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.

Objective

To examine the association between fracture and pelvic organ prolapse (POP) in postmenopausal women enrolled in the Women’s Health Initiative Estrogen plus Progestin (WHI-EP) trial.

Methods

POP was assessed as cystocele, rectocele or uterine prolapse, and was graded as “absent-to- mild” or “moderate-to-severe”. Cox proportional hazard analyses (adjusting for age, BMI, race, asthma, emphysema, thyroid disease, family history of fracture, regular menses, age at menopause, nulliparity, history of hormone therapy [HT], history of falls, SES, calcium and vitamin D supplementation and physical activity) explored 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). Over a follow up duration of 7.41 ± 2.18 years (mean ± SD), 2,156 incident fractures were observed; the most common fracture site was lower arm (n=615, 28.51%) followed by hip (n=205, 9.51%). Adjusted analyses confirmed moderate-to-severe POP (of any type) as an independent risk factor for incident hip fractures (HR 1.83, 95% CI 1.16–2.89, p=0.010). On analyses stratified by assigned treatment (HT versus 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.

Conclusion

We identify moderate-to-severe POP (any type) in postmenopausal women as a risk factor for hip fracture; moderate-to-severe rectocele holds additional risk for spine and lower arm fractures in women not on HT.

Although studies exploring relationships between obesity and cognitive impairment in the elderly are conflicting, literature suggests that overweight and obesity may be protective against cognitive impairment and dementia in older women. We examine the associations between changes in weight and waist circumference with global and domain-specific cognitive function in a large, well-defined cohort of 2283 older, post-menopausal women (age 65-79) prospectively followed through the Women's Health Initiative (WHI) Study of Cognitive Aging (WHISCA). We assessed the associations between changes in weight and waist circumference collected up to 5 years prior to WHISCA enrollment and mean levels of global and domain-specific cognitive performance across an average of 5.4 years of subsequent follow-up. There was a lack of associations between weight and cognition in women who remained stable or gained weight. The only significant relationships observed were in association with weight loss (p≤0.05), most likely signaling incipient disease. Moreover, cognition was not related to changes in waist circumference. Relationships were largely independent of initial BMI, self-reported caloric intake or dieting. The lack of associations between weight gain and cognition in women is consistent with the existent literature.

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 8 years 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 we were unable to determine the temporal relationships between DS and frontal lobe volume differences due to the availability of only one MRI scan.

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.

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 [hazard ratio comparing extreme quartiles (HRq4-q1) = 2.29; 95% confidence interval (CI) = 1.13–4.65; ptrend = 0.012). After additional adjustment for estradiol and insulin, this association was attenuated (HRq4-q1 = 1.70;95% CI= 0.78–3.68; ptrend = 0.127). Obesity (BMI ≥ 30 kg/m2) 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.

Purpose

Little is known about risk factors for triple negative breast cancer (TNBC), which has a worse prognosis compared to hormone receptor-positive breast cancer. We examined the association of smoking and alcohol intake with TNBC and estrogen receptor-positive (ER+) breast cancer.

Methods

Among 146,985 women enrolled in the Women’s Health Initiative, 300 TNBC cases and 2,479 ER+ cases were identified over a median of 8.0 years of follow-up. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI).

Results

Cigarette smoking was not associated with TNBC, whereas drinkers had reduced risk compared to never drinkers. In contrast, both exposures showed slight positive associations with ER+ breast cancer: for women with ≥40 pack-years of smoking, the HR was 1.24, 95% CI 1.06–1.44; for women consuming ≥7 servings of alcohol per week the HR was 1.26, 95% CI 1.06–1.50. Intakes of wine and hard liquor were also significantly positively associated with ER+ breast cancer.

Conclusions

These findings from a large cohort of postmenopausal women suggest that smoking and alcohol consumption are not associated with increased risk of TNBC, but may be modestly associated with increased risk of ER+ breast cancer.

OBJECTIVE

To investigate the association between circulating levels of hepatocyte growth factor (HGF), a mesenchymal-derived pleiotrophic factor that is elevated in obesity, and the prevalence of type 2 diabetes.

RESEARCH DESIGN AND METHODS

A cross-sectional analysis among 892 postmenopausal women within the Women's Health Initiative Observational Study (WHI-OS).

RESULTS

HGF levels positively correlated with BMI and homeostasis model assessment for insulin resistance. In the multivariable analysis comparing the highest tertile with the lowest tertile of HGF, the odds ratio for prevalent diabetes was 2.47 (95% CI [1.12–5.47], P for trend = 0.014) after accounting for age, race, BMI, and other risk factors for diabetes.

CONCLUSIONS

HGF levels are associated with the presence of type 2 diabetes in postmenopausal women. Future studies should consider the prospective evaluation of the association of HGF with the development of type 2 diabetes.

PURPOSE

The Hispanic Community Health Study (HCHS)/Study of Latinos (SOL) is a comprehensive multi-center community based cohort study of Hispanics/Latinos in the United States. Its rationale, objectives, design and implementation are described in this paper.

METHODS

The HCHS/SOL will recruit 16,000 men and women who self-identify as Hispanic or Latino, age 18-74 years, from a random sample of households in defined communities in the Bronx, Chicago, Miami and San Diego. The sites were selected so that the overall sample would consist of at least 2000 persons in each of the following origin designations: Mexican, Puerto Rican and Dominican, Cuban, and Central and South American. The study includes research in the prevalence of and risk factors for heart, lung, blood and sleep disorders, kidney and liver function, diabetes, cognitive function, dental conditions, and hearing disorders.

CONCLUSIONS

The HCHS/SOL will 1) characterize the health status and disease burden in the largest minority population in the U.S; 2) describe the positive and negative consequences of immigration and acculturation of Hispanics/Latinos to the mainstream U.S. life-styles, environment and health care opportunities; and 3) identify likely causal factors of many diseases in a population with diverse environmental exposures, genetic backgrounds and early life experiences.

Background and Purpose

While low levels of adiponectin are associated with coronary heart disease and cardiovascular disease (CVD) 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 controls, matched for age, race-ethnicity, date of entry into the cohort, and follow-up time. Odds ratios of incident ischemic stroke associated with baseline HMW adiponectin levels were calculated using conditional logistic regression modeling, adjusting for body mass index (BMI), type 2 diabetes, hypertension, smoking, LDL-C, HDL-C, physical activity, C-reactive protein, and aspirin use.

Results

Lower levels of HMW adiponectin were significantly associated with type 2 diabetes, hypertension, higher BMI, waist, glucose, and insulin levels, and lower HDL-C 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 odds ratios of stroke associated with the top three 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).

Conclusion

Despite moderate associations between HMW adiponectin and CVD risk factors, we found no evidence of an association between HMW adiponectin levels and incident ischemic stroke in these postmenopausal women.

Obesity is a major risk factor for endometrial cancer, a relationship thought to be largely explained by the prevalence of high estrogen levels in obese women. Obesity is also associated with high levels of insulin, a known mitogen. However, no prospective studies have directly assessed whether insulin and/or insulin-like growth factor-I (IGF-I), a related hormone, are associated with endometrial cancer while accounting for estrogen levels. We therefore conducted a case-cohort study of incident endometrial cancer in the Women’s Health Initiative Observational Study, a prospective cohort of 93,676 postmenopausal women. The study involved all 250 incident cases and a random subcohort of 465 subjects for comparison. Insulin, total IGF-I, free IGF-I, IGF-binding protein-3, glucose, and estradiol levels were measured in fasting baseline serum specimens. Cox models were used to estimate associations with endometrial cancer, particularly endometrioid adenocarcinomas, the main histologic type (n = 205). Our data showed that insulin levels were positively associated with endometrioid adenocarcinoma [hazard ratio contrasting highest versus lowest quartile (HRq4-q1), 2.33; 95% confidence interval (95% CI), 1.13–4.82] among women not using hormone therapy after adjustment for age and estradiol. Free IGF-I was inversely associated with endometrioid adenocarcinoma (HRq4-q1, 0.53; 95% CI, 0.31–0.90) after adjustment for age, hormone therapy use, and estradiol. Both of these associations were stronger among overweight/obese women, especially the association between insulin and endometrioid adenocarcinoma (HRq4-q1, 4.30; 95% CI, 1.62–11.43). These data indicate that hyperinsulinemia may represent a risk factor for endometrioid adenocarcinoma that is independent of estradiol. Free IGF-I levels were inversely associated with endometrioid adenocarcinoma, consistent with prior cross-sectional data.

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 was derived from levels of seven inflammatory and hemostasis-related biomarkers that appeared individually to predict risk of ischemic stroke: C-reactive protein, 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, C-reactive protein emerged as the only independent single predictor of ischemic stroke (adjusted odds ratio comparing Q4 versus Q1 = 1.64, 95% confidence interval: 1.15–2.32, p = 0.01) after adjustment for other biomarkers and standard stroke risk factors. The Biomarker Risk Score 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 = 0.02). Among the subset of individuals who met current criteria for “high risk” levels of C-reactive protein (> 3.0 mg/L), the Biomarker Risk Score defined an approximately two-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 >0.15).

Discussion

The findings support the further exploration of multiple-biomarker panels to develop approaches for stratifying an individual’s risk of stroke.

This paper evaluates the relationship of blood pressure (BP) levels at Women’s Health Initiative (WHI) baseline, treatment of hypertension, and white matter abnormalities among women in conjugated equine estrogen (CEE) and medroxyprogesterone acetate and CEE-alone arms. The WHI Memory Study—Magnetic Resonance Imaging (WHIMS-MRI) trial scanned 1424 participants. BP levels at baseline were significantly positively related to abnormal white matter lesion (WML) volumes. Participants treated for hypertension but who had BP ≥140/90 mm Hg had the greatest amount of WML volumes. Women with untreated BP ≥140/90 mm Hg had intermediate WML volumes. Abnormal WML volumes were related to hypertension in most areas of the brain and were greater in the frontal lobe than in the occipital, parietal, or temporal lobes. Level of BP at baseline was strongly related to amount of WML volumes. The results of the study reinforce the relationship of hypertension and BP control and white matter abnormalities in the brain. The evidence to date supports tight control of BP levels, especially beginning at younger and middle age as a possible and perhaps only way to prevent dementia.

Background

Despite compelling evidence that aspirin reduces fatal and non-fatal 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 325mg) and clinical outcomes among postmenopausal women with stable cardiovascular disease.

Methods

Women with cardiovascular disease (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).

Results

Among 8928 women with stable cardiovascular disease, 4101 (46%) reported taking aspirin, of whom 30% were on 81 and 70% were on 325mg. 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 HR 0.86, [0.75-0.99], P=0.04) and cardiovascular related mortality (adjusted HR 0.75, [0.60-0.95], P=0.01) compared with no aspirin. Aspirin use was associated with a lower risk of cardiovascular events (adjusted HR 0.90, [0.78-1.04], P=0.14) which did not meet statistical significance. Compared with 325mg, use of 81mg was not significantly different for all-cause mortality, cardiovascular events or any individual endpoint.

Conclusions

After multivariate adjustment, aspirin use was associated with significantly lower risk of all-cause mortality, specifically cardiovascular mortality, among postmenopausal women with stable cardiovascular disease. No significant difference was noted between 81 and 325mg of aspirin. Overall, aspirin use was low in this cohort of women with stable cardiovascular disease.

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, Ptrend = .02); however, the association with insulin level varied by hormone therapy (HT) use (Pinteraction = .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, Ptrend < .001). Obesity (BMI ≥30 kg/m2) was also associated with the risk of breast cancer among nonusers of HT (HR for BMI ≥30 kg/m2 vs 18.5 to <25 kg/m2 = 2.12, 95% CI = 1.26 to 3.58, Ptrend = .003); however, this association was attenuated by adjustment for insulin (Ptrend = .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.

Experimental and epidemiologic studies suggest that calcium and vitamin D supplements may lower blood pressure. We examined the effect of calcium plus vitamin D supplementation on blood pressure and the incidence of hypertension in post-menopausal women. The Women's Health Initiative calcium/vitamin D trial randomly assigned 36,282 post-menopausal women to receive 1000 mg of elemental calcium plus 400 IU of vitamin D3 daily, or placebo, in a double-blind fashion. Change in blood pressure and the incidence of hypertension were ascertained. Over a median follow-up time of 7 years, there was no significant difference in the mean change over time in systolic blood pressure (0.22 mm Hg, 95% CI −0.05 – 0.49 mm Hg) and diastolic blood pressure (0.11 mm Hg, 95% CI −0.04 – 0.27 mm Hg) between the active and placebo treatment groups. This null result was robust in analyses accounting for non-adherence to study pills and in baseline subgroups of interest, including Blacks, women with hypertension or high levels of blood pressure, with low intakes of calcium and vitamin D, or low serum levels of vitamin D. In 17,122 non-hypertensive participants at baseline, the hazard ratio for incident hypertension associated with calcium/vitamin D treatment was 1.01 (95% CI 0.96 – 1.06.) In postmenopausal women, calcium plus vitamin D3 supplementation did not reduce either blood pressure or the risk of developing hypertension over seven years of follow-up.

Women with benign proliferative breast disease are at increased risk of subsequent breast cancer. Estrogens and progesterone exert proliferative effects on mammary epithelium and combined hormone replacement therapy has been associated with increased breast cancer risk. We tested the effect of conjugated equine estrogen plus progestin on risk of benign proliferative breast disease in the Women's Health Initiative (WHI) randomized controlled trial. In the WHI trial of estrogen plus progestin, 16608 postmenopausal women were randomly assigned either to 0.625 mg/d of conjugated equine estrogen plus 2.5 mg/d of medroxyprogesterone acetate or to placebo. Baseline and annual breast exams and mammograms were required. The trial was terminated early (average follow-up, 5.5 years). We identified women who had had a biopsy for benign breast disease and subjected histologic sections from the biopsies to standardized review. Overall, 178 incident cases of benign proliferative breast disease were ascertained in the estrogen plus progestin group and 99 in the placebo group. Use of estrogen plus progestin was associated with a 74% increase in risk of benign proliferative breast disease (hazard ratio 1.74, 95% CI 1.35-2.25). For benign proliferative breast disease without atypia the hazard ratio was 2.00 (95% CI 1.50-2.66), while for atypical hyperplasia it was 0.76 (95% CI 0.38-1.52). Risk varied little by levels of baseline characteristics. The results of this study suggest that use of estrogen plus progestin may increase the risk of benign proliferative breast disease.

Objective

The Women's Health Initiative randomized hormone trials unexpectedly demonstrated an increase in early coronary events. In an effort to explain this finding, we examined lipoprotein particle concentrations and their interactions with hormone therapy in a case–control substudy.

Methods and Results

We randomized 16 608 postmenopausal women with intact uterus to conjugated estrogens 0.625 mg with medroxyprogesterone acetate 2.5 mg daily or to placebo, and 10 739 women with prior hysterectomy to conjugated estrogens 0.625 mg daily or placebo, and measured lipoprotein subclasses by nuclear magnetic resonance spectroscopy at baseline and year 1 in 354 women with early coronary events and matched controls. Postmenopausal hormone therapy raised high-density lipoprotein cholesterol and particle concentration and reduced low-density lipoprotein cholesterol (LDL-C; all P<0.001 versus placebo). In contrast, neither unopposed estrogen nor estrogen with progestin lowered low-density lipoprotein particle concentration (LDL-P).

Conclusions

Postmenopausal hormone therapy–induced reductions in LDL-C were not paralleled by favorable effects on LDL-P. This finding may account for the absence of coronary protection conferred by estrogen in the randomized hormone trials.

Background

Many studies have shown a U-shape association between sleep duration and mortality, but epidemiological evidence linking cardiovascular diseases (CVD) with habitual sleep patterns is limited and mixed.

Methods

We conducted a prospective study on 93175 older women (aged 50–79 years) in the Women’s Health Initiative Observational Study cohort to examine the risk of ischemic stroke in relation to self-reported sleep duration. Cox models were used to investigate the putative associations, adjusting for multiple sociodemographic and lifestyle factors, depression, snoring, sleepiness symptoms, and other CVD-related clinical characteristics.

Results

At baseline, 8.3% of subjects had their reported sleep duration ≤5h/night and 4.6% with long sleep (≥9h/night). After an average of 7.5 years of follow-up, 1166 cases of ischemic stroke had occurred. Multivariable-adjusted relative risks (RR; 95% confidence intervals) for ischemic stroke (using a sleep time of 7h/night as the reference) were 1.14 (0.97, 1.33), 1.24 (1.04, 1.47) and 1.70 (1.32, 2.21) for women reporting 6 or less, 8, and 9 or more hours of sleep. A modestly stronger association with sleep duration ≤ 6h/night (RR=1.22; 1.03, 1.44) was noted among women without prevalent CVD at baseline. Our analyses also reveal that the adverse effect of long sleep is likely independent of the increased risk for ischemic stroke associated with frequent snoring and sleepiness (RR=1.31; 1.00, 1.72).

Conclusions

Habitual sleep patterns are important neurobehavioral determinants of risk for ischemic stroke in postmenopausal women. The underlying neurobiology and mechanistic mediators for the putative adverse effect of long sleep (≥9h/night) need further elucidation.