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Background: Individuals with inflammatory bowel disease (IBD) who lack traditional cardiovascular disease (CVD) risk factors, such as young females, are observed to experience adverse CVD outcomes. Whether women with IBD have increased CVD risk after the menopause transition is unclear., Methods: We conducted a survival analysis of Women's Health Initiative (WHI) participants and excluded those with missing IBD diagnosis, model covariate data, follow-up data, or a baseline history of the following CVD outcomes: coronary heart disease (CHD), ischemic stroke, venous thromboembolism (VTE), peripheral arterial disease (PAD). Risk of outcomes between IBD and non-IBD women was performed using Cox proportional hazard models, stratified by WHI trial and follow-up. Models were adjusted for age, socio-demographics, comorbidities (e.g., hypertension, diabetes, hypercholesterolemia, etc.), family history, and lifestyle factors (e.g., smoking, alcohol, physical activity, body mass index, etc.)., Results: Of 134,022 WHI participants meeting inclusion criteria, 1367 (1.0%) reported IBD at baseline. Mean baseline age was 63.4 years. After adjusting for age and other confounders, no significant difference was observed between IBD and non-IBD women for the risk of CHD (HR 0.96, 95% CI 0.73-1.24), VTE (HR 1.11, 95% CI 0.81-1.52) or PAD (HR 0.64, 95% CI 0.28-1.42). After adjusting for age, risk of ischemic stroke was significantly higher (HR 1.41, 95% CI 1.06-1.88) in IBD than non-IBD women. With further adjustment, the excess risk of ischemic stroke among IBD women was attenuated and no longer statistically significant (HR 1.31, 95% CI 0.98-1.76)., Conclusions: Among postmenopausal women with IBD, risk of ischemic stroke may be higher than in non-IBD women., (© 2024. The Author(s).)

We investigated relations of depressive symptoms, antidepressant use, and epigenetic age acceleration with all-cause mortality risk among postmenopausal women. Data were analyzed from ≤1,900 participants in the Women's Health Initiative study testing four-way decomposition models. After a median 20.4y follow-up, 1,161 deaths occurred. Approximately 11% had elevated depressive symptoms (EDS + ), 7% were taking antidepressant medication at baseline (ANTIDEP + ), while 16.5% fell into either category (EDS&#95;ANTIDEP + ). Baseline ANTIDEP + , longitudinal transition into ANTIDEP + and accelerated epigenetic aging directly predicted increased mortality risk. GrimAge DNA methylation age acceleration (AgeAccelGrim) partially mediated total effects of baseline ANTIDEP + and EDS&#95;ANTIDEP + on all-cause mortality risk in socio-demographic factors-adjusted models (Pure Indirect Effect >0, P < 0.05; Total Effect >0, P < 0.05). Thus, higher AgeAccelGrim partially explained the relationship between antidepressant use and increased all-cause mortality risk, though only prior to controlling for lifestyle and health-related factors. Antidepressant use and epigenetic age acceleration independently predicted increased all-cause mortality risk. Further studies are needed in varying populations.

Inflammation can play a role in the pathophysiology of depression, and specific types of antidepressants may have inflammatory or anti-inflammatory properties. Furthermore, depression and antidepressant use has been linked to white blood cell (WBC) count, a routinely measured inflammatory marker. We examined the cross-sectional and longitudinal relationships of depressive symptoms and/or antidepressant use with WBC count among postmenopausal women. Analyses of cross-sectional data at enrollment were performed on 125,307 participants, 50-79 years of age, from the Women's Health Initiative Clinical Trials and Observational Studies who met eligibility criteria, and a subset of those with 3-year follow-up data were examined for longitudinal relationships. Depressive symptoms were defined using the Burnam Algorithm whereas antidepressant use was defined using therapeutic class codes. WBC count (Kcell/ml) was obtained through laboratory evaluations of fasting blood samples. Multivariable regression modeling was performed taking sociodemographic, lifestyle and health characteristics into consideration. At enrollment, nearly 85% were non-users of antidepressants with no depressive symptoms, 5% were antidepressant users with no depressive symptoms, 9% were non-users of antidepressants with depressive symptoms, and 2% were users of antidepressants with depressive symptoms. In fully-adjusted models, cross-sectional relationships were observed whereby women in the 2 nd (OR = 1.06, 95% CI: 1.01, 1.13), 3 rd (OR = 1.06, 95% CI: 1.00, 1.12) or 4 th (OR = 1.10, 95% CI: 1.05, 1.17) quartiles of WBC count were more likely to exhibit depressive symptoms, and women in the 4 th quartile were more likely to be users of antidepressants (OR = 1.07, 95% CI: 1.00, 1.15), compared to women in the 1 st quartile. Compared to women who exhibited no depressive symptoms at either visit, those with consistent depressive symptoms at enrollment and at 3-year follow-up had faster decline in WBC count (β = -0.73, 95% CI: -1.33, -0.14) over time. No significant bidirectional relationships were observed between changes in depressive symptoms score and WBC count over time. In conclusion, depressive symptoms and/or antidepressant use were cross-sectionally related to higher WBC counts among postmenopausal women. Further evaluation of observed relationships is needed in the context of prospective cohort studies involving older adult men and women, with repeated measures of depression, antidepressant use, and WBC count., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objective: To assess the relationship between body fat distribution and incident lower-extremity arterial disease (LEAD)., Research Design and Methods: We included 155,925 postmenopausal women with anthropometric measures from the Women's Health Initiative who had no known LEAD at recruitment. A subset of 10,894 participants had body composition data quantified by DXA. Incident cases of symptomatic LEAD were ascertained and adjudicated through medical record review., Results: We identified 1,152 incident cases of LEAD during a median 18.8 years follow-up. After multivariable adjustment and mutual adjustment, waist and hip circumferences were positively and inversely associated with risk of LEAD, respectively (both P-trend < 0.0001). In a subset (n = 22,561) where various cardiometabolic biomarkers were quantified, a similar positive association of waist circumference with risk of LEAD was eliminated after adjustment for diabetes and HOMA of insulin resistance (P-trend = 0.89), whereas hip circumference remained inversely associated with the risk after adjustment for major cardiometabolic traits (P-trend = 0.0031). In the DXA subset, higher trunk fat (P-trend = 0.0081) and higher leg fat (P-trend < 0.0001) were associated with higher and lower risk of LEAD, respectively. Further adjustment for diabetes, dyslipidemia, and blood pressure diminished the association for trunk fat (P-trend = 0.49), yet the inverse association for leg fat persisted (P-trend = 0.0082)., Conclusions: Among U.S. postmenopausal women, a positive association of upper-body fat with risk of LEAD appeared to be attributable to traditional risk factors, especially insulin resistance. Lower-body fat was inversely associated with risk of LEAD beyond known risk factors., (© 2021 by the American Diabetes Association.)

The potential role of nutritional factors in the development of peripheral arterial disease (PAD) remains poorly understood. We evaluated multiple recommended eating patterns as reflected by predefined diet quality indices in relation to long-term risk of PAD. We included 138 506 US postmenopausal women in the Women’s Health Initiative who had no known PAD at baseline (1993–1998). Four diet quality indices, including alternate Mediterranean diet index, alternate Healthy Eating Index-2010, Dietary Approaches to Stop Hypertension diet index, and Healthy Eating Index-2015, were derived using dietary information collected by a validated food frequency questionnaire at baseline. Incident cases of symptomatic PAD in the lower extremities were ascertained and adjudicated through March 2019 via medical record review. During a median 18.6 years of follow-up, 1036 incident PAD cases were identified. After multivariable adjustment, all diet quality scores were significantly and inversely associated with 21% (for alternate Healthy Eating Index 2010) to 34% (for Dietary Approaches to Stop Hypertension index) lower risk of PAD when comparing the highest with the lowest quartiles (all P-fortrend values ≤0.010). Among contributing food groups and nutrients, intakes of legumes, dietary fiber, and vegetable protein were associated lower risk of PAD, while intakes of unprocessed red meat, processed meat, and regular soft drinks were associated with higher risk. In a broad sample of US postmenopausal women, adhering to different recommended eating patterns is associated with lower risk of PAD. Our findings suggest that current clinical and public health strategies that recommend healthful eating patterns may also be applicable to PAD prevention. (

Background: The potential cardiovascular impact of dietary cholesterol intake has been actively debated for decades., Objectives: We aimed to evaluate associations of dietary cholesterol and egg intakes with incident cardiovascular disease (CVD) and all-cause and cause-specific mortality., Methods: We included 96,831 US postmenopausal women aged 50-79 y without known CVD or cancer during baseline enrollment (1993-1998) of the Women's Health Initiative. Dietary information was collected using a validated FFQ. Incident CVD [i.e., ischemic heart disease (IHD) and stroke] and all-cause and cause-specific mortality were ascertained and adjudicated through February 2018., Results: A total of 9808 incident CVD cases and 19,508 all-cause deaths occurred during a median follow-up of 17.8 y and 18.9 y, respectively. After multivariable adjustment for traditional risk factors and key dietary nutrients including dietary saturated fat, there were modest associations of dietary cholesterol intake with incident CVD (HRQ5versusQ1: 1.12; 95% CI: 1.03, 1.21; P-trend < 0.001) and all-cause mortality (HRQ5versusQ1: 1.09; 95% CI: 1.02, 1.15; P-trend < 0.001). Significant positive associations were also observed between dietary cholesterol and incident IHD (P-trend = 0.007), incident ischemic stroke (P-trend = 0.002), and CVD mortality (P-trend = 0.002), whereas there was an inverse association for incident hemorrhagic stroke (P-trend = 0.037) and no association for mortality from cancer, Alzheimer disease/dementia, respiratory diseases, or other causes (P-trend > 0.05). Higher egg consumption was also associated with modestly higher risk of incident CVD (P-trend = 0.004) and all-cause mortality (P-trend < 0.001), with HRs of 1.14 (95% CI: 1.04, 1.25) and 1.14 (95% CI: 1.07, 1.22), respectively, when comparing ≥1 egg/d with <1 egg/wk., Conclusions: Both higher dietary cholesterol intake and higher egg consumption appeared to be associated with modestly elevated risk of incident CVD and all-cause mortality in US postmenopausal women., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background Presence of clonal hematopoiesis of indeterminate potential (CHIP) is associated with a higher risk of atherosclerotic cardiovascular disease, cancer, and mortality. The relationship between a healthy lifestyle and CHIP is unknown. Methods and Results This analysis included 8709 postmenopausal women (mean age, 66.5 years) enrolled in the WHI (Women's Health Initiative), free of cancer or cardiovascular disease, with deep-coverage whole genome sequencing data available. Information on lifestyle factors (body mass index, smoking, physical activity, and diet quality) was obtained, and a healthy lifestyle score was created on the basis of healthy criteria met (0 point [least healthy] to 4 points [most healthy]). CHIP was derived on the basis of a prespecified list of leukemogenic driver mutations. The prevalence of CHIP was 8.6%. A higher healthy lifestyle score was not associated with CHIP (multivariable-adjusted odds ratio [OR] [95% CI], 0.99 [0.80-1.23] and 1.13 [0.93-1.37]) for the upper (3 or 4 points) and middle category (2 points), respectively, versus referent (0 or 1 point). Across score components, a normal and overweight body mass index compared with obese was significantly associated with a lower odds for CHIP (OR, 0.71 [95% CI, 0.57-0.88] and 0.83 [95% CI, 0.68-1.01], respectively; P -trend 0.0015). Having never smoked compared with being a current smoker tended to be associated with lower odds for CHIP. Conclusions A healthy lifestyle, based on a composite score, was not related to CHIP among postmenopausal women. However, across individual lifestyle factors, having a normal body mass index was strongly associated with a lower prevalence of CHIP. These findings support the idea that certain healthy lifestyle factors are associated with a lower frequency of CHIP.

Background: Obesity is a strong risk factor for endometrial cancer, but it is unclear whether metabolic syndrome (MetS) contributes to endometrial cancer risk over and above the contribution of obesity., Methods: We examined the association of MetS and its components with risk of endometrial cancer in a sub-cohort of 24,210 women enrolled in the Women's Health Initiative cohort study. Two variants of the National Cholesterol Education Program Adult Treatment Panel III definition of the MetS were used: one including and one excluding waist circumference (WC). Cox proportional hazards models were used to estimate the association of the study exposures with disease risk., Results: When WC was included in the definition, MetS showed an approximately two-fold increase in endometrial cancer risk (HR 2.20; 95% CI 1.61-3.02); however, when WC was excluded, MetS was no longer associated with risk. We also observed that women with hyperglycemia, dyslipidemia and hypertension, in combination, had almost a twofold increased risk of endometrial cancer, independent of WC (HR 1.94; 95% CI 1.09, 3.46). Glucose, and, in particular, WC and body mass index were also positively associated with risk., Conclusions: Our findings suggest that MetS may predict risk of endometrial cancer independent of obesity among women with the remaining four Mets components.

Importance: Obesity is associated with an increased risk of breast cancer, including the estrogen receptor (ER)-positive subtype in postmenopausal women. Whether excess adiposity is associated with increased risk in women with a normal body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) is unknown., Objective: To investigate the association between body fat and breast cancer risk in women with normal BMI., Design, Setting, and Participants: This ad hoc secondary analysis of the Women's Health Initiative (WHI) clinical trial and observational study cohorts was restricted to postmenopausal participants with a BMI ranging from 18.5 to 24.9. Women aged 50 to 79 years were enrolled from October 1, 1993, through December 31, 1998. Of these, 3460 participants underwent body fat measurement with dual-energy x-ray absorptiometry (DXA) at 3 US designated centers with follow-up. At a median follow-up of 16 years (range, 9-20 years), 182 incident breast cancers had been ascertained, and 146 were ER positive. Follow-up was complete on September 30, 2016, and data from October 1, 1993, through September 30, 2016, was analyzed August 2, 2017, through August 21, 2018., Main Outcomes and Measures: Body fat levels were measured at baseline and years 1, 3, 6, and 9 using DXA. Information on demographic data, medical history, and lifestyle factors was collected at baseline. Invasive breast cancers were confirmed via central review of medical records by physician adjudicators. Blood analyte levels were measured in subsets of participants., Results: Among the 3460 women included in the analysis (mean [SD] age, 63.6 [7.6] years), multivariable-adjusted hazard ratios for the risk of invasive breast cancer were 1.89 (95% CI, 1.21-2.95) for the highest quartile of whole-body fat and 1.88 (95% CI, 1.18-2.98) for the highest quartile of trunk fat mass. The corresponding adjusted hazard ratios for ER-positive breast cancer were 2.21 (95% CI, 1.23-3.67) and 1.98 (95% CI, 1.18-3.31), respectively. Similar positive associations were observed for serial DXA measurements in time-dependent covariate analyses. Circulating levels of insulin, C-reactive protein, interleukin 6, leptin, and triglycerides were higher, whereas levels of high-density lipoprotein cholesterol and sex hormone-binding globulin were lower in those in the uppermost vs lowest quartiles of trunk fat mass., Conclusions and Relevance: In postmenopausal women with normal BMI, relatively high body fat levels were associated with an elevated risk of invasive breast cancer and altered levels of circulating metabolic and inflammatory factors. Normal BMI categorization may be an inadequate proxy for the risk of breast cancer in postmenopausal women., Trial Registration: ClinicalTrials.gov identifier: NCT00000611.

Objective: The possibility that a subset of persons who are obese may be metabolically healthy-referred to as the 'metabolically healthy obese' (MHO) phenotype-has attracted attention recently. However, few studies have followed individuals with MHO or other obesity phenotypes over time to assess change in their metabolic profiles. The aim of the present study was to examine transitions over a 6-year period among different states defined simultaneously by body mass index (BMI) and the presence/absence of the metabolic syndrome (MetS)., Methods: We used repeated measurements available for a subcohort of participants enrolled in the Women's Health Initiative (N=3512) and followed for an average of 6 years to examine the frequency of different metabolic obesity phenotypes at baseline, the 6-year transition probabilities to other states and predictors of the risk of different transitions. Six phenotypes were defined by cross-tabulating BMI (18.5-<25.0, 25.0-<30.0, ⩾30.0 kg m -2 ) by MetS (yes, no). A continuous-time Markov model was used to estimate 6-year transition probabilities from one state to another., Results: Over the 6 years of follow-up, one-third of women with the healthy obese phenotype transitioned to the metabolically unhealthy obese (MUO) phenotype. Overall, there was a marked tendency toward increased metabolic deterioration with increasing BMI and toward metabolic improvement with lower BMI. Among MHO women, the 6-year probability of becoming MUO was 34%, whereas among unhealthy normal-weight women, the probability of 'regressing' to the metabolically healthy normal-weight phenotype was 52%., Conclusions: The present study demonstrated substantial change in metabolic obesity phenotypes over a 6-year period. There was a marked tendency toward metabolic deterioration with greater BMI and toward metabolic improvement with lower BMI.

Background: Known risk factors for intracerebral hemorrhage (ICH) include age, hypertension, smoking, alcohol intake, and anticoagulant use. Some previous reports have indicated that hemostatic factors measured many years before the onset of ICH might predict the later occurrence of ICH. The objective of this analysis was to test whether selected hemostatic factors measured years before the onset of ICH could identify patients at higher risk for future ICH., Methods: We performed a nested case-control study within the Women's Health Initiative (WHI) cohort. Postmenopausal women aged 50-79 years (mean 68) at baseline (1993-1998) were enrolled at 40 Clinical Centers in the United States and followed for adjudicated ICH for a mean of 11.4 years. ICH cases (N = 75) and controls (N = 75) were matched on age, ethnicity, blood pressure, anticoagulant use, and treated hypertension. Stored blood samples from the baseline WHI examination were tested for von Willebrand factor (vWF), a disintegrin-like and metalloprotease domain with thrombospondin type-1 motif, number 13 (ADAMTS13), tissue plasminogen activator (t-PA), and urokinase plasminogen activator (u-PA). Platelet count, white blood cell count, and hemoglobin concentration were also measured., Results: Mean baseline levels of vWF (1.03 and .95 U/mL), ADAMTS13 (1.0 and 1.1 µg/mL), vWF : ADAMTS13 ratio (.99 and .92), t-PA (14.75 and 14.80 IU/mL), and u-PA (.09 and .10 IU/mL) were not significantly different by case-control status. Significant differences were also not identified for platelet count, hemoglobin, white blood count, or reported alcohol use., Conclusion: None of the 4 baseline hemostatic factors nor the platelet count was predictive of future ICH risk in this long-term study of older postmenopausal women., (Copyright © 2016 National Stroke Association. All rights reserved.)

Anemia and low and high levels of hemoglobin have been associated with increased mortality and morbidity. However, most studies have measured hemoglobin at only 1 time point, and few studies have considered possible reverse causation. We used data from the Women's Health Initiative, in which baseline hemoglobin was measured in 160,081 postmenopausal women and year 3 hemoglobin was measured in 75,658 participants, to examine the associations of hemoglobin concentration with total mortality, coronary heart disease mortality, and cancer mortality. Women were enrolled from 1993 to 1998 and followed for a median of 16 years. Cox proportional hazards models were used to estimate the relative mortality hazards associated with deciles of baseline hemoglobin and the mean of baseline + year 3 hemoglobin. Both low and high deciles of baseline hemoglobin were positively associated with all 3 outcomes in the total cohort. In analyses restricted to women with 2 measurements, a low mean hemoglobin level was robustly and positively associated with all 3 outcomes, after exclusion of the early years of follow-up. High mean hemoglobin was also associated with increased risk of total mortality, whereas associations with heart disease mortality and cancer mortality were weaker and inconsistent. Our results provide evidence that low and high levels of hemoglobin are associated with increased risk of mortality in otherwise healthy women., (© The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: Considerable efforts have been undertaken to relate single nutrients to bone health. To this point, results are inconsistent. Suboptimal single nutrient intake does not occur in isolation but rather reflects a poor diet quality., Objective: To assess the association between adherence to a diet quality index constructed on the basis of dietary recommendations or existing healthy dietary patterns and fractures in postmenopausal women., Design, Setting, and Participants: Post hoc analysis was conducted of longitudinal data from 40 clinical centers throughout the United States included in the Women's Health Initiative (WHI) observational study. Participants in the prospective cohort included 93 676 women who were eligible for the WHI if they were aged 50 to 79 years. Recruitment was conducted from October 1, 1993, to December 31, 1998, with the study ending August 29, 2014. The WHI food frequency questionnaire was used to derive nutrient and food intake at baseline. Diet quality and adherence were assessed by scores on the alternate Mediterranean Diet (aMED), a 9-category measure of adherence to a Mediterranean dietary pattern; the Healthy Eating Index 2010 (HEI-2010), a 100-point measure of 12 food components; the 11-item Alternate Healthy Eating Index 2010 (AHEI-2010); or the 8-component Dietary Approaches to Stop Hypertension (DASH) diet score., Main Outcomes and Measures: Outcome measures included incident total and hip fractures. Hazard ratios (HRs) by quintiles of dietary index scores were estimated using Cox proportional hazards regression analyses., Results: Of the 93 676 participants, 90 014 were included in the analysis (mean [SD] age, 63.6 [7.4]) years. During a median follow-up time of 15.9 years, there were 2121 cases of hip fractures and 28 718 cases of total fractures. Women scoring in the highest quintile (Q5) of the aMED index had a lower risk for hip fractures (HR, 0.80; 95% CI, 0.66-0.97), with an absolute risk reduction of 0.29% and a number needed to treat of 342 (95% CI, 249-502). No association between the aMED score and total fractures was observed (Q5 HR, 1.01; 95% CI, 0.95-1.07). Higher HEI-2010 or DASH scores tended to be inversely related to hip fracture risk, but the results were nonsignificant (Q5 HR, 0.87; 95% CI, 0.75-1.02; and Q5 HR, 0.89; 95% CI, 0.75-1.06, respectively). The AHEI-2010 score was associated with neither hip nor total fractures., Conclusions and Relevance: Higher adherence to a Mediterranean diet is associated with a lower risk for hip fractures. These results support that a healthy dietary pattern may play a role in maintaining bone health in postmenopausal women.

Background: Depression and depressive symptoms are risk factors for hypertension (HTN) and cardiovascular disease (CVD). Hispanic women have higher rates of depressive symptoms compared to other racial/ethnic groups yet few studies have investigated its association with incident prehypertension and hypertension among postmenopausal Hispanic women. This study aims to assess if an association exists between baseline depression and incident hypertension at 3 years follow-up among postmenopausal Hispanic women., Methods: Prospective cohort study, Women's Health Initiative (WHI), included 4,680 Hispanic women who participated in the observational and clinical trial studies at baseline and at third-year follow-up. Baseline current depressive symptoms and past depression history were measured as well as important correlates of depression-social support, optimism, life events and caregiving. Multinomial logistic regression was used to estimate prevalent and incident prehypertension and hypertension in relation to depressive symptoms., Results: Prevalence of current baseline depression ranged from 26% to 28% by hypertension category and education moderated these rates. In age-adjusted models, women with depression were more likely to be hypertensive (OR = 1.25; 95% CI 1.04-1.51), although results were attenuated when adjusting for covariates. Depression at baseline in normotensive Hispanic women was associated with incident hypertension at year 3 follow-up (OR = 1.74; 95% CI 1.10-2.74) after adjustment for insurance and behavioral factors. However, further adjustment for clinical covariates attenuated the association. Analyses of psychosocial variables correlated with depression but did not alter findings. Low rates of antidepressant medication usage were also reported., Conclusions: In the largest longitudinal study to date of older Hispanic women which included physiologic, behavioral and psychosocial moderators of depression, there was no association between baseline depressive symptoms and prevalent nor incident pre-hypertension and hypertension. We found low rates of antidepressant medication usage among Hispanic women suggesting a possible point for clinical intervention., Trial Registration: Clinicaltrials.gov NCT00000611.

Background: Postmenopausal hormone therapy use has been associated with lower colorectal cancer risk in observational studies. However, the role of endogenous sex hormones in colorectal cancer development in postmenopausal women is uncertain., Methods: The relation of colorectal cancer risk with circulating levels of estradiol, estrone, free (bioactive) estradiol, progesterone and sex hormone-binding globulin (SHBG) was determined in a nested case-control study of 1203 postmenopausal women (401 case patients and 802 age and race/ethnicity-matched control patients) enrolled in the Women's Health Initiative Clinical Trial (WHI-CT) who were not assigned to the estrogen-alone or combined estrogen plus progestin intervention groups. We used multivariable-adjusted conditional logistic regression models that included established colorectal cancer risk factors. All statistical tests were two-sided., Results: Comparing extreme quartiles, estrone (odds ratio [OR]q4-q1 = 0.44, 95% confidence interval [CI] = 0.28 to 0.68, P trend = .001), free estradiol (ORq4-q1 = 0.43, 95% CI = 0.27 to 0.69, P trend ≤ .0001), and total estradiol (ORq4-q1 = 0.58, 95% CI = 0.38 to 0.90, P trend = .08) were inversely associated with colorectal cancer risk. SHBG levels were positively associated with colorectal cancer development (OR[q4-q1] = 2.30, 95% CI = 1.51 to 3.51, P trend ≤ .0001); this association strengthened after further adjustment for estradiol and estrone (ORq4-q1 = 2.50, 95% CI = 1.59 to 3.92, P trend < .0001). Progesterone was not associated with colorectal cancer risk., Conclusion: Endogenous estrogen levels were inversely, and SHBG levels positively, associated with colorectal cancer risk, even after control for several colorectal cancer risk factors. These results suggest that endogenous estrogens may confer protection against colorectal tumorigenesis among postmenopausal women., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Adiposity is an established risk factor for postmenopausal breast cancer. Recent data suggest that high insulin levels in overweight women may play a major role in this relationship, due to insulin's mitogenic/antiapoptotic activity. However, whether overweight women who are metabolically healthy (i.e., normal insulin sensitivity) have elevated risk of breast cancer is unknown. We investigated whether overweight women with normal insulin sensitivity [i.e., homeostasis model assessment of insulin resistance (HOMA-IR) index, or fasting insulin level, within the lowest quartile (q1)] have increased breast cancer risk. Subjects were incident breast cancer cases (N = 497) and a subcohort (N = 2,830) of Women's Health Initiative (WHI) participants with available fasting insulin and glucose levels. In multivariate Cox models, metabolically healthy overweight women, defined using HOMA-IR, were not at elevated risk of breast cancer compared with metabolically healthy normal weight women [HRHOMA-IR, 0.96; 95% confidence interval (CI), 0.64-1.42]. In contrast, the risk among women with high (q3-4) HOMA-IRs was elevated whether they were overweight (HRHOMA-IR, 1.76; 95% CI, 1.19-2.60) or normal weight (HRHOMA-IR, 1.80; 95% CI, 0.88-3.70). Similarly, using fasting insulin to define metabolic health, metabolically unhealthy women (insulin q3-4) were at higher risk of breast cancer regardless of whether they were normal weight (HRinsulin, 2.06; 95% CI, 1.01-4.22) or overweight (HRinsulin, 2.01; 95% CI, 1.35-2.99), whereas metabolically healthy overweight women did not have significantly increased risk of breast cancer (HRinsulin, 0.96; 95% CI, 0.64-1.42) relative to metabolically healthy normal weight women. Metabolic health (e.g., HOMA-IR or fasting insulin) may be more biologically relevant and more useful for breast cancer risk stratification than adiposity per se., (©2014 American Association for Cancer Research.)

Purpose: Some studies suggest that anthropometric measures of abdominal obesity may be superior to body mass index (BMI) for the prediction of cardiometabolic risk factors; however, most studies have been cross-sectional. Our aim was to prospectively examine the association of change in BMI, waist-to-hip ratio (WHR), waist circumference (WC), and waist circumference-to-height ratio (WCHtR) with change in markers of cardiometabolic risk in a population of postmenopausal women., Methods: We used a subsample of participants in the Women's Health Initiative aged 50 to 79 years at entry with available fasting blood samples and anthropometric measurements obtained at multiple time points over 12.8 years of follow-up (n = 2672). The blood samples were used to measure blood glucose, insulin, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), and triglycerides at baseline, and at years 1, 3, and 6. We conducted mixed-effects linear regression analyses to examine associations at baseline and longitudinal associations between change in anthropometric measures and change in cardiometabolic risk factors, adjusting for covariates., Results: In longitudinal analyses, change in BMI, WC, and WCHtR robustly predicted change in cardiometabolic risk, whereas change in WHR did not. The strongest associations were seen for change in triglycerides, glucose, and HDL-C (inverse association)., Conclusion: Increase in BMI, WC, and WCHtR strongly predicted increases in serum triglycerides and glucose, and reduced HDL-C. WC and WCHtR were superior to BMI in predicting serum glucose, HDL-C, and triglycerides. WCHtR was superior to WC only in predicting serum glucose. BMI, WC, and WCHtR were all superior to WHR.

Objectives: Mean and visit-to-visit variability (VVV) of blood pressure (BP) are associated with an increased cardiovascular disease risk. We examined the effect of hormone therapy on mean and VVV of BP in postmenopausal women from the Women's Health Initiative (WHI) randomized controlled trials., Methods: BP was measured at baseline and annually in the two WHI hormone therapy trials, in which 10 739 and 16 608 postmenopausal women were randomized to conjugated equine estrogens (CEEs, 0.625 mg/day) or placebo, and CEEs and medroxyprogesterone acetate (MPA, 2.5 mg/day) or placebo, respectively., Results: At the first annual visit (year 1), mean SBP was 1.04 mmHg [95% confidence interval (CI) 0.58, 1.50] and 1.35 mmHg (95% CI 0.99, 1.72) higher in the CEEs and CEEs and MPA arms, respectively, compared with the corresponding placebos. These effects remained stable after year 1. CEEs also increased the VVV of SBP (ratio of VVV in CEEs vs. placebo, 1.03; P < 0.001), whereas CEEs and MPA did not (ratio of VVV in CEEs and MPA vs. placebo, 1.01; P = 0.20). After accounting for study drug adherence, the effects of CEEs and CEEs and MPA on mean SBP increased at year 1, and the differences in the CEEs and CEEs and MPA arms vs. placebos also continued to increase after year 1. Further, both CEEs and CEEs and MPA significantly increased the VVV of SBP (ratio of VVV in CEEs vs. placebo, 1.04; P < 0.001; ratio of VVV in CEEs and MPA vs. placebo, 1.05; P < 0.001)., Conclusion: Among postmenopausal women, CEEs and CEEs and MPA at conventional doses increased mean and VVV of SBP.

Objective: Nearly, a third of obese individuals, termed metabolically benign obese, have a low burden of adiposity-related cardiometabolic abnormalities, whereas a substantial proportion of normal-weight individuals possess risk factors., Methods: In cross-sectional analyses of 699 normal weight and 1,294 overweight/obese postmenopausal women enrolled in a nested case-control stroke study ancillary to the Women's Health Initiative Observational Study, we compared levels of adiponectin, leptin, and resistin among metabolically benign normal weight, at-risk normal weight, metabolically benign obese, and at-risk obese women using components of the ATP III definition of the metabolic syndrome (metabolically benign: ≤1 of the four components; at-risk phenotype: ≥2 components or diabetes)., Results: Overall, 382/699 normal-weight women (54.6%) and 328/1,194 overweight/obese women (27.5%) were metabolically benign. Among normal-weight women, at-risk women had higher leptin and lower adiponectin levels compared to metabolically benign women; multivariate-adjusted odds ratios were significant for having leptin (OR: 2.51; 95% CI: 1.28-5.01) and resistin (1.46; 1.03-2.07) in the top tertile and adiponectin in the bottom tertile (2.64; 1.81-3.84). Compared to metabolically benign overweight/obese women, at-risk obese women had higher odds of having leptin in the top tertile (1.62; 1.24-2.12) and adiponectin in the bottom tertile (2.78; 2.04-3.77)., Conclusions: Overall, metabolically benign overweight/obese women had an intermediate adipokine profile (between at-risk obese and metabolically benign normal-weight women), whereas at-risk normal-weight women had a less favorable profile compared to metabolically benign normal-weight women. As adiponectin was the only adipokine independent of BMI, it may be most likely to have a role in the etiological pathway of these phenotypes., (Copyright © 2012 The Obesity Society.)

Background: There is a paucity of research on prehypertension and incident hypertension among postmenopausal Hispanic women. The overall objective is to determine the multiple risk factors associated with the prevalence of hypertension status at baseline and incident hypertension at year 3 in postmenopausal Hispanic women., Methods: For the analyses in this paper, we included a total of 4,680 Hispanic women who participated in the Women's Health Initiative (WHI), a randomized clinical trial and observational study, at baseline (1994-1998) and at third-year follow-up and for whom blood pressure was measured at year 3 (n = 3,848). Multivariable logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of hypertension status, defined as systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg, to assess the odds of incident hypertension at year 3 of follow-up in association with the factors included in the baseline models., Results: At year 3 of follow-up, 27.3% of Hispanic women who were normotensive at baseline had progressed to prehypertension, and 9.0% had become hypertensive. Among the prehypertensive participants at baseline, 30.4% had progressed to hypertension. Compared with normotensive Hispanic women, hypertensive participants had a higher number of cardiovascular risk factors: body mass index ≥30 kg/m(2) (OR = 3.76; 95% CI = 3.01-4.71), a family history of diabetes, stroke, and/or myocardial infarction (OR = 1.12; 95% CI 1.03-1.23), treated hypercholesterolemia (OR = 1.57; 95% CI = 1.23-1.99), treated diabetes (OR = 2.04; 95% CI = 1.40-2.97), and a history of cardiovascular disease (OR = 2.04; 95% CI = 1.58-2.64)., Conclusions: Hispanic women seem to experience an increased risk of incident hypertension in later adulthood. On a practical level, recommendations for preventive care and population-wide adoption of health behaviors, such as community-focused campaigns to engage in physical activity, may contribute to reductions in hypertension risk factors., Clinical Trials Registration: Trial Number NCT00000611.

Background: Data on cardiovascular diseases (CVD) and cognitive decline are conflicting. Our objective was to investigate if CVD is associated with an increased risk for cognitive decline and to examine whether hypertension, diabetes, or adiposity modify the effect of CVD on cognitive functioning., Methods and Results: Prospective follow-up of 6455 cognitively intact, postmenopausal women aged 65 to 79 years old enrolled in the Women's Health Initiative Memory Study (WHIMS). CVD was determined by self-report. For cognitive decline, we assessed the incidence of mild cognitive impairment (MCI) or probable dementia (PD) via modified mini-mental state examination (3 MS) score, neurocognitive, and neuropsychiatric examinations. The median follow-up was 8.4 years. Women with CVD tended to be at increased risk for cognitive decline compared with those free of CVD (hazard ratio [HR], 1.29; 95% CI: 1.00, 1.67). Women with myocardial infarction or other vascular disease were at highest risk (HR, 2.10; 95% CI: 1.40, 3.15 or HR, 1.97; 95% CI: 1.34, 2.87). Angina pectoris was moderately associated with cognitive decline (HR 1.45; 95% CI: 1.05, 2.01) whereas no significant relationships were found for atrial fibrillation or heart failure. Hypertension and diabetes increased the risk for cognitive decline in women without CVD. Diabetes tended to elevate the risk for MCI/PD in women with CVD. No significant trend was seen for adiposity., Conclusions: CVD is associated with cognitive decline in elderly postmenopausal women. Hypertension and diabetes, but not adiposity, are associated with a higher risk for cognitive decline. More research is warranted on the potential of CVD prevention for preserving cognitive functioning.

Objective: Atrial fibrillation (AF) is the most common arrhythmia in women. Large studies evaluating key AF risk factors in older women are lacking. We aimed to identify risk factors for AF in postmenopausal women and measure population burden of modifiable risk factors., Design: Prospective observational study., Setting: The Women's Health Initiative (WHI) Observational Study., Patients: 93 676 postmenopausal women were followed for an average of 9.8 years for cardiovascular outcomes. After exclusion of women with prevalent AF or incomplete data, 8252 of the remaining 81 892 women developed incident AF., Main Outcome Measures: Incident AF was identified by WHI-ascertained hospitalisation records and diagnosis codes from Medicare claims. Multivariate Cox hazard regression analysis identified independent risk factors for incident AF., Results: Age, hypertension, obesity, diabetes, myocardial infarction and heart failure were independently associated with incident AF. Hypertension and overweight status accounted for 28.3% and 12.1%, respectively, of the population attributable risk. Hispanic and African-American participants had lower rates of incident AF (HR 0.58, 95% CI 0.47 to 0.70 and HR 0.59, 95% CI 0.53 to 0.65, respectively) than Caucasians., Conclusions: Caucasian ethnicity, traditional cardiovascular risk factors and peripheral arterial disease were independently associated with higher rates of incident AF in postmenopausal women. Hypertension and overweight status accounted for a large proportion of population attributable risk. Measuring burden of modifiable AF risk factors in older women may help target interventions.

Objectives: The aim of this study was to estimate the annual incidence rate of sudden cardiac death (SCD) and to identify risk factors for SCD in post-menopausal women., Background: With the aging U.S. population, post-menopausal women now have the greatest population burden of cardiovascular disease including SCD., Methods: We examined 161,808 women who participated in the Women's Health Initiative clinical trials and observational study. The women were recruited at 40 clinical sites across the United States, enrolled between 1993 and 1998, and followed until August 2009. Our primary endpoint is incident SCD, defined as death occurring within 1 h of symptom onset or within 1 h after the participant was last seen without symptoms and death that occurred in the absence of a potentially lethal non-coronary disease process., Results: Four hundred eighteen women experienced adjudicated SCD. The incidence rate of SCD was 2.4/10,000 women/year (95% confidence interval: 2.2 to 2.7). We identified the following independent risk factors for SCD: older age, African-American race, tobacco use, higher pulse, higher waist-to-hip ratio, elevated white blood cell count, history of heart failure, diabetes, history of myocardial infarction, previous carotid artery disease, and hypertension. Population-attributable fractions were greatest for hypertension, waist-to-hip ratio, and myocardial infarction., Conclusions: Besides traditional risk factors for coronary heart disease, risk factors for sudden cardiac death in post-menopausal women include African-American race, higher pulse, higher waist-to-hip ratio, elevated white blood cell count, and heart failure. Nearly one-half of women who experienced sudden cardiac death had no previous diagnosis of coronary heart disease., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objective: To examine the associations between dietary fat intake and ischemic stroke among postmenopausal women., Methods: We conducted a prospective cohort study of 87,025 generally healthy postmenopausal women (age, 50-79 years) enrolled in the Women's Health Initiative Observational Study. Repeated and validated dietary assessments were done using a self-administered food frequency questionnaire. We used Cox proportional hazards models to estimate hazard ratios (HRs) of ischemic stroke based on quintiles of the cumulative average of fat intake., Results: We documented 1,049 incident cases of ischemic stroke over 663,041 person-years of follow-up. Women in the highest quintile of trans fat intake had a significantly higher incidence of ischemic stroke (HR, 1.39; 95% confidence interval [CI], 1.08-1.79; p-trend = 0.048) compared with women in the lowest quintile, while controlling for multiple covariates. The observed association was modified by aspirin use (p-interaction = 0.02). The HR was 1.66 (95% CI, 1.21-2.36; p-trend < 0.01) among baseline non-aspirin users (n = 67,288) and 0.95 (95% CI, 0.60-1.48; p-trend = 0.43) among aspirin users (n = 19,736). No significant associations were found between intakes of saturated, monounsaturated, or polyunsaturated fat and ischemic stroke or any ischemic stroke subtypes., Interpretation: In this large cohort of postmenopausal women, higher intake of trans fat was associated with incident ischemic stroke independent of major lifestyle/dietary factors. Aspirin use may attenuate the potential adverse effect of trans fat intake on ischemic stroke., (Copyright © 2012 American Neurological Association.)

Accumulating evidence suggests that increased visit-to-visit variability (VVV) of blood pressure is associated with stroke. No study has examined the association between VVV of blood pressure and stroke in postmenopausal women, and scarce data exist as to whether this relation is independent of the temporal trend of blood pressure. We examined the association of VVV of blood pressure with stroke in 58,228 postmenopausal women enrolled in the Women's Health Initiative. Duplicate blood pressure readings, which were averaged, were taken at baseline and at each annual visit. VVV was defined as the SD for the participant's mean systolic blood pressure (SBP) across visits (SD) and about the participant's regression line with SBP regressed across visits (SDreg). Over a median follow-up of 5.4 years, 997 strokes occurred. In an adjusted model including mean SBP over time, the hazard ratios (95% CI) of stroke for higher quartiles of SD of SBP compared with the lowest quartile (referent) were 1.39 (1.03-1.89) for quartile 2, 1.52 (1.13-2.03) for quartile 3, and 1.72 (1.28-2.32) for quartile 4 (P trend <0.001). The relation was similar for SDreg of SBP quartiles in a model that additionally adjusted for the temporal trend in SBP (P trend <0.001). The associations did not differ by stroke type (ischemic versus hemorrhagic). There was a significant interaction between mean SBP and SDreg on stroke with the strongest association seen below 120 mmHg. In postmenopausal women, greater VVV of SBP was associated with increased risk of stroke, particularly in the lowest range of mean SBP.

Background: Few studies simultaneously investigated lipids and lipoprotein biomarkers as predictors of ischemic stroke. The value of these biomarkers as independent predictors of ischemic stroke remains controversial., Methods: We conducted a prospective nested case-control study among postmenopausal women from the Women's Health Initiative Observational Study to assess the relationship between fasting lipids (total cholesterol, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], and triglycerides), lipoproteins (LDL, HDL, and very low-density lipoprotein [VLDL] particle number and size, intermediate-density lipoprotein [IDL] particle number, and lipoprotein (a)), and risk of ischemic stroke. Among women free of stroke at baseline, 774 ischemic stroke patients were matched according to age and race to control subjects, using a 1:1 ratio., Results: In bivariate analysis, baseline triglycerides (P<0.001), IDL particles (P<0.01), LDL particles (P<0.01), VLDL triglyceride (P<0.001), VLDL particles (P<0.01), VLDL size (P<0.001), LDL size (P=0.03), and total/HDL cholesterol ratio (P<0.01) were significantly higher among women with incident ischemic stroke, whereas levels of HDL-C (P<0.01) and HDL size (P<0.01) were lower. No significant baseline difference for total cholesterol (P=0.15), LDL-C (P=0.47), and lipoprotein (a) (P=0.11) was observed. In multivariable analysis, triglycerides (odds ratio for the highest versus lowest quartile, 1.56; 95% confidence interval, 1.13-2.17; P for trend=0.02), VLDL size (odds ratio, 1.59; 95% confidence interval, 1.10-2.28; P for trend=0.03), and IDL particle number (odds ratio, 1.46; 95% confidence interval, 1.04-2.04; P for trend=0.02) were significantly associated with ischemic stroke., Conclusions: Among a panel of lipid and lipoprotein biomarkers, baseline triglycerides, VLDL size, and IDL particle number were significantly associated with incident ischemic stroke in postmenopausal women.

In randomized trials, the effect of vitamin D supplementation on blood pressure has been equivocal, while most prospective cohort studies have shown that the risk of incident hypertension is lower in people with higher levels of 25-hydroxyvitamin D (25(OH)D). The authors examined the association between levels of 25(OH)D and changes in blood pressure and incident hypertension in 4,863 postmenopausal women recruited into the Women's Health Initiative between 1993 and 1998. Over 7 years, there were no significant differences in the adjusted mean change in systolic or diastolic blood pressure by quartile of 25(OH)D. The covariate-adjusted risk of incident hypertension was slightly lower in the upper 3 quartiles of 25(OH)D compared with the lowest quartile, but this was statistically significant only in the third quartile (hazard ratio = 0.67, 95% confidence interval: 0.46, 0.96). There was no significant linear or nonlinear trend in the risk of incident hypertension by untransformed or log-transformed continuous values of 25(OH)D. In postmenopausal women in this study, serum levels of 25(OH)D were not related to changes in blood pressure, and evidence for an association with lower risk of incident hypertension was weak.

Purpose: The contribution of menstrual and reproductive factors to risk of ductal carcinoma (DCIS) of the breast is poorly understood., Methods: The association between menstrual and reproductive factors and subsequent DCIS risk was examined in Women's Health Initiative (WHI) clinical trial participants, in which mammography was protocol mandated. The cohort consisted of 64,060 women, among whom 664 cases of DCIS were ascertained over a median follow-up of 12.0 years. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI)., Results: After adjustment for covariates, only older age at menopause (HR ≥ 55 vs. 45-54 : 1.39, 95% CI 1.08-1.79) was significantly associated with risk; however, greater parity (HR ≥ 5 live births vs. 0: 0.70, 95% CI 0.47-1.03), among parous women, and age at first live birth (HR ≥ 30 years relative to <20 years: 1.32, 95% CI 0.92-1.90) were of borderline significance. Age at menarche and months of breast-feeding were not associated with risk. Associations did not differ between high- and low-/moderate-grade DCIS, or by level of body mass index or family history of breast cancer; however, there was a suggestion that the associations of age at menopause, parity, and age at first live birth were limited to women who had ever used hormone therapy., Conclusions: Findings from this large cohort of postmenopausal women suggest that age at menopause, and possibly, age at first live birth, and parity are associated with risk of DCIS, whereas age at menarche and duration of breast-feeding are not.

Objective: The aim of this study was to examine the association between fracture and pelvic organ prolapse (POP) in postmenopausal women enrolled in the Women's Health Initiative Estrogen Plus Progestin trial., Methods: POP was assessed as cystocele, rectocele, or uterine prolapse and was graded as either "absent to mild" or "moderate to severe." Cox proportional hazard analyses (adjusting for age, body mass index, race, asthma, emphysema, thyroid disease, family history of fracture, regular menses, age at menopause, nulliparity, history of hormone therapy [HT], history of falls, socioeconomic status, calcium, and vitamin D supplementation and physical activity) explored the relationships between moderate to severe POP and incident bone fractures., Results: Moderate- to severe-grade POP was identified in almost 8% of women (n = 1,192). During a follow-up duration of 7.41 (2.18) years (mean [SD]), 2,156 incident fractures were observed; the most common fracture site was the lower arm (n = 615; 28.51%) followed by the hip (n = 205; 9.51%). Adjusted analyses confirmed moderate to severe POP (of any type) as an independent risk factor for incident hip fractures (hazard ratio [HR], 1.83; 95% CI, 1.16-2.89; P = 0.010). On analyses stratified by assigned treatment (HT vs placebo), moderate to severe rectocele emerged as an independent predictor of incident spine (HR, 2.61; 95% CI, 1.04-6.56; P = 0.042) and lower arm fractures (HR, 1.87; 95% CI, 1.06-3.29; P = 0.030) in the placebo group., Conclusions: We identify moderate to severe POP (any type) in postmenopausal women as a risk factor for hip fracture; moderate to severe rectocele holds an additional risk of spine and lower arm fractures in women not taking HT.

Objective: Late-life depressive symptoms (DS) increase the risk of incident mild cognitive impairment and probable dementia in the elderly. Our objectives were to examine the relationship between elevated DS and regional brain volumes including frontal lobe subregions, hippocampus and amygdala, and to determine whether elevated DS were associated with increased subclinical cerebrovascular disease in postmenopausal women., Methods: DS were assessed an average of 8years prior to structural brain MRI in 1372 women. The 8-item Burnam regression algorithm was used to define DS with a cut-point of 0.009. Adjusting for potential confounders, mean differences in total brain, frontal lobe subregions, hippocampus and amygdala volumes and total ischemic lesion volumes in the basal ganglia and the cerebral white and gray matter outside the basal ganglia were compared between women with and without DS., Results: Depressed women had lower baseline global cognition and were more likely to have prior hormone therapy history. After full adjustment, DS at baseline were associated with smaller superior and middle frontal gyral volumes. Hippocampal and amygdala volumes, and ischemic lesion volumes were similar in depressed and non-depressed women., Limitations: Depression was not assessed based on semi-structured interview, and MRI scans were obtained cross-sectionally rather than longitudinally. Longitudinal MRI assessments will be necessary to define the temporal relationships between DS and frontal lobe volumes., Conclusions: Elevated DS were associated with lower volumes in certain frontal lobe subregions but not in the medial temporal lobe structures. Our findings support the role of frontal lobe structures in late-life DS among women., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: It is hypothesized that inflammation may mediate the relationship between obesity and endometrial cancer risk. We examined the associations of three inflammation markers, C-reactive protein (CRP), interleukin (IL)-6 and tumor necrosis factor (TNF)-α, with risk of endometrial cancer., Methods: A case-cohort study was nested within the Women's Health Initiative, a cohort of postmenopausal women. Baseline plasma samples of 151 incident endometrial cancer cases and 301 subcohort subjects not using hormones were assayed., Results: CRP, but not IL-6 or TNF-α, was positively associated with endometrial cancer risk after adjusting for age and BMI [HR comparing extreme quartiles (HR q(4)-q(1)) = 2.29; 95% CI = 1.13-4.65; P(trend) = 0.012). After additional adjustment for estradiol and insulin, this association was attenuated (HRq(4)-q(1) = 1.70; 95% CI = 0.78-3.68; P(trend) = 0.127). Obesity (BMI ≥ 30 kg/m(2)) was associated with endometrial cancer risk in an age-adjusted model. The obesity effect was reduced by 48%, 67%, and 77% when either estradiol, CRP, or insulin, respectively, was included in the model, and it became null when all three factors were adjusted for simultaneously., Conclusions: The association between inflammation, as indicated by a relatively high level of CRP, and endometrial cancer risk may partially be explained by hyperinsulinemia and elevated estradiol. Nevertheless, all three factors contribute to and mediate the link between obesity and endometrial cancer in postmenopausal women not using hormones., Impact: The association between obesity and endometrial cancer risk in postmenopausal women may be attributed to inflammation, insulin resistance, and elevated estrogen., (©2011 AACR.)

Objective: To assess the association of recreational physical activity and anthropometric factors in relation to risk of ductal carcinoma in situ (DCIS) of the breast., Methods: The association was examined in a cohort of 58,055 postmenopausal women participating in the Women's Health Initiative (WHI) clinical trials, among whom 450 cases of DCIS were ascertained after a median follow-up of 8.0 years. Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI)., Results: After adjustment for covariates, the hazard ratio for DCIS among women with ≥ 20 metabolic equivalent task-hours per week (MET-h/week) of total recreational physical activity compared to women who did not engage in any recreational physical activity (0 MET-h/week) was 0.97 (95% CI 0.70-1.34). Neither body mass index nor waist circumference was associated with risk. In addition, physical activity and anthropometric factors were not associated with risk of either high-grade or low-/moderate-grade DCIS., Conclusions: Recreational physical activity and anthropometric factors showed no association with risk of DCIS in postmenopausal women in the WHI clinical trial.

In numerous studies, investigators have examined the association of active smoking with risk of invasive breast cancer, but to the authors' knowledge, no cohort study has assessed smoking in relation to the risk of in situ breast cancer, the postulated penultimate stage preceding invasive breast cancer. The authors examined the latter association using data collected at baseline from 63,393 women in the Women's Health Initiative Clinical Trial. A total of 486 cases of ductal carcinoma in situ (DCIS) of the breast were identified during 8 years of follow-up between 1993 and 2005. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals. For the primary analysis, invasive breast cancer was treated as a competing risk. After adjustment for covariates, associations with smoking status, smoking intensity, duration, pack-years, and age at quitting were all close to the null value and showed few meaningful trends. Sensitivity analyses performed to address different possibilities with respect to the natural history of breast cancer also did not provide consistent evidence of an association of smoking with DCIS. The results of this large cohort study provide little support for an association of cigarette smoking with risk of DCIS in postmenopausal women.

Background and Purpose: Although low levels of adiponectin are associated with coronary heart disease and cardiovascular disease risk factors, it is unclear whether adiponectin levels are related to the risk of developing ischemic stroke., Methods: We examined the relationship between baseline high-molecular-weight (HMW) adiponectin levels and incident ischemic stroke in postmenopausal women using data and specimens from the Hormones and Biomarkers Predicting Stroke Study, a case-control study nested within the Women's Health Initiative Observational Study. Included were 855 incident ischemic stroke cases and 855 control subjects matched for age, race-ethnicity, date of entry into the cohort, and follow-up time. ORs of incident ischemic stroke associated with baseline HMW adiponectin levels were calculated using conditional logistic regression modeling adjusting for body mass index, type 2 diabetes, hypertension, smoking, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, physical activity, C-reactive protein, and aspirin use., Results: Lower levels of HMW adiponectin were significantly associated with type 2 diabetes, hypertension, higher body mass index, waist circumference, glucose, and insulin levels and lower high-density lipoprotein cholesterol levels. The distribution of incident stroke cases by HMW adiponectin quartiles was 49.9%, 50.5%, 50.7%, and 48.9%, respectively (P=0.96). Multivariable-adjusted ORs of stroke associated with the top 3 quartiles of HMW adiponectin versus the first quartile were 0.99 (95% CI, 0.71 to 1.37), 1.37 (0.99 to 1.91), and 1.25 (0.88 to 1.79), respectively (P trend=0.14)., Conclusions: Despite moderate associations between HMW adiponectin and cardiovascular disease risk factors, we found no evidence of an association between HMW adiponectin levels and incident ischemic stroke in these postmenopausal women.

Background: Although several observational studies have consistently reported an inverse association between moderate alcohol consumption and risk of coronary heart disease (CHD), it is yet not well established if this association also exists among people with type 2 diabetes. The aim of this study is to evaluate the association between the frequency and quantity of alcohol intake and the risk of developing CHD among postmenopausal women with diabetes., Methods: We conducted a prospective cohort study, which included 3,198 women with self-reported diabetes and without any history of cardiovascular disease at baseline, in the Women's Health Initiative Observational Study. Alcohol intake was assessed by a semiquantitative food frequency questionnaire. The primary outcome of this study was CHD, which was validated by medical record review. Cox proportional hazards regression was used to estimate the hazard ratio (HR) for the association of alcohol intake and risk of incident CHD while adjusting for several potential confounders., Results: During the 22,546 person-years of follow-up, there were 336 incident cases of CHD. Both frequency and quantity of alcohol intake were inversely associated with the risk of developing CHD. Compared to nondrinkers, the multivariable HRs across categories of frequency of alcohol consumption (or=2 drinks/week) were 0.89 (95% confidence intervals [CI]: 0.63, 1.26), 0.84 (95% CI: 0.56, 1.25) and 0.65 (95% CI: 0.43, 0.99), respectively (p for trend: 0.04). This association did not appear to differ based on the type of the alcoholic beverage consumed., Conclusions: Moderate alcohol consumption of postmenopausal women with type 2 diabetes may have a benefit on CHD similar to that seen in postmenopausal nondiabetic women. The potential risks of alcohol on noncardiac outcomes may need consideration when recommending alcohol to women with diabetes.

Background and Purpose: Hepatocyte growth factor (HGF) is a potent angiogenic factor and may play a role in the development and progression of atherosclerotic lesions, the underlying mechanism of cardiovascular disease. However, there have been no prospective studies examining the relationship between HGF levels and risk of stroke., Methods: We conducted a nested case-control study (972 incident stroke cases and 1:1 age-matched and race-matched controls) to prospectively evaluate the association between plasma HGF and risk of ischemic stroke within the Women's Health Initiative Observational Study, a cohort of postmenopausal women aged 50 to 79 years., Results: Baseline HGF levels were correlated positively with body mass index, systolic blood pressure, low-density lipoprotein cholesterol, insulin resistance, and inflammatory markers, such as C-reactive protein, and inversely with high-density lipoprotein cholesterol (all P<0.05). Baseline HGF levels were higher among cases than controls (geometric means, 601.8 vs 523.2 pg/mL; P=0.003). Furthermore, the risk of incident ischemic stroke was significantly greater among women in the highest vs lowest quartile of plasma HGF levels (OR, 1.46; 95% CI, 1.12-1.91; P(trend)=0.003) in a conditional logistic regression model that adjusted for body mass index. These results were only slightly attenuated after further adjustment for additional stroke risk factors (OR, 1.39; 95% CI, 1.04-1.85; P(trend)=0.023)., Conclusions: Circulating levels of HGF are associated with an increased risk of incident ischemic stroke, independent of obesity and other risk factors for cardiovascular disease, among postmenopausal women aged 50 to 79 years.

Background: Despite compelling evidence that aspirin reduces fatal and nonfatal vascular events among the overall population in various settings, women have frequently been underrepresented and their data underreported. We sought to evaluate the relationship between aspirin use, dose (81 or 325 mg), and clinical outcomes among postmenopausal women with stable cardiovascular disease (CVD)., Methods and Results: Women with CVD (n=8928) enrolled in the Women's Health Initiative Observational Study were used for this analysis. The primary outcome was the incidence of all-cause mortality and cardiovascular events (myocardial infarction, stroke, and cardiovascular death). Among 8928 women with stable CVD, 4101 (46%) reported taking aspirin, of whom 30% were on 81 mg and 70% were on 325 mg. At 6.5 years of follow-up, no significant association was noted for aspirin use and all-cause mortality or cardiovascular events. However, after multivariate adjustment, aspirin use was associated with a significantly lower all-cause (adjusted hazard ratio, 0.86 [0.75 to 0.99]; P=0.04) and cardiovascular-related mortality (adjusted hazard ratio, 0.75 [0.60 to 0.95]; P=0.01) compared with no aspirin. Aspirin use was associated with a lower risk of cardiovascular events (adjusted hazard ratio, 0.90 [0.78 to 1.04]; P=0.14), which did not meet statistical significance. Compared with 325 mg, use of 81 mg was not significantly different for all-cause mortality, cardiovascular events, or any individual end point., Conclusions: After multivariate adjustment, aspirin use was associated with significantly lower risk of all-cause mortality, specifically, cardiovascular mortality, among postmenopausal women with stable CVD. No significant difference was noted between 81 mg and 325 mg of aspirin. Overall, aspirin use was low in this cohort of women with stable CVD.

Background: Millions of postmenopausal women use multivitamins, often believing that supplements prevent chronic diseases such as cancer and cardiovascular disease (CVD). Therefore, we decided to examine associations between multivitamin use and risk of cancer, CVD, and mortality in postmenopausal women., Methods: The study included 161 808 participants from the Women's Health Initiative clinical trials (N = 68 132 in 3 overlapping trials of hormone therapy, dietary modification, and calcium and vitamin D supplements) or an observational study (N = 93 676). Detailed data were collected on multivitamin use at baseline and follow-up time points. Study enrollment occurred between 1993 and 1998; the women were followed up for a median of 8.0 years in the clinical trials and 7.9 years in the observational study. Disease end points were collected through 2005. We documented cancers of the breast (invasive), colon/rectum, endometrium, kidney, bladder, stomach, ovary, and lung; CVD (myocardial infarction, stroke, and venous thromboembolism); and total mortality., Results: A total of 41.5% of the participants used multivitamins. After a median of 8.0 years of follow-up in the clinical trial cohort and 7.9 years in the observational study cohort, 9619 cases of breast, colorectal, endometrial, renal, bladder, stomach, lung, or ovarian cancer; 8751 CVD events; and 9865 deaths were reported. Multivariate-adjusted analyses revealed no association of multivitamin use with risk of cancer (hazard ratio [HR], 0.98, and 95% confidence interval [CI], 0.91-1.05 for breast cancer; HR, 0.99, and 95% CI, 0.88-1.11 for colorectal cancer; HR, 1.05, and 95% CI, 0.90-1.21 for endometrial cancer; HR, 1.0, and 95% CI, 0.88-1.13 for lung cancer; and HR, 1.07, and 95% CI, 0.88-1.29 for ovarian cancer); CVD (HR, 0.96, and 95% CI, 0.89-1.03 for myocardial infarction; HR, 0.99, and 95% CI, 0.91-1.07 for stroke; and HR, 1.05, and 95% CI, 0.85-1.29 for venous thromboembolism); or mortality (HR, 1.02, and 95% CI, 0.97-1.07)., Conclusion: After a median follow-up of 8.0 and 7.9 years in the clinical trial and observational study cohorts, respectively, the Women's Health Initiative study provided convincing evidence that multivitamin use has little or no influence on the risk of common cancers, CVD, or total mortality in postmenopausal women.

Background: The positive association between obesity and postmenopausal breast cancer has been attributed, in part, to the fact that estrogen, a risk factor for breast cancer, is synthesized in adipose tissue. Obesity is also associated with high levels of insulin, a known mitogen. However, no prospective studies have directly assessed associations between circulating levels of insulin and/or insulin-like growth factor (IGF)-I, a related hormone, and the risk of breast cancer independent of estrogen level., Methods: We conducted a case-cohort study of incident breast cancer among nondiabetic women who were enrolled in the Women's Health Initiative Observational Study (WHI-OS), a prospective cohort of 93,676 postmenopausal women. Fasting serum samples obtained at study entry from 835 incident breast cancer case subjects and from a subcohort of 816 randomly chosen WHI-OS subjects were tested for levels of insulin, glucose, total IGF-I, free IGF-I, insulin-like growth factor binding protein-3, and estradiol. Multivariable Cox proportional hazards models were used to estimate associations between levels of the serologic factors and baseline characteristics (including body mass index [BMI]) and the risk of breast cancer. All statistical tests were two-sided. Results Insulin levels were positively associated with the risk of breast cancer (hazard ratio [HR] for highest vs lowest quartile of insulin level = 1.46, 95% confidence interval [CI] = 1.00 to 2.13, P(trend) = .02); however, the association with insulin level varied by hormone therapy (HT) use (P(interaction) = .01). In a model that controlled for multiple breast cancer risk factors including estradiol, insulin level was associated with breast cancer only among nonusers of HT (HR for highest vs lowest quartile of insulin level = 2.40, 95% CI = 1.30 to 4.41, P(trend) < .001). Obesity (BMI >or=30 kg/m(2)) was also associated with the risk of breast cancer among nonusers of HT (HR for BMI >or=30 kg/m(2) vs 18.5 to <25 kg/m(2) = 2.12, 95% CI = 1.26 to 3.58, P(trend) = .003); however, this association was attenuated by adjustment for insulin (P(trend) = .40)., Conclusion: These data suggest that hyperinsulinemia is an independent risk factor for breast cancer and may have a substantial role in explaining the obesity-breast cancer relationship.

Background: Inflammatory and hemostasis-related biomarkers may identify women at risk of stroke., Methods: Hormones and Biomarkers Predicting Stroke is a study of ischemic stroke among postmenopausal women participating in the Women's Health Initiative observational study (n = 972 case-control pairs). A Biomarker Risk Score (BRS) was derived from levels of 7 inflammatory and hemostasis-related biomarkers that appeared individually to predict risk of ischemic stroke: C-reactive protein (CRP), interleukin-6, tissue plasminogen activator, D-dimer, white blood cell count, neopterin, and homocysteine. The c index was used to evaluate discrimination., Results: Of all the individual biomarkers examined, CRP emerged as the only independent single predictor of ischemic stroke (adjusted odds ratio comparing Quartile(4)v Quartile(1) = 1.64, 95% confidence interval: 1.15-2.32, P = .01) after adjustment for other biomarkers and standard stroke risk factors. The BRS identified a gradient of increasing stroke risk with a greater number of elevated inflammatory/hemostasis biomarkers, and improved the c index significantly compared with standard stroke risk factors (P = .02). Among the subset of individuals who met current criteria for high-risk levels of CRP (>3.0 mg/L), the BRS defined an approximately 2-fold gradient of risk. We found no evidence for a relationship between stroke and levels of E-selectin, fibrinogen, tumor necrosis factor-alpha, vascular cell adhesion molecule-1, prothrombin fragment 1+2, Factor VIIC, or plasminogen activator inhibitor-1 antigen (P > .15)., Discussion: The findings support the further exploration of multiple biomarker panels to develop approaches for stratifying an individual's risk of stroke.

Few studies have investigated the role of elevated lipoprotein-associated phospholipase A2 (Lp-PLA(2)) with stroke risk, and those that have are based on small numbers of strokes. No study has evaluated the effect of hormone therapy use on the association of Lp-PLA(2) and stroke. We assessed the relationship between Lp-PLA(2) and the risk of incident ischemic stroke in 929 stroke patients and 935 control subjects in the Hormones and Biomarkers Predicting Stroke Study, a nested case-control study from the Women's Health Initiative Observational Study. Mean (SD) levels of Lp-PLA(2) were significantly higher among case subjects (309.0 [97.1]) than control subjects (296.3 [87.3]; P<0.01). Odds ratio for ischemic stroke for the highest quartile of Lp-PLA(2), compared with lowest, controlling for multiple covariates, was 1.08 (95% CI: 0.75 to 1.55). However, among 1137 nonusers of hormone therapy at baseline, the corresponding odds ratio was 1.55 (95% CI: 1.05 to 2.28),whereas there was no significant association among 737 hormone users (odds ratio: 0.70; 95% CI: 0.42 to 1.17; P for interaction=0.055). Moreover, among nonhormone users, women with high C-reactive protein and high Lp-PLA2 had more than twice the risk of stroke (odds ratio: 2.26; 95% CI: 1.55 to 3.35) compared with women low levels in both biomarkers. Furthermore, different stroke cases were identified as high risk by Lp-PLA(2) rather than by C-reactive protein. Lp-PLA(2) was associated with incident ischemic stroke independently of C-reactive protein and traditional cardiovascular risk factors among nonusers of hormone therapy with highest risk in those who had both high C-reactive protein and high Lp-PLA(2).

Background and Purpose: Walking speed is a simple, reliable, and valid measure of functional status that has been shown to be strongly correlated with age-related outcomes and may be an indicator of subclinical cerebrovascular disease. However, few studies have investigated the association of walking speed with risk of incident ischemic stroke., Methods: The present analyses included 13,048 postmenopausal women (mean age 65 years) from the Women's Health Initiative free of stroke at baseline, 264 of whom had incident ischemic strokes on follow-up. Cox proportional hazards regression was used to obtain hazard ratios (HRs) and 95% confidence intervals (CIs) to assess the relationship between performance on a timed walk and risk of incident ischemic stroke. Multivariate adjustment included age, race/ethnicity, body mass index, waist-hip ratio, depression, arthritis, hypertension, smoking, systolic blood pressure, treated diabetes, hormone use, NSAID use, aspirin use, self-reported general health, and history of coronary heart disease., Results: Slower walking speed was a significant predictor of incident ischemic stroke. After multivariate adjustment, the hazard for incident ischemic stroke was increased for the slowest walking speed tertile compared to the fastest walking speed tertile (HR=1.69, 95% CI: 1.21, 2.36). Additional adjustment for other physical function variables (grip strength and chair stands) did not change the association significantly., Conclusions: Slow walking speed was found to be a strong predictor of increased risk of incident ischemic stroke among postmenopausal women independent of other established risk factors for stroke.

Objective: Testing a hypothesis that pelvic organ prolapse (POP) is a focal manifestation of disordered connective tissue, we evaluated whether there is an association between POP and history of fracture., Design: This was a case-control study. Baseline data were from postmenopausal women aged 60 years or older enrolled in the Women's Health Initiative Estrogen Plus Progestin trial. Distinct variants (cystocele, rectocele, and uterovaginal) and severity (mild, moderate, or severe) of POP were recognized. A history of "fracture after age 55" was considered as the event of interest., Results: Moderate to severe POP was identified in 9% of 11,096 participants aged 60 years or older. Women with moderate to severe rectocele were significantly more likely to report fracture (odds ratio: 1.37, 95% CI: 1.06-1.77, P = 0.02) compared with those with absent to mild prolapse. Of the subset of participants who underwent bone mineral density assessment, those with moderate to severe prolapse demonstrated significantly lower whole-body bone mineral density ([beta] = -0.03, SE 0.02); this difference was of borderline significance (P = 0.05) compared with that for participants with absent to mild POP. Multivariate logistic regression analysis confirmed an independent association between moderate to severe rectocele and fracture (odds ratio: 1.45, 95% CI: 1.08-1.95, P = 0.01)., Conclusions: We demonstrate a relationship between moderate to severe POP and low bone mineral density in postmenopausal women enrolled in the Women's Health Initiative Estrogen Plus Progestin trial. Our findings of an association between clinically significant (moderate to severe) POP, specifically rectocele, and a history of fracture suggest that suboptimal collagen status purported to associate with POP may also involve bone collagen and hence translate into skeletal compromise.

Obesity is a risk factor for colorectal cancer, and hyperinsulinemia, a common condition in obese patients, may underlie this relationship. Insulin, in addition to its metabolic effects, has promitotic and antiapoptotic activity that may be tumorigenic. Insulin-like growth factor (IGF)-I, a related hormone, shares sequence homology with insulin, and has even stronger mitogenic effects. However, few prospective colorectal cancer studies directly measured fasting insulin, and none evaluated free IGF-I, or endogenous estradiol, a potential cofactor in postmenopausal women. Therefore, we conducted a case-cohort investigation of colorectal cancer among nondiabetic subjects enrolled in the Women's Health Initiative Observational Study, a prospective cohort of 93,676 postmenopausal women. Fasting baseline serum specimens from all incident colorectal cancer cases (n = 438) and a random subcohort (n = 816) of Women's Health Initiative Observational Study subjects were tested for insulin, glucose, total IGF-I, free IGF-I, IGF binding protein-3, and estradiol. Comparing extreme quartiles, insulin [hazard ratio (HR)(q4-q1), 1.73; 95% confidence interval (CI), 1.16-2.57; P(trend) = 0.005], waist circumference (HR(q4-q1), 1.82; 95% CI, 1.22-2.70; P(trend) = 0.001), and free IGF-I (HR(q4-q1), 1.35; 95% CI, 0.92-1.98; P(trend) = 0.05) were each associated with colorectal cancer incidence in multivariate models. However, these associations each became nonsignificant when adjusted for one another. Endogenous estradiol levels, in contrast, were positively associated with risk of colorectal cancer (HR comparing high versus low levels, 1.53; 95% CI, 1.05-2.22), even after control for insulin, free IGF-I, and waist circumference. These data suggest the existence of at least two independent biological pathways that are related to colorectal cancer: one that involves endogenous estradiol, and a second pathway broadly associated with obesity, hyperinsulinemia, and free IGF-I.

Context: Previous studies have documented an association of depression and phobic anxiety with cardiovascular morbidity and mortality, but little is known about the cardiovascular sequelae of panic anxiety., Objective: To determine whether panic attacks are associated with risk of cardiovascular morbidity and mortality in postmenopausal women., Design: Prospective cohort survey., Setting: Ten clinical centers of the 40-center Women's Health Initiative., Participants: A total of 3369 community-dwelling, generally healthy postmenopausal women (aged 51-83 years) enrolled between 1997 and 2000 in the Myocardial Ischemia and Migraine Study who completed a questionnaire about occurrence of panic attacks in the previous 6 months., Main Outcome Measures: Cardiovascular/cerebrovascular outcomes (fatal and nonfatal myocardial infarction and stroke) and all-cause mortality were ascertained after a mean of 5.3 years of follow-up., Results: A 6-month history of full-blown panic attacks, endorsed by 10% of postmenopausal women in this cohort, was associated with both coronary heart disease (hazard ratio, 4.20; 95% confidence interval, 1.76-9.99) and the combined end point of coronary heart disease or stroke (hazard ratio, 3.08; 95% confidence interval, 1.60-5.94) after controlling for multiple potential confounders. The hazard ratio for all-cause mortality, excluding those with a history of cardiovascular/cerebrovascular events, was 1.75 (95% confidence interval, 1.04-2.94)., Conclusion: Panic attacks are relatively common among postmenopausal women and appear to be an independent risk factor for cardiovascular morbidity and mortality in older women.

Background: Subclinical depression, often clinically unrecognized, may pose increased risk of cardiovascular disease. Few studies have prospectively investigated cardiovascular events related to depression in older women. We describe prevalence, cardiovascular correlates, and relationship to subsequent cardiovascular events of depressive symptoms among generally healthy postmenopausal women., Methods: The Women's Health Initiative Observational Study followed up 93 676 women for an average of 4.1 years. Depression was measured at baseline with a short form of the Center for Epidemiological Studies Depression Scale. Risks of cardiovascular disease (CVD) events were estimated from Cox proportional hazards models adjusting for multiple demographic, clinical, and risk factor covariates., Results: Current depressive symptoms above the screening cutoff point were reported by 15.8% of women. Depression was significantly related to CVD risk and comorbidity (odds ratios ranging from 1.12 for hypertension to 1.60 for history of stroke or angina). Among women with no history of CVD, depression was an independent predictor of CVD death (relative risk, 1.50) and all-cause mortality (relative risk, 1.32) after adjustment for age, race, education, income, diabetes, hypertension, smoking, high cholesterol level requiring medication, body mass index, and physical activity. Taking antidepressant medications did not alter the depression-associated risks associated., Conclusions: A large proportion of older women report levels of depressive symptoms that are significantly related to increased risk of CVD death and all-cause mortality, even after controlling for established CVD risk factors. Whether early recognition and treatment of subclinical depression will lower CVD risk remains to be determined in clinical trials.

Background: Panic attacks are known to be more common in women than in men, but the prevalence and correlates of panic in the postmenopausal period have not been well defined., Methods: Cross-sectional survey of 3369 community-dwelling postmenopausal women enrolled between December 1, 1997, and November 30, 2000, in the Myocardial Ischemia and Migraine Study, a 10-center ancillary study of the 40-center Women's Health Initiative. Participants, aged 50 to 79 years and predominantly white (73%), completed questionnaires about the occurrence of panic attacks in the previous 6 months and about migraine headaches and underwent 24-hour ambulatory electrocardiographic monitoring. The 6-month prevalences of full-blown and limited-symptom panic attacks were calculated, and their associations with other sociodemographic and clinical variables were examined in multivariate analyses., Results: One of the panic attack types was reported by 17.9% (95% confidence interval, 16.6%-19.2%) of women (full-blown attacks, 9.8%; limited-symptom attacks, 8.1%). Adjusting for age and race or ethnicity, full-blown panic attacks were more common in women with a history of migraine, emphysema, cardiovascular disease, chest pain during ambulatory electrocardiography, and symptoms of depression. Full-blown panic attacks were associated in a dose-response manner with negative life events during the past year. Panic attacks were associated with functional impairment even after adjusting for comorbid medical conditions and depression. There was no significant association with self-reported use of hormone replacement therapy., Conclusions: Panic attacks may be relatively common among postmenopausal women and seem to be associated with stressful life events, medical comorbidity, and functional impairment.

Little is known about the patterns of treatment and adequacy of blood pressure control in older women. The Women's Health Initiative, a 40-center national study of risk factors and prevention of heart disease, breast and colorectal cancer, and osteoporosis in postmenopausal women, provides a unique opportunity to examine these issues in the largest, multiethnic, best-characterized such cohort. Baseline data from the initial 98 705 women, aged 50 to 79 years, enrolled were analyzed to relate prevalence, treatment, and control of hypertension to demographic, clinical, and risk-factor covariates, and logistic regression analyses were performed to estimate odds ratios after adjusting for multiple potential confounders. Overall, 37.8% of the women had hypertension, which is defined as systolic blood pressure >/=140 mm Hg and/or diastolic blood pressure >/=90 mm Hg or being on medication for high blood pressure; 64.3% were treated with drugs, and blood pressure was controlled in only 36.1% of the hypertensive women, with lower rates of control in the oldest group. After adjustment for multiple covariates, current hormone users had higher prevalence than did nonusers (odds ratio 1.25). Hypertensive women had more comorbid conditions than did nonhypertensive women, and women with comorbidities were more likely to be treated pharmacologically. Diuretics were used by 44.3% of hypertensives either as monotherapy or in combination with other drug classes. As monotherapy, calcium channel blockers were used in 16%, angiotensin-converting enzyme inhibitors in 14%, beta-blockers in 9%, and diuretics in 14% of the hypertensive women. Diuretics as monotherapy were associated with better blood pressure control than any of the other drug classes as monotherapy. In conclusion, hypertension in older women is not being treated aggressively enough because a large proportion, especially those most at risk for stroke and heart disease by virtue of age, does not have sufficient blood pressure control.

The article focuses on a study concerning estrogen plus progestin which increased the risk of stroke and probable dementia in postmenopausal women in postmenopausal women. Respondents are 50 to 79 years old that underwent hormone replacement therapy (HRT). It mentions the Women's Health Initiative (WHI) hormone therapy study of estrogen plus progestin. Moreover, it notes the placebo controlled trial with a specific mean follow up period.