely to receive guideline-indicated therapies. In the setting of non-ST elevation acute myocardial infarction, interventional strategies are equally effective in biomarker positive women and men, while conservative management is indicated for biomarker negative women. For women with evidence of ischemia but no obstructive CAD, anti-anginal and anti-ischemic therapies can improve symptoms, endothelial function, and quality of life; however trials evaluating adverse outcomes are needed. We hypothesize that women experience more adverse outcomes compared to men because obstructive CAD remains the current focus of therapeutic strategies. Continued research is indicated to devise therapeutic regimens to improve symptom burden and reduce risk in women with IHD.
Ischemic Heart Disease; Sex Differences; Women
Results from studies examining the association between hormone therapy (HT) and lung cancer risk disagree.
We examined the associations between HT use and lung cancer risk among 60,592 postmenopausal women enrolled in the prospective California Teachers Study cohort. Between 1995 and 2007, 727 women were diagnosed with lung cancer. Multivariable Cox proportional hazards regression models were fit using age as the time metric.
No measure of HT use was associated with lung cancer risk (all p-values for trend≥0.4). In addition, no variations in risk by smoking status (never, ever, former, current), type of HT (E-alone, E+P use), type of menopause, or lung cancer histology were observed.
Our findings do not support an association between HT and lung cancer.
This large-scale, prospective study, which capitalizes on the detailed hormone use, smoking history, and type of menopause information available within this unique cohort, was unable to find any association between intake of HT and lung cancer risk.
Health Professional Shortage Areas (HPSA) receive extra federal resources, but recent reports suggest that HPSA may not consistently identify areas of need.
To assess areas of need based on county-level ischemic heart disease (IHD) and stroke mortality regions.
Need was defined by lack of awareness, treatment, or control of hypertension, diabetes, or hyperlipidemia. Counties were categorized into race-specific tertiles of IHD and stroke mortality using 1999–2006 CDC data. Multivariable logistic regression was used to model the relationships between IHD and stroke mortality region and each element of need.
Awareness and treatment of cardiovascular (CVD) risk factors were similar for residents in counties across IHD and stroke mortality tertiles, but control tended to be lower in counties with the highest mortality.
High stroke and IHD mortality identify distinct regions from current HPSA designations, and may be an additional criterion for designating areas of need.
Control; ischemia; stroke; HPSA
Before age 65, women have less heart disease than men. For many years, estrogen was the most popular explanation for this female advantage, and observational studies through the 1980s showed a lower risk of heart attacks in postmenopausal women taking “replacement” estrogen. But the Women’s Health Initiative (WHI), the first placebo-controlled trials of hormone therapy with the size and statistical power necessary to study clinical cardiovascular outcomes, did not confirm the hormone-healthy heart hypothesis. Now, at least 5 years later, the most unexpected WHI result may be how resilient the estrogen hypothesis has been. Where, beyond estrogen therapy, should we go from here to explain the striking sex differences in heart disease rates? A broader spectrum of research about the female cardiovascular advantage and its translation is needed.
Heart Disease; Estrogen; Timing Hypothesis; Sex Differences
We compare recent trends in ischemic heart disease (IHD) and stroke mortality in California among the 6 major sex-racial or -ethnic groups. Rates of age-specific and -adjusted mortality were calculated for persons aged 35 and older during the years 1985 to 1991. Log-linear regression modeling was performed to estimate the average annual percentage change in mortality. During 1985 through 1991, the mortality for IHD and stroke was generally highest for African Americans, intermediate for non-Hispanic whites, and lowest for Hispanics. Age-adjusted mortality for IHD declined significantly in all sex-racial or -ethnic groups except African-American women, and stroke rates declined significantly in all groups except African-American and Hispanic men. African Americans had excess IHD mortality relative to non-Hispanic whites until late in life, after which mortality of non-Hispanic whites was higher. Similarly, African Americans and Hispanics had excess stroke mortality relative to non-Hispanic whites early in life, whereas stroke mortality in non-Hispanic whites was higher at older ages. The lower IHD and stroke mortality among Hispanics was paradoxical, given the generally adverse risk profile and socioeconomic status observed among Hispanics. An alarmingly high prevalence of self-reported cardiovascular disease risk factors in 1994 to 1996, particularly hypertension, leisure-time sedentary lifestyle, and obesity, is a serious public health concern, with implications for future trends in cardiovascular disease mortality. Of particular concern was the growing disparities in stroke and IHD mortality among younger-aged African Americans relative to Hispanics and non-Hispanic whites.
An emerging body of research suggests that depressive symptoms may confer an “accelerated risk” for cardiovascular disease (CVD) in African-Americans, compared with whites. Research in this area has been limited to cardiovascular risk factors and early markers; less is known about black-white differences in associations with important clinical endpoints.
The authors examined the association between depressive symptoms and overall CVD mortality, ischemic heart disease (IHD) mortality, and stroke mortality in a sample of 6,158 (62% African-American; 61% female) community-dwelling older adults. Cox proportional hazards models were used to model time-to-CVD, IHD and stroke death over follow-up.
In race-stratified models adjusted for age and sex, elevated depressive symptoms were associated with CVD mortality over follow-up in African-Americans (HR=1.95, 95% CI= 1.61-2.36, p<.001), but were not significantly associated with CVD mortality in whites (HR=1.26, 95% CI=.95-1.68, p=.11; race by depressive symptoms interaction p=.03). Similar findings were observed for IHD mortality (African-American HR=1.99, 95% CI=1.49-2.64, p<.001; white HR=1.28, 95% CI=.86-1.89, p=.23); and stroke mortality (African-American HR=2.08, 95% CI=1.32-3.27, p=.002; white HR=1.32, 95% CI=.69-2.52, p=.40). Findings for total CVD mortality and IHD mortality were attenuated, but remained significant after adjusting for standard risk factors. Findings for stroke were reduced to marginal significance.
Elevated depressive symptoms were associated with multiple indicators of CVD mortality in older African-Americans, but not whites. Findings were not completely explained by standard risk factors. Efforts aimed at reducing depressive symptoms in African-Americans may ultimately prove beneficial for their cardiovascular health.
Depressive Symptoms; cardiovascular disease (CVD); race; psychosocial risk factors; epidemiology
Appropriate and safe use of hormone replacement therapy (HRT) in postmenopausal women is an evolving saga, triggered by the unexpected results from the first publication of the Women's Health Initiative (WHI) Trial in 2002. These results showed a slight but significantly increased risk of breast cancer, stroke, and dementia with standard HRT compared with placebo. A reanalysis of these results shows that use of HRT within the first few years after the onset of menopause may be associated with decreased risk of dementia and coronary artery disease. However, HRT in its commonly used form of conjugated equine estrogen and medroxyprogesterone acetate can increase seizure frequency in menopausal women with epilepsy; this outcome may be an adverse effect of these neuroactive steroids on the epileptic female brain, which is already in a hormonally deprived state. To explore this possibility, more information about the neurophysiologic activity of medroxyprogesterone acetate is needed and alternatives to this specific HRT regimen should be considered for women with epilepsy.
To test whether estrogen receptor polymorphisms modify the effects of postmenopausal hormone therapy on biomarkers and on risk of coronary heart disease events, stroke, or venous thrombo-embolism.
Methods and Results
The design was a nested case-control study in the Women’s Health Initiative trials of postmenopausal hormone therapy. The study included all cases in the first 4 years: coronary heart disease, 359; stroke, 248; venous thrombo-embolism, 217). Six estrogen receptor-αand one estrogen receptor-β polymorphisms were genotyped; 8 biomarkers known to be affected by hormone therapy were measured at baseline and one year after randomization. The polymorphisms were not associated with risk of vascular events, and did not modify the increased risks of coronary heart disease, stroke, or venous thrombo-embolism due to hormone therapy. However, a reduced response of plasmin-antiplasmin (PAP) to hormone therapy was noted for ESR1 IVS1-354 (interaction P<0.0001, corrected for multiple comparisons P=0.014) and ESR1 IVS1-1415 (interaction P<0.0001, corrected P= 0.014).
Estrogen receptor polymorphisms reduce the effect of postmenopausal hormone therapy on PAP, a marker of coagulation and fibrinolysis. However screening for ER polymorphisms to identify women at less risk of adverse cardiovascular outcomes is not likely to be useful for making HT treatment decisions.
coronary heart disease; stroke; venous thromboembolism; estrogen; estrogen receptor; genetics; single nucleotide polymorphisms
Although postmenopausal hormone therapy (HT) use declined significantly after publication of the Women's Health Initiative (WHI) results, many women still continue taking HT for menopausal symptom relief. It is clear that the breast cancer risk associated with combination estrogen and progesterone therapy (EPT) is greater than that with estrogen therapy alone (ET), but questions still remain about the safety of longer term ET use. Studies since the WHI have tried to clarify whether various factors can modify the risk of HT, such as the age at initiation, dose, or type of HT or characteristics of the individual, such as family history of body mass index. At this point, the relative risks breast cancer associated with HT across various subgroups of women should still be considered similar, but absolute risks can vary significantly among women and this may inform individual decision making. For breast cancer survivors, systemic HT should be discouraged.