Folic acid, vitamin B6, and vitamin B12 act in concert in the one-carbon metabolism and may protect against colorectal neoplasia. We examined the effect of combined B-vitamin treatment on the occurrence of colorectal adenoma.
The Women’s Antioxidant and Folic Acid Cardiovascular Study was a randomized, double-blind, placebo-controlled trial of 5442 female health professionals at high risk for cardiovascular disease from April 1998 through July 2005. Participants were randomly assigned to receive a combination pill of folic acid (2.5mg), vitamin B6 (50mg), and vitamin B12 (1mg) or placebo. This study included 1470 participants who were followed up for as long as 9.2 years and underwent an endoscopy at any point during follow-up. We estimated relative risks using a generalized linear model with a natural logarithm link function and Poisson distributed errors. All statistical tests were two-sided.
The risk of colorectal adenoma was similar among participants receiving treatment (24.3%, 180 of 741 participants) vs placebo (24.0%, 175 of 729 participants) (multivariable adjusted relative risk = 1.00, 95% confidence interval = 0.83 to 1.20). Treatment was not associated with the risk of adenoma when data were analyzed by subsite, size, stage, and the number of adenomas. There was no statistically significant effect modification by alcohol intake, history of cancer or adenoma, or baseline plasma levels or intakes of folate, vitamin B6, or vitamin B12.
Our results indicate no statistically significant effect of combined folic acid, vitamin B6, and vitamin B12 treatment on colorectal adenoma among women at high risk for cardiovascular disease.
To report long-term health outcomes and mortality after oophorectomy or ovarian conservation.
We conducted a prospective, observational study of 29,380 women participants of the Nurses’ Health Study who had a hysterectomy for benign disease; 16,345 (55.6%) had hysterectomy with bilateral oophorectomy and 13,035 (44.4%) had hysterectomy with ovarian conservation. We evaluated incident events or death due to coronary heart disease (CHD), stroke, breast cancer, ovarian cancer, lung cancer, colorectal cancer, total cancers, hip fracture, pulmonary embolus, and death from all causes.
Over 24 years of follow-up, for women with hysterectomy and bilateral oophorectomy, compared with ovarian conservation, the multivariable hazard ratios (HR) were 1.12 (95% CI 1.03, 1.21) for total mortality, 1.17 (95% CI 1.02, 1.35) for fatal plus nonfatal CHD, and 1.14 (95% CI 0.98, 1.33) for stroke. Although the risks of breast (HR 0.75 95% CI 0.68, 0.84), ovarian (HR 0.04 95% CI 0.01, 0.09, NNT = 220), and total cancers (HR 0.92 95% CI 0.86, 0.98) decreased after oophorectomy, lung cancer incidence (HR =1.26, 95% CI 1.02, 1.56, NNH = 190) and total cancer mortality (HR=1.17, 95% CI 1.04, 1.32) increased. For never-users of estrogen therapy, bilateral oophorectomy before age 50 was associated with an increased risk of all-cause mortality, CHD, and stroke. With an approximate 35-year life span following surgery, one additional death would be expected for every 9 oophorectomies performed.
Compared with ovarian conservation, bilateral oophorectomy at the time of hysterectomy for benign disease is associated with a decreased risk of breast and ovarian cancer, but an increased risk of all-cause mortality, fatal and non-fatal coronary heart disease, and lung cancer. In no analysis or age-group was oophorectomy associated with increased survival.
To examine placental growth factor’s (PlGF) predictive value in relation to coronary heart disease (CHD) risk in healthy women.
Methods and results
Among 32,826 women from the Nurses’ Health Study who provided blood samples at baseline, 453 CHD events were documented during 14 years of follow-up. Controls were matched to cases (2:1) for age, smoking, fasting status, and date of blood sampling. PlGF was inversely correlated with HDL-cholesterol (HDL-C), and positively correlated with several coronary risk factors. In multivariate models, women in the highest versus lowest quintile of PlGF had a greater risk of CHD (RR:1.58;95%CI:1.03-2.41). Additional adjustment for many coronary risk factors did not substantively alter this relationship, but HDL-C attenuated the association (RR:1.25;95%CI:0.81-1.94). In exploratory time to event analysis, higher PlGF levels, measured > 10 years prior to CHD event, but not < 10 years pre-clinical event, were associated with increased risk of CHD, even after adjustment for co-morbid conditions and HDL-C levels (RR:2.79;95%CI:1.19-6.56).
Elevated prediagnostic PlGF levels were modestly associated with subsequent risk of CHD events and results were attenuated after controlling for HDL-C. PlGF may be most strongly associated with long term prediction of CHD, consistent with a potential role in early plaque formation and growth.
PlGF; CHD; women
Adiponectin may have a protective role in the development of obesity-related metabolic and vascular disorders including hypertension. We conducted a prospective, nested case-control study to investigate the relationship between baseline plasma adiponectin, measures of adiposity, and subsequent risk of hypertension.
We selected 400 White and 400 Black postmenopausal women, aged <70 years, who have developed incident hypertension during 5.9-year follow-up and an equal number of age and race matched controls in the Women's Health Initiative Observational Study. We measured plasma concentrations of total adiponectin in their baseline bloods.
In crude matched models, plasma adiponectin was inversely associated with risk of hypertension among both White and Black women. The association appeared to be non-linear in White women but dose-related in Black women. Adjustment for lifestyle factors, measures of obesity, and obesity-related clinical factors attenuated these associations. The multivariable relative risks (95% confidence interval) of hypertension across increasing quartiles of plasma adiponectin were 1.00, 0.98 (0.66-1.46), 0.63 (0.41-0.97), and 0.92 (0.60-1.42) in White women (p, trend: 0.38) and 1.00, 0.96 (0.64-1.46), 0.83 (0.53-1.29), and 0.58 (0.36-0.94) in Black women (p, trend: 0.02). Further adjustment for inflammatory markers and endothelial markers eliminated the association in White, but not Black, women.
In this prospective, nested case-control study, we found an inverse association between plasma adiponectin and risk of hypertension in White and Black postmenopausal women. The reduced risk of hypertension was limited to intermediate levels of adiponectin in White women while was graded across quartiles of adiponectin in Black women.
adiponectin; hypertension; epidemiology; prospective study; postmenopausal women
Menopausal hormone therapy (MHT) increases risk of coronary heart disease (CHD) in older women with elevated low-density lipoprotein (LDLC) levels. The endogenous estrogen receptor antagonist 27-hydroxycholesterol (27OHC) is correlated with LDLC levels and may block beneficial effects of estrogen on the cardiovascular system.
Methods and Results
We conducted a nested case-control study in the Women’s Health Initiative trials of 350 CHD cases and 813 matched controls to explore potential mediation by 27OHC of the dependence of the CHD risk elevation with MHT on LDLC. Baseline levels of 27OHC were not associated with CHD risk when LDLC was included in the multivariable models. The odds ratio for CHD associated with increased LDLC was 1.15 (95% confidence interval 1.08, 1.23) and was unchanged at 1.14 (1.07, 1.22) when 27OHC was added to the model. Baseline 27OHC did not interact with MHT on CHD risk (p = 0.81). In contrast, LDLC levels modified the effect of MHT on CHD risk (p for interaction = 0.02), and adding 27OHC did not affect this result. Using log scales the MHT effect on CHD increased linearly with increasing level of baseline LDLC, with a transition from no risk to increased risk at approximately 3.36 mmol/L (130 mg/dl).
27OHC does not independently increase risk of CHD, does not modify the increased risk of CHD due to MHT, and does not mediate the interaction of LDLC with MHT. Measuring blood lipids may aid in counseling individual women about initiating MHT and cardiovascular risk mitigation.
acute coronary syndrome; atherosclerosis; estrogen; low-density lipoprotein (LDL)-cholesterol; pathophysiology
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 exists 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 standard deviation about 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 to 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 vs. 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.
hypertension; blood pressure; stroke; postmenopause; women
Epidemiologic data regarding the association between ABO blood groups and risk of coronary heart disease (CHD) have been inconsistent. We sought to investigate the associations between ABO blood group and CHD risk in prospective cohort studies.
Methods and Results
Two large, prospective cohort studies (the Nurses’ Health Study [NHS] including 62,073 women and the Health Professionals Follow-up Study [HPFS] including 27, 428 men) were conducted with more than 20 years of follow-up (26 years in NHS and 24 years in HPFS). A meta-analysis was performed to summarize the associations from the present study and previous studies. In NHS, during 1,567,144 person-years of follow-up, 2,055 participants developed CHD; in HPFS, 2,015 participants developed CHD during 517,312 person-years of follow-up. ABO blood group was significantly associated with the risk of developing CHD in both women and men (log-rank test; P = 0.0048 and 0.0002 respectively). In the combined analysis adjusted for cardiovascular risk factors, compared with participants with blood group O, those with blood groups A, B or AB, were more likely to develop CHD (adjusted hazard ratios [95% CI] for incident CHD were 1.06 [ 0.99-1.15], 1.15 [ 1.04-1.26], and 1.23 [1.11-1.36]; respectively). Overall, 6.27% of the CHD cases were attributable to inheriting a non-O blood group. Meta-analysis indicated that non-O blood group had higher risk of CHD (RR= 1.11; 95% CI, 1.05 – 1.18; P = 0.001) compared with O blood group.
These data suggest that ABO blood group is significantly associated with CHD risk. Compared with other blood groups, those with the blood type O have moderately lower risk of developing CHD.
ABO; coronary heart disease; cohort study; meta-analysis
Findings regarding the association of lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and mass with incident cardiovascular disease (CVD) have been inconsistent, and their role in risk prediction is uncertain.
A case-cohort sample from the Women’s Health Initiative Observational Study (WHI-OS) comprised 1,821 CVD cases and a subcohort of 1,992. Cox regression models with inverse sampling weights assessed the association of Lp-PLA2 mass and activity with CVD (myocardial infarction [MI], stroke, and CVD mortality).
Subcohort means were 184.3 mmol/min/mL for Lp-PLA2 activity and 499.2 ng/mL for Lp-PLA2 mass, with 99% having mass above 200 ng/mL, the clinically recommended cut-point. Both activity and mass were positively associated with incident CVD in age- and race/ethnicity-adjusted analyses. Following adjustment by CVD risk factors, the association with activity became null (hazard ratio [HR] = 1.02 for top vs. bottom quartile, 95% confidence interval [CI] = 0.79-1.33, p-trend=0.65), but the association with mass remained (HR = 1.84, 95% CI = 1.45-2.34, p-trend <0.0001). In contrast to blood pressure, HDL, and hsCRP, reclassification statistics for Lp-PLA2 mass did not suggest improvement for overall CVD after full adjustment.
In the WHI-OS Lp-PLA2 mass, but not activity, was independently associated with CVD. However, model fit did not significantly improve with Lp-PLA2, and assay calibration remains a clinical concern.
Magnesium plays an essential role in the synthesis and metabolism of vitamin D and magnesium supplementation substantially reversed the resistance to vitamin D treatment in patients with magnesium-dependent vitamin-D-resistant rickets. We hypothesized that dietary magnesium alone, particularly its interaction with vitamin D intake, contributes to serum 25-hydroxyvitamin D (25(OH)D) levels, and the associations between serum 25(OH)D and risk of mortality may be modified by magnesium intake level.
We tested these novel hypotheses utilizing data from the National Health and Nutrition Examination Survey (NHANES) 2001 to 2006, a population-based cross-sectional study, and the NHANES III cohort, a population-based cohort study. Serum 25(OH)D was used to define vitamin D status. Mortality outcomes in the NHANES III cohort were determined by using probabilistic linkage with the National Death Index (NDI).
High intake of total, dietary or supplemental magnesium was independently associated with significantly reduced risks of vitamin D deficiency and insufficiency respectively. Intake of magnesium significantly interacted with intake of vitamin D in relation to risk of both vitamin D deficiency and insufficiency. Additionally, the inverse association between total magnesium intake and vitamin D insufficiency primarily appeared among populations at high risk of vitamin D insufficiency. Furthermore, the associations of serum 25(OH)D with mortality, particularly due to cardiovascular disease (CVD) and colorectal cancer, were modified by magnesium intake, and the inverse associations were primarily present among those with magnesium intake above the median.
Our preliminary findings indicate it is possible that magnesium intake alone or its interaction with vitamin D intake may contribute to vitamin D status. The associations between serum 25(OH)D and risk of mortality may be modified by the intake level of magnesium. Future studies, including cohort studies and clinical trials, are necessary to confirm the findings.
Magnesium intake; Serum 25-hydroxyvitamin D levels; Vitamin D insufficiency; Vitamin D deficiency; Parathyroid hormone; Mortality; Colorectal cancer; Cardiovascular diseases
To test whether supplementation with alternate-day vitamin E or daily vitamin C affects the incidence of the diagnosis of age-related macular degeneration (AMD) in a large-scale randomized trial of male physicians.
Randomized, double-masked, placebo-controlled trial.
We included 14 236 apparently healthy United States male physicians aged ≥50 years who did not report a diagnosis of AMD at baseline.
Participants were randomly assigned to receive 400 international units (IU) of vitamin E or placebo on alternate days, and 500 mg of vitamin C or placebo daily. Participants reported new diagnoses of AMD on annual questionnaires and medical record data were collected to confirm the reports.
Main Outcome Measures
Incident diagnosis of AMD responsible for a reduction in best-corrected visual acuity to ≤20/30.
After 8 years of treatment and follow-up, a total of 193 incident cases of visually significant AMD were documented. There were 96 cases in the vitamin E group and 97 in the placebo group (hazard ratio [HR], 1.03; 95% confidence interval [CI], 0.78–1.37). For vitamin C, there were 97 cases in the active group and 96 in the placebo group (HR, 0.99; 95% CI, 0.75–1.31).
In a large-scale, randomized trial of United States male physicians, alternate-day use of 400 IU of vitamin E and/or daily use of 500 mg of vitamin C for 8 years had no appreciable beneficial or harmful effect on risk of incident diagnosis of AMD.
The Women’s Health Initiative randomized trial found greater coronary heart disease (CHD) risk in women assigned to estrogen/progestin therapy than in those assigned to placebo. Observational studies had previously suggested reduced CHD risk in hormone users.
Using data from the observational Nurses’ Health Study, we emulated the design and intention-to-treat (ITT) analysis of the randomized trial. The observational study was conceptualized as a sequence of “trials” in which eligible women were classified as initiators or noninitiators of estrogen/progestin therapy.
The ITT hazard ratios (95% confidence intervals) of CHD for initiators versus noninitiators were 1.42 (0.92 – 2.20) for the first 2 years, and 0.96 (0.78 – 1.18) for the entire follow-up. The ITT hazard ratios were 0.84 (0.61 – 1.14) in women within 10 years of menopause, and 1.12 (0.84 – 1.48) in the others (P value for interaction = 0.08). These ITT estimates are similar to those from the Women’s Health Initiative. Because the ITT approach causes severe treatment misclassification, we also estimated adherence-adjusted effects by inverse probability weighting. The hazard ratios were 1.61 (0.97 – 2.66) for the first 2 years, and 0.98 (0.66 – 1.49) for the entire follow-up. The hazard ratios were 0.54 (0.19 – 1.51) in women within 10 years after menopause, and 1.20 (0.78 – 1.84) in others (P value for interaction = 0.01). Finally, we also present comparisons between these estimates and previously reported NHS estimates.
Our findings suggest that the discrepancies between the Women’s Health Initiative and Nurses’ Health Study ITT estimates could be largely explained by differences in the distribution of time since menopause and length of follow-up.
While global measures of cardiovascular (CV) risk are used to guide prevention and treatment decisions, these estimates fail to account for the considerable interindividual variability in pre-clinical risk status. This study investigated heterogeneity in CV risk factor profiles and its association with demographic, genetic, and cognitive variables.
A latent profile analysis was applied to data from 727 recently postmenopausal women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS). Women were cognitively healthy, within three years of their last menstrual period, and free of current or past CV disease. Education level, apolipoprotein E ε4 allele (APOE4), ethnicity, and age were modeled as predictors of latent class membership. The association between class membership, characterizing CV risk profiles, and performance on five cognitive factors was examined. A supervised random forest algorithm with a 10-fold cross-validation estimator was used to test accuracy of CV risk classification.
The best-fitting model generated two distinct phenotypic classes of CV risk 62% of women were “low-risk” and 38% “high-risk”. Women classified as low-risk outperformed high-risk women on language and mental flexibility tasks (p = 0.008) and a global measure of cognition (p = 0.029). Women with a college degree or above were more likely to be in the low-risk class (OR = 1.595, p = 0.044). Older age and a Hispanic ethnicity increased the probability of being at high-risk (OR = 1.140, p = 0.002; OR = 2.622, p = 0.012; respectively). The prevalence rate of APOE-ε4 was higher in the high-risk class compared with rates in the low-risk class.
Among recently menopausal women, significant heterogeneity in CV risk is associated with education level, age, ethnicity, and genetic indicators. The model-based latent classes were also associated with cognitive function. These differences may point to phenotypes for CV disease risk. Evaluating the evolution of phenotypes could in turn clarify preclinical disease, and screening and preventive strategies.
Red meat consumption has been associated with an increased risk of chronic diseases. However, its relationship with mortality remains uncertain.
We prospectively followed 37698 men from the Health Professionals Follow-up Study (1986-2008) and 83644 women from the Nurses' Health Study (1980-2008), who were free of cardiovascular disease (CVD) and cancer at baseline. Diet was assessed by validated food-frequency questionnaires and updated every four years.
We documented 23926 deaths (including 5910 CVD and 9464 cancer deaths) during 2.96 million person-years of follow-up. After multivariate adjustment for major lifestyle and dietary risk factors, the pooled hazard ratio (HR) and 95% confidence interval of total mortality was 1.13 (1.07-1.20) for 1-serving per day increase of unprocessed red meat, 1.20 (1.15-1.24) for processed red meat. The corresponding HRs were 1.18 (1.13-1.23) and 1.21 (1.13-1.31) for CVD mortality, 1.10 (1.06-1.14) and 1.16 (1.09-1.23) for cancer mortality. We estimated that substitutions of 1-serving per day of other foods (including fish, poultry, nuts, legumes, low-fat dairy, and whole grains) for 1-serving per day of red meat were associated with a 7%-19% lower mortality risk. We also estimated that 9.3% of deaths in men and 7.6% in women in our cohorts could be prevented at the end of follow-up if all individuals consumed <0.5 serving/d (≈42 g/d) of red meat.
Red meat consumption is associated with an increased risk of total, CVD and cancer mortality. Substitution of other healthy protein sources for red meat is associated with a lower mortality risk.
Genome-wide association studies of obesity measures have identified associations with single nucleotide polymorphisms (SNPs). However, no large-scale evaluation of gene-environment interactions has been performed. We conducted a search of gene-environment (G×E) interactions in post-menopausal African-American and Hispanic women from the Women’s Health Initiative SNP Health Association Resource GWAS study. Single SNP linear regression on body mass index (BMI) and waist-to-hip circumference ratio (WHR) adjusted for multidimensional-scaling-derived axes of ancestry and age was run in race-stratified data with 871,512 SNPs available from African-Americans (N=8,203) and 786,776 SNPs from Hispanics (N=3,484). Tests of G×E interaction at all SNPs for recreational physical activity (met-hrs/wk), dietary energy intake (kcal/day), alcohol intake (categorical), cigarette smoking years, and cigarette smoking (ever vs. never) were run in African-Americans and Hispanics adjusted for ancestry and age at interview, followed by meta-analysis of G×E interaction terms. The strongest evidence for concordant G×E interactions in African-Americans and Hispanics was for smoking and marker rs10133840 (Q statistic P=0.70, beta=−0.01, P=3.81×10−7) with BMI as the outcome. The strongest evidence for G×E interaction within a cohort was in African-Americans with WHR as outcome for dietary energy intake and rs9557704 (SNP×kcal =−0.04, P=2.17×10−7). No results exceeded the Bonferroni–corrected statistical significance threshold.
BMI; WHR; genetic epidemiology; disparity; obesity; GWAS
Compelling biological pathways suggest that selenium (Se) may lower onset of type 2 diabetes mellitus (T2DM), but very few studies have evaluated this relationship, with mixed results. We examined the association between toenail Se and incidence of T2DM.
RESEARCH DESIGN AND METHODS
We performed prospective analyses in two separate U.S. cohorts, including 3,630 women and 3,535 men, who were free of prevalent T2DM and heart disease at baseline in 1982–1983 and 1986–1987, respectively. Toenail Se concentration was quantified using neutron activation analysis, and diabetes cases were identified by biennial questionnaires and confirmed by a detailed supplementary questionnaire. Hazard ratios of incident T2DM according to Se levels were calculated using Cox proportional hazards.
During 142,550 person-years of follow-up through 2008, 780 cases of incident T2DM occurred. After multivariable adjustment, the risk of T2DM was lower across increasing quintiles of Se, with pooled relative risks across the two cohorts of 1.0 (reference), 0.91 (95% CI 0.73–1.14), 0.78 (0.62–0.99), 0.72 (0.57–0.91), and 0.76 (0.60–0.97), respectively (P for trend = 0.01). Results were similar excluding the few individuals (4%) who used Se supplements. In semiparametric analyses, the inverse relationship between Se levels and T2DM risk appeared to be linear.
At dietary levels of intake, individuals with higher toenail Se levels are at lower risk for T2DM. Further research is required to determine whether varying results in this study versus prior trials relate to differences in dose, source, statistical power, residual confounding factors, or underlying population risk.
While observational studies have suggested that vitamin D deficiency increases risk of depression, few clinical trials have tested whether vitamin D supplementation affects the occurrence of depression symptoms. The authors evaluated the impact of daily supplementation with 400 IU of vitamin D3 combined with 1,000 mg of elemental calcium on measures of depression in a randomized, double-blinded US trial comprising 36,282 postmenopausal women. The Burnam scale and current use of antidepressant medication were used to assess depressive symptoms at randomization (1995–2000). Two years later, women again reported on their antidepressant use, and 2,263 completed a second Burnam scale. After 2 years, women randomized to receive vitamin D and calcium had an odds ratio for experiencing depressive symptoms (Burnam score ≥0.06) of 1.16 (95% confidence interval: 0.86, 1.56) compared with women in the placebo group. Supplementation was not associated with antidepressant use (odds ratio = 1.01, 95% confidence interval: 0.92, 1.12) or continuous depressive symptom score. Results stratified by baseline vitamin D and calcium intake, solar irradiance, and other factors were similar. The findings do not support a relation between supplementation with 400 IU/day of vitamin D3 along with calcium and depression in older women. Additional trials testing higher doses of vitamin D are needed to determine whether this nutrient may help prevent or treat depression.
antidepressive agents; calcium; clinical trial; depression; dietary supplements; postmenopause; vitamin D; women
To relate dietary fat types to cognitive change in healthy community-based elders.
Among 6,183 older participants in the Women’s Health Study, we related intake of major fatty acids (FAs) (saturated [SFA], mono-unsaturated [MUFA], total poly-unsaturated [PUFA], trans-unsaturated) to late-life cognitive trajectory. Serial cognitive testing, conducted over 4 years, began 5 years post-dietary assessment. Primary outcomes were global cognition (averaging tests of general cognition, verbal memory and semantic fluency) and verbal memory (averaging tests of recall). We used analyses of response profiles and logistic regression to estimate multivariable-adjusted differences in cognitive trajectory and risk of worst cognitive change (worst 10%) by fat intake.
Higher SFA intake was associated with worse global cognitive (p-linear-trend=0.008) and verbal memory (p-linear-trend=0.01) trajectories. There was a higher risk of worst cognitive change, comparing highest vs. lowest SFA quintiles: the multivariable-adjusted odds ratio (OR) (95% confidence interval, CI) was 1.64 (1.04,2.58) for global cognition and 1.65 (1.04,2.61) for verbal memory. By contrast, higher MUFA intake was related to better global cognitive (p-linear-trend<0.001) and verbal memory (p-linear-trend=0.009) trajectories, and lower OR (95% CI) of worst cognitive change in global cognition (0.52 [0.31,0.88]) and verbal memory (0.56 [0.34,0.94]). Total fat, PUFA, and trans fat intakes were not associated with cognitive trajectory.
Higher SFA intake was associated with worse global cognitive and verbal memory trajectories, while higher MUFA intake was related to better trajectories. Thus, different consumption levels of the major specific fat types, rather than total fat intake itself, appeared to influence cognitive aging.
The associations between breast tenderness during use of conjugated equine estrogen (CEE) therapy with or without medroxyprogesterone (MPA) therapy and subsequent breast cancer risk are unknown.
We analyzed data from the Women’s Health Initiative Estrogen plus Progestin (N = 16,608, 5.6 years intervention) and Estrogen-Alone (N = 10,739, 6.8 years intervention) clinical trials until trial close-out (Spring 2005). At baseline and annually, participants underwent mammography and clinical breast exam. Self-reported breast tenderness was assessed at baseline and 12 months. Invasive breast cancer was confirmed by medical record review.
The risk of new-onset breast tenderness after 12 months was significantly higher among women assigned to active therapy than placebo (CEE alone vs. placebo risk ratio [RR] 2.15, 95% confidence interval [CI] 1.97–2.35; CEE + MPA vs. placebo RR 3.07, 95% CI 2.85–3.30). CEE + MPA doubled the risk of invasive breast cancer among women with baseline breast tenderness (hazard ratio [HR] 2.16, 95% CI 1.29–3.74), but had a smaller effect among women without baseline breast tenderness (HR 1.17; 95%CI 0.97–1.41). New-onset breast tenderness was associated with a higher risk of breast cancer among women assigned to CEE + MPA (HR 1.33, 95% CI 1.02–1.72, P=0.03), but not among women assigned to CEE alone (HR 0.98, 95% CI 0.62–1.53).
New-onset breast tenderness during use of CEE + MPA was associated with increased subsequent breast cancer risk. The association of CEE + MPA therapy with increased breast cancer risk was especially pronounced among women with baseline breast tenderness.
breast tenderness; breast cancer; menopausal hormone therapy; conjugated equine estrogens; medroxyprogesterone acetate
We examined the association between new-onset breast tenderness and change in mammographic density after initiation of conjugated equine estrogens (CEE).
We analyzed baseline, year 1, and year 2 data from 695 participants of the Women's Health Initiative Estrogen + Progestin (daily CEE 0.625 mg + medroxyprogesterone acetate 2.5 mg [MPA] or placebo) and Estrogen-Alone (CEE 0.625 mg or placebo) trials who participated in the Mammogram Density Ancillary Study. Using multivariable repeated measures models, we analyzed the association between new-onset breast tenderness (i.e. absence of baseline tenderness and presence of tenderness at year 1 follow-up) and change from baseline in percent mammographic density.
Active therapy increased the odds of new-onset breast tenderness (CEE + MPA vs. placebo risk ratio [RR] 3.01, 95% confidence interval [95% CI] 1.96-4.62; CEE vs. placebo RR 1.70, 95% CI 1.14-2.53). Among women assigned to CEE + MPA, mean increase in mammographic density was greater among participants reporting new-onset of breast tenderness than among participants without new-onset breast tenderness (11.3% vs. 3.9% at year 1, 9.4% vs. 3.2% at year 2, P < 0.001). Among women assigned to CEE alone, increase in mammographic density at year 1 follow-up was not significantly different in women with new-onset breast tenderness compared to women without new-onset breast tenderness (2.4% vs. 0.6% at year 1, 2.2% vs. 1.0% at year 2, P = 0.30).
The new-onset of breast tenderness after initiation of CEE + MPA, but not CEE alone, is associated with greater increases in mammographic density.
Mammographic density; breast density; breast tenderness; mastalgia; mastodynia; conjugated equine estrogen; medroxyprogesterone acetate
Experimental studies have shown that estrogen- or progesterone-activated signaling leads to growth inhibition effects on colon cancer cells through the upregulation of several cell cycle regulators. However, epidemiologic studies evaluating hormone therapy (HT) use and colorectal cancer risk by the status of cell cycle regulators are lacking. In this study, we used data from the prospective Nurses’ Health Study to evaluate whether the association between HT use and colorectal cancer risk differs by the molecular pathological status of microsatellite instability (MSI) and expression of cell cycle-related tumor biomarkers, including CDKN1A (p21, CIP1), CDKN1B (p27, KIP1), and TP53 (p53) by immunohistochemistry. Duplication Cox regression analysis was used to determine an association between HT use, cancer risk, and specific tumor biomarkers in 581 incident colon and rectal cancer cases that occurred during 26 years of follow-up among 105520 postmenopausal women. We found a difference between HT use and colorectal cancer risk according to CDKN1A expression (p-value for heterogeneity=0.01). Current HT use was associated with a reduced risk for CDKN1A-nonexpressed (multivariate relative risk (RR)=0.61, 95% confidence interval (CI), 0.46–0.82), but not for CDKN1A-expressed (RR=1.32, 95% CI, 0.76–2.31) tumors. The lower risk for CDKN1A-nonexpressed, but not for CDKN1A-expressed cancers was also present among current users of estrogen-alone therapy. We found no significant difference in the relations between HT use and cancer risk according to MSI, CDKN1B, or TP53 status. Together, our molecular epidemiology findings suggest a preventive effect of HT against colorectal carcinogenesis which depends, in part, on loss of cyclin-dependent kinase inhibitor CDKN1A.
Background and Purpose
Despite evidence suggesting that vitamin D deficiency may lead to elevated cardiovascular disease risk, results regarding the association of 25(OH)D levels with stroke risk are inconclusive. We aimed to examine this association in a prospective study in women and to summarize all existing data in a meta-analysis.
We measured 25(OH)D levels among 464 women who developed ischemic stroke and an equal number of controls who were free of stroke through 2006 in the Nurses’ Health Study (NHS). We searched MEDLINE and EMBASE for articles published through March 2011 that prospectively evaluated 25(OH)D levels in relation to stroke.
After multivariable adjustment for lifestyle and dietary covariates, lower 25(OH)D levels were associated with an elevated risk of ischemic stroke in the NHS: the odds ratio (95% CI) comparing women in the lowest vs. highest tertiles was 1.49 (1.01, 2.18; Ptrend=0.04). We found 6 other prospective studies that examined 25(OH)D in relation to stroke outcomes. After pooling our results with these prospective studies that included 1,214 stroke cases in total, low 25(OH)D levels were associated with increased risk of developing stroke outcomes in comparison to high levels: the pooled relative risk (95% CI) was 1.52 (1.20, 1.85; I2 = 0.0%, Pheterogeneity=0.63). In two studies that explicitly examined ischemic stroke, this association was 1.59 (1.07, 2.12; I2 = 0.0%, Pheterogeneity=0.80).
These data provide evidence that low vitamin D levels are modestly associated with risk of stroke. Maintaining adequate vitamin D status may lower risk of stroke in women.
vitamin D; stroke; meta-analysis
The Women’s Health Initiative Estrogen-alone Trial was stopped early after 7.1 years (mean) follow-up. Postintervention health outcomes have not been reported.
To examine health outcomes associated with randomization to conjugated equine estrogen (CEE) treatment in women with prior hysterectomy after 10.7 (mean) years follow-up through August 2009.
Design, Setting, and Participants
The intervention phase was a double-blind, placebo-controlled, randomized trial of CEE, 0.625 mg/day or placebo in 10,739 US postmenopausal women aged 50–79 years with prior hysterectomy. Follow-up continued after the planned trial completion date among 7645 (78%) surviving participants who provided written consent.
Main Outcome Measures
The primary outcomes were CHD and invasive breast cancer. A global index of risks and benefits included these 2 endpoints plus stroke, pulmonary embolism, colorectal cancer, hip fracture, and death.
Postintervention risks for women assigned to CEE vs. placebo were similar to the intervention period for CHD (annualized rates 0.64% in CEE vs. 0.67% in placebo; hazard ratio (HR)=0.97, 95% CI 0.75–1.25), breast cancer (0.26% vs. 0.34%; HR=0.75, 0.51–1.09), and total mortality (1.47% vs. 1.48%; HR=1.00, CI 0.84–1.18). Postintervention risks changed for stroke (0.36% vs. 0.41%; HR=0.89, 0.64–1.24), deep vein thrombosis (0.17% vs. 0.27%; HR=0.63, 0.41–0.98), and hip fracture (0.36% vs. 0.28%; HR=1.27, 0.88–1.82). Over the entire follow-up, lower breast cancer incidence in the CEE group persisted (0.27% vs. 0.35%; HR=0.77, 0.62–0.95). Health outcomes were more favorable for younger compared to older women for CHD (p for age-interaction=0.049), total MI (p-interaction=0.007), colorectal cancer (p-interaction=0.04), total mortality (p-interaction =0.04), and global index (p-interaction=0.009).
Among postmenopausal women with prior hysterectomy followed for 10.7 years, CEE use for a median of 5.9 years was not associated with an increased or decreased risk of CHD, deep vein thrombosis, stroke, hip fracture, colorectal cancer, or total mortality. A decreased risk of breast cancer persisted.
estrogen; coronary heart disease; breast cancer; stroke; pulmonary embolism; hip fracture; colorectal cancer; total mortality; Women’s Health Initiative
Although public health campaigns stress leisure time physical activity (LTPA) as essential for obesity prevention, few epidemiological studies have focused on the association of specific types and intensities of LTPA and the clinical endpoints of overweight and obesity. Therefore, we prospectively assessed whether moderate and vigorous intensity as well as total LTPA were associated with the risk of becoming either overweight or obese using a prospective cohort design of 19,003 women enrolled in the Women’s Health Study. Women reported their participation in walking and LTPA at baseline. During a median follow-up of 11.6 years, 7865 women became overweight or obese. In multivariable-adjusted models that included demographic, lifestyle, and dietary factors, both vigorous intensity and total LTPA showed a modest inverse relationship with the development of overweight/obesity. The hazard ratios (HR) and 95% confidence interval (CI) for the highest categories of vigorous intensity LTPA (>2000 kilocalories/week) and total LTPA (>3000 kilocalories/week) compared to no LTPA were 0.79 (0.71–0.89) and 0.87 (0.78–0.96), respectively. In addition, a greater percentage of total LTPA spent performing vigorous intensity activities was associated with a lower risk of overweight/obesity (multivariable HR 0.93, 95% CI 0.87–0.98 for performing > 50% compared to < 50% of activity as vigorous). In conclusion, higher amounts of total LTPA should be encouraged to prevent obesity. Among those willing to participate in vigorous LTPA, and for whom such activities are not contraindicated, vigorous LPTA should be encouraged.
In contrast to many observational studies, women in the Women’s Health Initiative (WHI) trial randomised to oestrogen-alone had lower invasive breast cancer incidence than those assigned placebo. Influence of oestrogen use on breast cancer mortality has not been reported.
Between 1993 and 1998, the WHI enrolled 10,739 postmenopausal women from 40 US centres into a randomized, double-masked, placebo-controlled trial evaluating oral conjugated equine oestrogen (0·625 mg/d). Women aged 50–79 years with prior hysterectomy, anticipated 3-year survival, and mammography clearance were randomized by a computerized, permuted block algorithm, stratified by age group and centre, to receive oestrogen or matching placebo. The trial was terminated early, in 2004, for an adverse effect on stroke. In extended follow-up through August 2009, we assessed long-term effects of oestrogen use on invasive breast cancer incidence, tumor characteristics, and mortality. Cox regression models were used to estimate intention-to-treat hazard ratios [HRs].
After a median 11.8 (interquartile range [IQR], 9·1 to 12·9) years of follow-up, conjugated equine oestrogen-alone use for a median of 5·9 (IQR, 2·5 to 7·3) years was associated with lower invasive breast cancer incidence compared to placebo (151 vs. 199 breast cancers; annualized rates, 0·27% vs. 0·35%; HR, 0·77; 95% confidence interval [CI], 0·62 to 0·95; P=0·02) with no difference (P=0·76) between intervention-phase (HR, 0·79; 95% CI, 0·61 to 1·02) and post-intervention effects (HR, 0·75; 95% CI: 0·51 to 1·09) ). Potential effect modification by benign breast disease (P=0·01) and family history of breast cancer (P=0·02) was observed. In the oestrogen-alone group fewer women died from breast cancer (6 vs.16 deaths; annualized rates 0·009% vs. 0·024%; HR, 0·37; 95% CI, 0·13 to 0·91; P=0.03) and fewer died from all causes after a breast cancer diagnosis (30 vs. 50 deaths; annualized rates, 0·046% vs. 0·076%; HR, 0·62; 95% CI, 0·39 to 0·9;, P=0·04).
Women with hysterectomy seeking relief of climacteric symptoms may be given reassurance regarding breast cancer influence of oestrogen use consistent with durations observed in this trial. However, these findings do not support oestrogen use for breast cancer risk reduction since this benefit may not apply to populations at higher risk.
US National Heart, Lung and Blood Institute. Wyeth provided study medications.
menopausal hormone therapy; breast neoplasms; breast cancer mortality; prevention trial