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INTRODUCTION: Physical activity can attenuate cancer-related declines in physical functioning, improve emotional well-being, and prolong survival among older (≥65 years) breast cancer survivors. However, factors associated with physical activity among older breast cancer survivors are not well-understood. MATERIALS AND METHODS: Participants were enrolled in the Women's Health Initiative (WHI) Life and Longevity After Cancer (LILAC) study. Descriptive statistics, multiple linear regression, and relative risk [RR] regression were used to assess the association of demographic, clinical, physical and psychosocial variables with the total duration of and participation in physical activity among postmenopausal breast cancer survivors. Age-specific correlates (65–74 years vs. 75–84 years vs. ≥85 years) of physical activity were also examined. RESULTS: The majority of participants (n = 3710, mean age = 78.8 ± 5.9) were white (90.7%) and had in situ/localized breast cancer (78.9%). Women who had higher education (RR = 1.47 for graduate/professional school versus high school or less, 95% CI: 1.32, 1.63), higher self-rated health (RR = 1.04 for 10 point increase, 95% CI:1.02, 1.07), higher physical functioning (RR = 1.03 for 5 point increase, 95% CI: 1.02, 1.04), and higher social support (RR = 1.41 for social support all of the time versus none of the time, 95% CI: 1.01, 1.96), were more likely to engage in any physical activity. Similar results were observed for duration of physical activity. Among women aged

Background Prospective evidence on associations between diet quality indices and lung cancer risk is limited, particularly among older women. Objectives We investigated associations between 4 diet quality indices [Healthy Eating Index-2015 (HEI-2015), Alternate Healthy Eating Index 2010 (AHEI-2010), alternate Mediterranean Diet (aMED), and Dietary Approaches to Stop Hypertension (DASH)] and lung cancer incidence and mortality in the Women's Health Initiative Observational Study. Methods Postmenopausal women aged 50-79 y at baseline (1993-1998) self reported their diet intake and information on relevant covariates. We used Cox proportional hazards regression models to estimate HRs and 95% CIs after controlling for age, smoking, and other relevant covariates. Results During ∼17 y of follow-up among 86,090 participants, 1491 lung cancer cases and 1393 lung cancer deaths were documented. Dietary indices were not associated with overall lung cancer incidence but were protective against squamous cell carcinoma (12.8% of total lung cancer) cases (HEI-2015: HR: 0.85; 95% CI: 0.76, 0.96; AHEI-2010: HR: 0.87; 95% CI: 0.78, 0.98; aMED: HR: 0.90; 95% CI: 0.81, 0.99; DASH: HR: 0.87; 95% CI: 0.77, 0.98). Among the indices, only HEI-2015 showed an inverse trend (P-trend = 0.02) with overall lung cancer mortality. Smoking status or participant age at baseline did not modify the association between dietary indices and lung cancer incidence or mortality. Conclusions After comprehensive control of smoking exposure, we found that diet quality was not associated with overall lung cancer among postmenopausal women. However, a high-quality diet was inversely related to incident lung cancer of the squamous cell subtype. Future studies in populations with diverse age, smoking history, and dietary intake may further elucidate the relation between diet quality indices and lung cancer, especially by histological subtype.

Background Riboflavin, vitamin B-6, and vitamin B-12 are key players in one-carbon metabolism as enzymatic cofactors, and deficiency of these nutrients may influence reproductive outcomes possibly through affecting reproductive hormones. Objective The goal was to investigate associations between dietary intakes of riboflavin, vitamin B-6, and vitamin B-12, and menstrual function among premenopausal women. Design This was a secondary analysis of a prospective cohort study conducted at the University at Buffalo during 2005 to 2007. Participants/setting Participants were 259 healthy, regularly menstruating women (aged 18 to 44 years) with self-reported menstrual cycles between 21 and 35 days, who were not trying to conceive, and who had not used hormonal contraception during the past 3 months. Main outcome measures Intakes of B vitamins were assessed via 24-hour dietary recalls four times per menstrual cycle for two cycles. Serum reproductive hormones and plasma homocysteine were measured eight and three times, respectively, per cycle for two cycles. Anovulatory cycles were determined by progesterone concentrations ≤5 ng/mL (15.9 nmol/L) and no observed serum luteinizing hormone peak during the mid or late luteal phase visit. Statistical analysis Weighted linear mixed regressions were used to evaluate associations between cycle-averaged B vitamin intakes and hormones and homocysteine, and generalized linear regressions for associations with anovulation. Models were adjusted for age, race, body mass index, physical activity, alternate Mediterranean diet score, intakes of total energy, protein, fiber, and folate, and percentage of energy intake from fat. Results Higher intakes of riboflavin (per 0.1 mg increase in intake) were inversely correlated with estradiol (−0.87%, 95% CI −1.67 to −0.06) and homocysteine levels (−0.61%, 95% CI −1.10 to −0.12). Higher vitamin B-6 intakes were suggestive of higher follicle-stimulating hormone, although the results were not statistically significant (0.63% difference, 95% CI −0.03 to 1.29, per 0.1 mg increase in intake; P=0.06). Small increases in testosterone and decreases in homocysteine were found with vitamin B-12 intake. No associations were observed between intake of B vitamins and a risk of sporadic anovulation. Conclusions Higher intakes of riboflavin were associated with a small decrease in serum estradiol among healthy, regularly menstruating women. Higher intakes of riboflavin and vitamin B-12 were associated with lower plasma homocysteine concentrations. Overall, riboflavin, vitamin B-6, and vitamin B-12 that are one-carbon nutrients do not appear to influence the ovarian cycle among premenopausal women.

Background Phthalates are ubiquitous endocrine disrupting chemicals present in a wide variety of consumer products. However, the personal characteristics associated with phthalate exposure are unclear. Objectives We sought to describe personal, behavioral, and reproductive characteristics associated with phthalate metabolite concentrations in an ongoing study nested within the Women's Health Initiative (WHI). Materials and Methods We measured thirteen phthalate metabolites in two or three archived urine samples collected in 1993–2001 from each of 1257 WHI participants (2991 observations). We fit multivariable generalized estimating equation models to predict urinary biomarker concentrations from personal, behavioral, and reproductive characteristics. Results Older age was predictive of lower concentrations of monobenzyl phthalate (MBzP), mono-carboxyoctyl phthalate (MCOP), mono-3-carboxypropyl phthalate (MCPP), and the sum of di-n-butyl phthalate metabolites (ΣDBP). Phthalate metabolite concentrations varied by race/region, with generally higher concentrations observed among non-Whites and women from the West region. Higher neighborhood socioeconomic status predicted lower MBzP concentrations, and higher education predicted lower monoethyl phthalate (MEP) and higher concentrations of the sum of metabolites of di-isobutyl phthalate (ΣDiBP). Overweight/obesity predicted higher MBzP, MCOP, monocarboxynonyl phthalate (MCNP), MCPP, and the sum of metabolites of di(2-ethylhexyl) phthalate (ΣDEHP) and lower MEP concentrations. Alcohol consumption predicted higher concentrations of MEP and ΣDBP, while current smokers had higher ΣDBP concentrations. Better diet quality as assessed by Healthy Eating Index 2005 scores predicted lower concentrations of MBzP, ΣDiBP, and ΣDEHP. Conclusion Factors predictive of lower biomarker concentrations included increased age and healthy behaviors (e.g. lower alcohol intake, lower body mass index, not smoking, higher quality diet, and moderate physical activity). Racial group (generally higher among non-Whites) and geographic regions (generally higher in Northeast and West compared to South regions) also were predictive of phthalate biomarker concentrations.

OBJECTIVES: Magnesium, an essential mineral, are antagonistic in many physiologic processes. However, few studies have investigated the associations of magnesium intake with liver cancer risk. METHODS: We evaluated the association between intake of magnesium and risk of liver cancer in the Women's Health Initiative (WHI) Observational Study. This analysis included 77,170 participants who completed a food frequency questionnaire, free of cancer, and without missing values for follow-up dates and body mass index (BMI). Magnesium intakes from diet and supplements were estimated through the baseline food frequency questionnaire. Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI). RESULTS: After 15.8 years’ cumulative follow-up, there were 207 liver cancer cases. After adjustment for known risk factors of liver cancer, and intakes of energy, total vitamin D and calcium, higher intake of magnesium was inversely associated with risk of liver cancer (HR = 0.26, 95% CI, 0.09–0.76) for highest vs. lowest quartile; P trend = 0.01). Every 100 mg increase in intake of magnesium was associated with a 34% reduction in the risk of liver cancer. Although interactions between magnesium intake and alcohol use and BMI at baseline were not significant (P > 0.05), inverse associations between magnesium intake and liver cancer risk were primarily presented among postmenopausal women who were current alcohol drinkers at the baseline and had BMI ≥ 25. CONCLUSIONS: We found that higher magnesium intake may reduce liver cancer incidence among postmenopausal women particularly among those who were current alcohol drinkers and overweight/obese. FUNDING SOURCES: No

Background Osteoporotic fractures are associated with high morbidity, mortality, and cost. Methods We performed a post hoc analysis of the Women's Health Initiative (WHI) clinical trials data to assess osteoporosis treatment and identify participant characteristics associated with utilization of osteoporosis medication(s) after new diagnoses of osteoporosis or fracture. Information from visits prior to and immediately subsequent to the first fracture event or osteoporosis diagnosis were evaluated for medication use. A full logistic regression model was used to identify factors predictive of osteoporosis medication use after a fracture or a diagnosis of osteoporosis. Results The median length of follow-up from enrollment to the last WHI clinic visit for the study cohort was 13.9 years. Among the 13,990 women who reported new diagnoses of osteoporosis or fracture between enrollment and their final WHI visit, and also had medication data available, 21.6% reported taking an osteoporosis medication other than estrogen. Higher daily calcium intake, diagnosis of osteoporosis alone or both osteoporosis and fracture (compared with diagnosis of fracture alone), Asian or Pacific Islander race/ethnicity (compared with White/Caucasian), higher income, and hormone therapy use (past or present) were associated with significantly higher likelihood of osteoporosis pharmacotherapy. Women with Black/African American race/ethnicity (compared with White/Caucasian), body mass index ≥30 (compared with body mass index of 18.5-24.9), current tobacco use (compared with past use or lifetime nonusers), and history of arthritis were less likely to use osteoporosis treatment. Conclusion Despite well-established treatment guidelines in postmenopausal women with osteoporosis or history of fractures, pharmacotherapy use was suboptimal in this study. Initiation of osteoporosis treatment after fragility fracture may represent an opportunity to improve later outcomes in these high-risk women. Specific attention needs to be paid to increasing treatment among women with fragility fractures, obesity, current tobacco use, history of arthritis, or of Black race/ethnicity.

Background Magnesium and calcium are antagonistic in many physiologic processes. However, few studies have investigated the associations of supplemental calcium with lung cancer risk taking this antagonism into account. We evaluated the effect of calcium and vitamin D supplementation on lung cancer incidence and explored whether the ratio of baseline calcium to magnesium (Ca:Mg) intake modifies the association in the Women’s Health Initiative (WHI) calcium plus vitamin D supplementation (CaD) trial. Methods The intervention phase of the WHI CaD was a double-blinded, randomized, placebo-controlled trial in 36,382 postmenopausal women aged 50–79 years, recruited at 40 U.S. centers. Post-intervention follow-up continued among 29,862 (86%) of the surviving participants. Risk of lung cancer in association with CaD supplementation was evaluated using proportional hazard regression models. Results After 11 years’ cumulative follow-up, there were 207 lung cancers (incidence 0.11% per year) in the supplement arm and 241 (0.12%) in the placebo arm (hazard ratio (HR) for the intervention, 0.91; 95% confidence interval (CI), 0.71–1.17). Subgroup analyses suggested that the HR for lung cancer varied by baseline Ca:Mg intake ratio among women who were current smokers at enrollment ( p = 0.04 for interaction). Conclusions Over the entire follow-up period, calcium and vitamin D supplementation did not reduce lung cancer incidence among postmenopausal women. In exploratory analyses, an interaction was found for the baseline Ca:Mg intake ratio on lung cancer among current smokers at the trial entry. This findings need to be further studied for the role of calcium with magnesium in lung carcinogenesis in current smokers.

Background: Fracture is a complex trait, affected by both genetic and environmental factors. A meta-analysis of genome-wide association studies (GWASs) identified multiple bone mineral density (BMD) and fracture-associated loci.Objective: We conducted a study to evaluate whether fracture genetic risk score (Fx-GRS) and bone mineral density genetic risk score (BMD-GRS) modify the association between the intake of calcium with vitamin D (CaD) and fracture risk.Design: Data from 5823 white postmenopausal women from the Women's Health Initiative CaD randomized trial were included. Participants received 1000 mg elemental Ca with 400 IU vitamin D3/d or placebo (median follow-up: 6.5 y). Total fracture was defined as first fracture of any type. We computed the Fx-GRS with 16 fracture- and BMD-associated variants, and the BMD-GRS with 50 BMD-associated variants. We used Cox regression and a case-only approach to test for multiplicative interaction. Additive interaction was assessed with the relative excess risk due to interaction (RERI). We analyzed genetic risk score as a continuous variable and a categorical variable based on quartile (quartile 1, quartiles 2-3, and quartile 4).Results: We observed no interaction between the Fx-GRS and CaD on fracture risk; however, we observed a significant multiplicative interaction between the BMD-GRS and CaD assignment (P-interaction = 0.01). In addition, there was a significant negative additive interaction between placebo assignment and higher BMD-GRS: quartiles 2-3, PRERI = 0.03; quartile 4, PRERI = 0.03. In a stratified analysis, the protective effect of CaD on fracture risk was observed in women in the lowest BMD-GRS quartile (HR: 0.60, 95% CI: 0.44, 0.81) but not in women with a higher BMD-GRS.Conclusions: We observed significant effects of CaD intake on fracture risk only in women with the lowest genetic predisposition to low BMD. Future large-scale studies with functional characterization of GWAS findings are warranted to assess the utility of genetic risk score in analysis of risks and benefits of CaD for bone.

Background: Evidence is growing that the equilibrium between reactive oxygen species and antioxidants plays a vital role in women’s reproductive health. Objective: The objective of this study was to evaluate variations in serum antioxidant concentrations across the menstrual cycle and associations between antioxidants and reproductive hormones and anovulation among healthy women. Methods: The BioCycle Study, a prospective cohort, followed 259 women aged 18–44 y for up to 2 menstrual cycles. Serum fat-soluble vitamin and micronutrient (α-tocopherol, γ-tocopherol, retinol, lutein, lycopene, and β-carotene), ascorbic acid, and reproductive hormone concentrations were measured 5–8 times/cycle. We used weighted linear mixed models to assess associations between antioxidants and hormone concentrations, after adjustment for age, race, body mass index, parity, sleep, pain medication use, total energy intake, concurrent hormones, serum cholesterol, F2-isoprostanes, and other antioxidants. Generalized linear models were used to identify associations with anovulation. Results: Serum antioxidant concentrations varied across the menstrual cycle. Retinol and α-tocopherol were associated with higher estradiol [RR: 1.00 pg/mL (95% CI: 0.67, 1.34 pg/mL); RR: 0.02 pg/mL (95% CI: 0.003, 0.03 pg/mL), respectively] and testosterone [RR: 0.61 ng/dL (95% CI: 0.44, 0.78 ng/dL); RR: 0.01 ng/dL (95% CI: 0.001, 0.01 ng/dL), respectively]. Ascorbic acid was associated with higher progesterone (RR: 0.15 ng/mL; 95% CI: 0.05, 0.25 ng/mL) and with lower follicle-stimulating hormone (RR: −0.06 mIU/mL; 95% CI: −0.09, −0.03 mIU/mL). The ratio of α- to γ-tocopherol was associated with an increased risk of anovulation (RR: 1.03; 95% CI: 1.01, 1.06). Conclusions: These findings shed new light on the intricate associations between serum antioxidants and endogenous hormones in healthy premenopausal women and support the hypothesis that concentrations of serum vitamins affect steroidogenesis even after adjustment for oxidative stress.

Background: Although habitual low-to-moderate alcohol intakehas been linked with reduced all-cause mortality and morbidity,the effect of recent alcohol intake on female reproductive functionhas not been clearly established.Objective: We assessed the relation between acute alcohol con-sumption, reproductive hormones, and markers of menstrual cycledysfunction including sporadic anovulation, irregular cycle length,luteal phase deficiency, long menses, and heavy blood loss.Design: A total of 259 healthy, premenopausal women from WesternNew York were followed for #2 menstrual cycles (2005–2007) andprovided fasting blood specimens during #8 visits/cycle and four 24-hdietary recalls/cycle. Linear mixed models were used to estimate as-sociations between previous day’s alcohol intake and hormone con-centrations, whereas Poisson regression was used to assess RR ofcycle-average alcohol intake and menstrual cycle function.Results: For every alcoholic drink consumed, the geometric meantotal and free estradiol, total and free testosterone, and luteinizinghormone were higher by 5.26% (95% CI: 1.27%, 9.41%), 5.82%(95% CI: 1.81%, 9.99%), 1.56% (95% CI: 0.23%, 2.90%), 1.42%(95% CI: 0.02%, 2.84%), and 6.18% (95% CI: 2.02%, 10.52%),respectively, after adjustment for age, race, percentage of body fat,perceived stress, pain-medication use, sexual activity, caffeine, andsleep. Binge vs. nonbinge drinking (defined as reporting $4vs.,4drinks/d, respectively) was associated with 64.35% (95% CI: 18.09%,128.71%) and 63.53% (95% CI: 17.41%, 127.73%) higher total andfree estradiol. No statistically significant associations were shown be-tween cycle-average alcohol intake and menstrual cycle function.Conclusion: Although recent moderate alcohol intake does not appearto have adverse short-term effects on menstrual cyclefunction,includingsporadic anovulation, potential prote ctive and deleterious long-term ef-fects of alterations in reproductive hormones on other chronic diseaseswarrant additional investigation. Am J Clin Nutr doi: 10.3945/ajcn.114.102160.Keywords: alcohol, estradiol, menstrual cycle, ovulation, proges-teroneINTRODUCTIONAlcohol intake is common in US women of reproductive agewith over one-half of women aged 18–44 y consuming alcohol(1). Although epidemiologic evidence has indicated that habitualmoderate alcohol intake (1–2 drinks/d) is associated with re-duced all-cause mortality and morbidity (2, 3), the effect of al-cohol intake on female reproductive function has not been clearlyestablished (4–19). It is challenging to study the effects of alcoholon female reproductive function because of the complex time-dependent hormonal feedback loops that regulate the menstrualcycle and women’s fertility coupled with alcohol’s relativelyrapidmetabolism (20),whichclearthebodyofalcohol in12–24h(21). Because of potential sensitivity of menstrual cycle functionsto critical windows of exposure, studies are needed that take intoaccount recent alcohol intake relative to the outcome being as-sessed, such as ovulation, conception, and implantation.Although there have been large observational studies thatevaluated chronic alcohol exposure and menstrual cycle function(15, 16, 19), studies that evaluated acute alcohol intake and men-strualcyclefunctionhavebeenlimitedtoexperimentalstudiesthatassessed alcohol-mediated changes in reproductive hormone con-centrations in nonpregnant women (22–25). The majority of thesecontrolled studies showed relevant positive associations betweenacute, high alcohol ($2 drinks/d) administration and elevatedestradiol and testosteroneconcentrations, which are believedtobethe result of potentially several mechanistic pathways includingchanges in hepatic redox states (22–25), the stimulation of the ad-renal gland (26, 27), and the aromatization of testosterone toestradiol (28). Although these studies have helped to informmechanistic pathways, they have limited generalizability becauseof small sample sizes, high alcohol exposures, and experimental con-ditions. In addition, most of these studies were limited to a single

There is conflicting evidence whether heart failure (HF) is associated with incident cancer. Despite population-based cohorts demonstrating this association, no association was found in the Physician's Health Study. We aimed to study this in women. In this Women's Health Initiative cohort, 146,817

Background: Meta-analyses of observational studies associate adherence to several dietary patterns with cognitive health. However, limited evidence from full scale, randomized controlled trials precludes causal inference regarding dietary effects on cognitive function. Methods: The Women's Health Initiative (WHI) Dietary Modification (DM) randomized trial, in 48,835 postmenopausal women, included a subset of 1,606 WHI Memory Study (WHIMS) participants >= 65 years old, to assess low-fat dietary pattern influence on global cognitive function, evaluated with annual screening (Modified Mini–Mental State Examinations [3MSE]). Participants were randomized by a computerized, permuted block algorithm, stratified by age group and center, to a dietary intervention (40%) to reduce fat intake to 20% of energy and increase fruit, vegetable and grain intake or usual diet comparison groups (60%). The study outcome was possible cognition impairment (failed cognitive function screening) through the 8.5 year (median) dietary intervention. Those failing screening received a comprehensive, multi-phase cognitive function assessment to classify as: no cognitive impairment, mild cognitive impairment, or probable dementia. Exploratory analyses examined the composite endpoint of death after possible cognitive impairment through 18.7 years (median) follow-up. The WHI trials are registered at ClinicalTrials.gov:NCT00000611. Findings: Among the 1,606 WHIMS participants, the dietary intervention statistically significantly reduced the incidence of possible cognitive impairment (n = 126; hazard ratio [HR] 0.59 95% confidence interval [CI] 0.38–0. 91, P = 0.01) with HR for dietary influence on subsequent mild cognitive impairment of 0.65 (95% CI 0.35–1.19) and HR of 0.63 (95% CI 0.19–2.10) for probable dementia (PD). Through 18.7 years, deaths from all-causes after possible cognitive impairment were non-significantly lower in the dietary intervention group (0.56% vs 0.77%, HR 0.83 95% CI 0.35 to 2.00, P = 0.16). Interpretation: Adoption of a low-fat eating pattern, representing dietary moderation, significantly reduced risk of possible cognitive impairment in postmenopausal women. Funding: Several Institutes of the US National Institutes of Health. Keywords: Cognition, Dietary modification, Low-fat dietary pattern, Randomized clinical trial, Women's Health Initiative

It is unknown whether supplementation with calcium and vitamin D has an impact on menopause-related symptoms.As part of the Women's Health Initiative Calcium/Vitamin D Supplementation Trial (CaD), women were randomized at 40 clinical sites to elemental calcium carbonate 1000 mg with vitamin D 400 IU daily or placebo. At the CaD baseline visit (year 1 or year 2) and during a mean follow-up of 5.7 years, participants provided data on menopause-related symptoms via questionnaires. Generalized linear mixed effects techniques were used to address research questions.After excluding participants with missing data (N=2125), we compared menopause-related symptoms at follow-up visits of 17,101 women randomized to CaD with those of 17,056 women given the placebo. Women in the CaD arm did not have a different number of symptoms at follow-up compared to women taking the placebo (p=0.702). Similarly, there was no difference between sleep disturbance, emotional well-being, or energy/fatigue at follow-up in those who were randomized to CaD supplementation compared to those taking the placebo.Our data suggest that supplementation with 1000 mg of calcium plus 400 IU of vitamin D does not influence menopause-related symptoms over an average of 5.7 years of follow-up among postmenopausal women with an average age of 64 at the WHI baseline visit.

To determine whether depressive symptoms are associated with ovulation or reproductive hormone concentrations in eumenorrheic women without a reported diagnosis of clinical depression.A prospective cohort of 248 regularly menstruating women, aged 18 to 44 years (27.3 ± 8.2) were evaluated for depressive symptoms at baseline using the 20-item Center for Epidemiological Studies Depression (CES-D) scale and categorized dichotomously (16, no depressive symptoms [92%] vs. ≥ 16, depressive symptoms [8%]). Serum concentrations of estradiol, progesterone, luteinizing hormone, and follicle-stimulating hormone were measured up to eight times per cycle for up to two menstrual cycles. Linear mixed models estimated associations between depressive symptoms and hormone concentrations, whereas generalized linear mixed models assessed their relationship with sporadic anovulation.No significant associations were identified between depressive symptoms and reproductive hormone levels (all P.05) or the odds of sporadic anovulation (adjusted odds ratio, 1.1; 95% confidence interval, [0.02-5.0]), after adjusting for age, race, body mass index, perceived stress level, and alcohol consumption.Despite reported associations between mental health and menstrual cycle dysfunction, depressive symptoms were not associated with reproductive hormone concentrations or sporadic anovulation in this cohort of regularly menstruating women with no recent (within 1 year) self-reported history of clinical depression.

a b s t r a c t Objectives: Testosterone supplementation is being prescribed increasingly to treat symptoms of hor- mone deficiency in pre- and postmenopausal women; however, studies of the association of testosterone therapy, alone or in combination with estrogen, with risk of breast cancer are limited. The current study assessed the association of combination conjugated esterified estrogen and methyltestosterone (CEE + MT) use and breast cancer risk in postmenopausal women in the Women's Health Initiative (WHI). Study design: At Year 3 of follow-up, women in the WHI observational study (N = 71,964) provided infor- mation on CEE + MT use in the past two years, duration of use, and the brand name of the product. In addition, in each of years 4-8, women were asked whether they had used CEE + MT in the previous year. After 10 years of follow-up, 2832 incident breast cancer cases were identified. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for the association of CEE + MT use (irrespective of use of other hormones) and of exclusive CEE + MT use in relation to breast cancer risk. Results: Neither CEE + MT use nor exclusive use of CEE + MT was associated with risk: multivariable- adjusted HR 1.06, 95% CI 0.82-1.36 and HR 1.22, 95% CI 0.78-1.92, respectively. Among women with a natural menopause, the HR for exclusive use was 1.32 (95% CI 0.68-2.55). There was no indication of an association when repeated measures of CEE + MT use were included in a time-dependent covariates analysis. Conclusion: The present study, the largest prospective study to date, did not show a significant association of CEE + MT supplementation and risk of breast cancer.

Few detailed data are available on the wide range of determinants of vitamin D status among postmenopausal women, and it is also unclear whether there may be undiscovered determinants. The objective of this study was to comprehensively evaluate determinants of serum 25-hydroxyvitamin D [25(OH)D] concentrations in a large cohort of postmenopausal women. Data from a subset of the Women's Health Initiative Observational Study were analyzed (50-79 y; n = 3345). Information on diet, lifestyle behaviors, secondhand smoke, use of dietary supplements and medication, chronic diseases, and anthropometry was collected at baseline (1993-1998) and on sun exposure at year 4 follow-up. Linear regression was performed to estimate regression coefficients (β). Significant determinants were total vitamin D intake (food plus supplements per 100 IU/d, β = 2.08), years of supplemental vitamin D use (β = 0.15), total fat intake (grams per day, β = -0.03), smoking status (β = -2.64, current vs. never), regional solar irradiance (β = 6.26, 475-500 vs. 300-325 Langleys), daylight time spent outdoors in summer (β = 5.15, >2 h vs.

Author(s): Orchard, Tonya S; Larson, Joseph C; Alghothani, Nora; Bout-Tabaku, Sharon; Cauley, Jane A; Chen, Zhao; LaCroix, Andrea Z; Wactawski-Wende, Jean; Jackson, Rebecca D | Abstract: BackgroundMagnesium is a necessary component of bone, but its relation to osteoporotic fractures is unclear.ObjectiveWe examined magnesium intake as a risk factor for osteoporotic fractures and altered bone mineral density (BMD).DesignThis prospective cohort study included 73,684 postmenopausal women enrolled in the Women's Health Initiative Observational Study. Total daily magnesium intake was estimated from baseline food-frequency questionnaires plus supplements. Hip fractures were confirmed by a medical record review; other fractures were identified by self-report. A baseline BMD analysis was performed in 4778 participants.ResultsBaseline hip BMD was 3% higher (P l 0.001), and whole-body BMD was 2% higher (P l 0.001), in women who consumed g422.5 compared with l206.5 mg Mg/d. However, the incidence and RR of hip and total fractures did not differ across quintiles of magnesium. In contrast, risk of lower-arm or wrist fractures increased with higher magnesium intake [multivariate-adjusted HRs of 1.15 (95% CI: 1.01, 1.32) and 1.23 (95% CI: 1.07, 1.42) for quintiles 4 and 5, respectively, compared with quintile 1; P-trend = 0.002]. In addition, women with the highest magnesium intakes were more physically active and at increased risk of falls [HR for quintile 4: 1.11 (95% CI: 1.06, 1.16); HR for quintile 5: 1.15 (95% CI: 1.10, 1.20); P-trend l 0.001].ConclusionsLower magnesium intake is associated with lower BMD of the hip and whole body, but this result does not translate into increased risk of fractures. A magnesium consumption slightly greater than the Recommended Dietary Allowance is associated with increased lower-arm and wrist fractures that are possibly related to more physical activity and falls.

Objective To assess the association of total isoflavone intake with ovulatory function, including sporadic anovulation in healthy premenopausal women. Design Prospective cohort study. Setting University. Patient(s) Participants included 259 healthy regularly menstruating women aged 18–44 years. Intervention(s) None. Main Outcome Measure(s) Serum concentrations of E 2 , free E 2 , P, LH, FSH, and SHBG and sporadic anovulation in healthy premenopausal women. Result(s) Isoflavone intake was not associated with E 2 , free E 2 , P, LH, and FSH concentrations. Consumption in the highest quartile (Q4: 1.6–78.8 mg/d) was significantly associated with greater SHBG concentrations (β = 0.09; 95% confidence interval [CI] 0.02–0.16), compared with the first quartile (Q1: 0.0–0.3 mg/d). Conclusion(s) Isoflavone intake was not associated with sporadic anovulation (Q4 vs. Q1: odds ratio 0.87, 95% CI 0.32–1.66). Dietary isoflavone intake among young premenopausal women was not related to sex hormone concentrations or anovulation, but was associated with minimally increased SHBG concentrations. These results suggest potential endocrine effects with no subsequent effects on ovulation, easing concerns regarding their impacts on fertility.

PurposeThe osteoprotogerin/receptor activator of NF-kappa β/receptor activator of NF-kappa β ligand (OPG/RANK/RANKL) pathway plays a critical role in bone remodeling. This study investigated associations between serum levels of OPG, soluble RANKL (sRANKL), and the ratio of OPG/sRANKL to risk of incident hip fracture.MethodsA nested case-control study was conducted among postmenopausal, Caucasian women aged 50-79 at baseline (1993-1998), followed for hip fracture through March 2005 in the Women's Health Initiative Observational Study. 400 incident hip fracture cases were selected and individually matched to 400 controls with no prior fracture or incident hip fracture. Matching factors were baseline age, enrollment date and hormone therapy (HT) exposure. Baseline serum OPG and sRANKL levels were measured using high sensitivity ELISA. Odds ratios were computed for quartiles of each biomarker adjusting for matching factors and hip fracture risk factors.ResultsSerum OPG was significantly associated with older age, low physical activity and poorer physical function in control women. sRANKL was inversely associated with total calcium intake in control women, but not associated with age or other fracture risk factors. The odds ratio for hip fracture comparing the highest to lowest quartiles of OPG was 2.28 (95% confidence interval (CI), 1.45-3.61) after adjusting for the matching variables (p-value for linear trend

Background Smoking is associated with tooth loss. However, smoking's relationship to the specific reason for tooth loss in postmenopausal women is unknown. Methods Postmenopausal women (n = 1,106) who joined a Women's Health Initiative ancillary study (The Buffalo OsteoPerio Study) underwent oral examinations for assessment of the number of missing teeth, and they reported the reasons for tooth loss. The authors obtained information about smoking status via a self-administered questionnaire. The authors calculated odds ratios (ORs) and 95 percent confidence intervals (CIs) by means of logistic regression to assess smoking's association with overall tooth loss, as well as with tooth loss due to periodontal disease (PD) and with tooth loss due to caries. Results After adjusting for age, education, income, body mass index, history of diabetes diagnosis, calcium supplement use and dental visit frequency, the authors found that heavy smokers (≥ 26 pack-years) were significantly more likely to report having experienced tooth loss compared with never smokers (OR = 1.82; 95 percent CI, 1.10-3.00). Smoking status, packs smoked per day, years of smoking, pack-years and years since quitting smoking were significantly associated with tooth loss due to PD. For pack-years, the association for heavy smokers compared with that for never smokers was OR=6.83 (95 percent CI, 3.40 –13.72). The study results showed no significant associations between smoking and tooth loss due to caries. Conclusions and Practical Implications Smoking may be a major factor in tooth loss due to PD. However, smoking appears to be a less important factor in tooth loss due to caries. Further study is needed to explore the etiologies by which smoking is associated with different types of tooth loss. Dentists should counsel their patients about the impact of smoking on oral health, including the risk of experiencing tooth loss due to PD.

While low physical activity and high body mass index (BMI) have been associated with higher endometrial cancer incidence, no previous studies have evaluated the association between physical activity and survival after endometrial cancer diagnosis, and studies on BMI and survival have not been performed in a prospective cohort.We examined pre-diagnosis BMI and moderate- to vigorous-intensity physical activity in relation to overall and disease-specific survival among 983 postmenopausal women who were diagnosed with endometrial cancer in the Women's Health Initiative Observational Study and Clinical Trials.Over a median 5.2 (max 14.1) years from diagnosis to death or end of follow-up, 163 total deaths were observed, 66 of which were due to endometrial cancer. We observed a higher all-cause mortality hazard ratio (HR) = 1.85 (95% CI 1.19-2.88) comparing women with a BMI ≥ 35 kg/m(2) to women with BMI25 kg/m(2). For endometrial cancer-specific mortality the HR = 2.23 (95% CI 1.09-4.54) comparing extreme BMI categories. To examine histologic subtypes we analyzed type I endometrial tumors separately and found an HR = 1.20 (95% CI 1.07-1.35) associated with all-cause mortality for each 5-unit change in BMI. Moderate- to vigorous-intensity physical activity was not associated with all-cause or endometrial cancer-specific mortality.Pre-diagnosis BMI, but not physical activity, was associated with survival among women with endometrial cancer. Future studies should investigate mechanisms and timing of BMI onset to better understand the burden of disease attributable to BMI.

Exposure to metals, specifically cadmium, lead, and mercury, is widespread and is associated with reduced bone mineral density (BMD) in older populations, but the associations among premenopausal women are unclear. Therefore, we evaluated the relationship between these metals in blood and BMD (whole body, total hip, lumbar spine, and non-dominant wrist) quantified by dual energy x-ray absorptiometry in 248 premenopausal women, aged 18–44. Participants were of normal body mass index (mean BMI 24.1), young (mean age 27.4), 60% were white, 20% non-Hispanic black, 15% Asian, and 6% other race group, and were from the Buffalo, New York region. The median (interquartile range) level of cadmium was 0.30 μg/l (0.19–0.43), of lead was 0.86 μg/dl (0.68–1.20), and of mercury was, 1.10 μg/l (0.58–2.00). BMD was treated both as a continuous variable in linear regression and dichotomized at the 10th percentile for logistic regression analyses. Mercury was associated with reduced odds of decreased lumbar spine BMD (0.66, 95% confidence interval: 0.44, 0.99), but overall, metals at environmentally relevant levels of exposure were not associated with reduced BMD in this population of healthy, reproductive-aged women. Further research is needed to determine if the blood levels of cadmium, lead, and mercury in this population are sufficiently low that there is no substantive impact on bone, or if effects on bone can be expected only at older ages.

Few studies have prospectively examined predictors of change in plasma concentrations of 25-hydroxyvitamin D [25(OH)D]. We sought to determine the predictors of 5-y change in 25(OH)D. Plasma 25(OH)D concentrations were assessed at baseline (1997–2000) and 5 y later (2002–2005) in 668 postmenopausal women enrolled in the Osteoporosis and Periodontal Disease Study. Baseline and changes in demographic, dietary, lifestyle, and health-related factors were tested as predictors of change in 25(OH)D concentrations by using multivariable linear regression. The mean 5-y change in 25(OH)D (mean ± SD) was 7.7 ± 0.7 nmol/L (P < 0.001). In our predictive model (n = 643), predictors explained 31% of the variance in change in 25(OH)D concentrations and included baseline 25(OH)D, baseline and change in vitamin D supplementation and physical activity, change in season of blood draw, BMI, whole-body T score, and baseline hormone therapy use. Baseline 25(OH)D and change in vitamin D supplementation explained the most variation (25%) in 25(OH)D. Exploratory analyses showed a borderline significant interaction between tertiles of baseline 25(OH)D and change in vitamin D supplementation over time (P = 0.06). The greatest mean increase in 25(OH)D (22.9 ± 16.8 nmol/L), with adjustment for other statistically significant predictors, occurred in women whose baseline 25(OH)D concentration was ≤51.0 nmol/L (tertile 1) and who increased supplementation use over time. These results confirm the importance of supplementation in increasing 25(OH)D concentrations in aging women, even after other statistically significant predictors are controlled for. These data also suggest that this is especially true among aging women with inadequate 25(OH)D (e.g.

Few cohort studies have examined smoking and alcohol consumption in relation to risk of thyroid cancer, and their findings are conflicting.We therefore assessed the association of smoking and alcohol intake with risk of thyroid cancer in a cohort of 159,340 women enrolled in the Women's Health Initiative. Over 12.7 years of follow-up 331 cases of thyroid cancer, of which 276 were papillary thyroid cancer, were identified. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI).Compared to never smokers, ever smokers did not have altered risk. Current smokers had reduced risk for all thyroid cancer (HR 0.54, 95% CI 0.29-1.00) and for papillary thyroid cancer (HR 0.34, 95% CI 0.15-0.78); however, the number of current smokers among cases was small. No associations or trends were seen for amount smoked, age of starting smoking, or age at quitting. Smokers of ≥40 pack-years had a significantly reduced risk of papillary thyroid cancer (HR 0.44, 95% CI 0.21-0.89). In contrast, women who had smoked for20 years had increased risk of thyroid cancer (HR 1.35, 95% CI 1.05-1.74) and papillary cancer (HR 1.43, 95% CI 1.09-1.89). Alcohol intake was not associated with risk.Our findings suggest that current smoking and having higher pack-years of exposure are associated with a modestly reduced risk of thyroid cancer, whereas alcohol consumption does not appear to affect risk.

Background : Incidence rates of non-Hodgkin's lymphoma (NHL) increased substantially in the United States and worldwide during the latter part of the 20th century, but little is known about its etiology. Obesity is associated with impaired immune function through which it may influence the risk of NHL; other factors reflecting energy homeostasis (height, abdominal adiposity, and physical activity) may also be involved. Methods : We examined the association of anthropometric factors and physical activity with risk of NHL and its major subtypes in a large cohort of women aged 50–79 years old who were enrolled at 40 clinical centers in the United States between 1993 and 1998. Over a mean follow-up period of 11 years, 1123 cases of NHL were identified among 158,975 women. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Results : Height at baseline was positively associated with risk of all NHL and with that of diffuse large B-cell lymphoma (HRs q4vs.q1 1.19, 95% CI 1.00–1.43 and 1.43, 95% CI 1.01–2.03, respectively). Measures of obesity and abdominal adiposity at baseline were not associated with risk. Hazard ratios for NHL were increased for women in the highest quartile of weight and body mass index at age 18 (HRs q4vs.q1 1.29, 95% CI 1.01–1.65 and 1.27, 95% CI 1.01–1.59, respectively). Some measures of recreational physical activity were modestly associated with increased risk of NHL overall, but there were no clear associations with specific subtypes. Conclusion : Our findings regarding anthropometric measures are consistent with those of several previous reports, suggesting that early life influences on growth and immune function may influence the risk of NHL later in life.

To investigate whether the association between physical activity and serum 25-hydroxyvitamin D (25(OH)D) concentrations is independent of sun exposure, body size, and other potential explanatory variables.By using data from a sample of 1343 postmenopausal women from the Women's Health Initiative, we used linear regression to examine the associations of duration (minutes/week) of recreational activity and of yard work with 25(OH)D concentrations (nmol/L).In age-adjusted analyses, positive associations were observed between 25(OH)D concentrations and both duration of recreational physical activity (β = 0.71, SE [0.09], p.001) and yard work (β = 0.36, SE [0.10], p = .004). After further adjustment for vitamin D intake, self-reported sunlight exposure, waist circumference, and season of blood draw, 25(OH)D was significantly associated with recreational activity (β = 0.21, SE [0.09], p = .014) but not with yard work (β = 0.18, SE [0.09], p = .061). Interactions were observed between season and both recreational activity (P(interaction) = .082) and yard work (P(interaction) = .038) such that these activity-25(OH)D associations were greater during summer/fall compared with winter/spring. Self-reported sunlight exposure and measures of body size did not modify the associations.The observed age-adjusted activity-25(OH)D associations were attenuated after adjusting for explanatory variables and were modified by season of blood draw. Adopting a lifestyle that incorporates outdoor physical activity during summer/fall, consuming recommended amounts of vitamin D, and maintaining a healthy weight may improve or maintain vitamin D status in postmenopausal women.

Background: The Women's Health Initiative Dietary Modification (DM) Trial was a randomized controlled trial that compared the effects of a low-fat (≤20% of total energy) or a usual diet in relation to chronic disease risk in postmenopausal women. Objective: We characterized long-term body-composition changes associated with the DM trial and potential modifiers of these associations. Design: In the DM trial, 48,835 women aged 50–79 y were randomly assigned to intervention (40%) or comparison (60%) groups. We studied a subset with whole-body dual-energy X-ray absorptiometry scans at baseline and during follow-up. Changes in fat mass (FM), lean mass (LM), and percentage body fat between the intervention (n = 1580) and comparison (n = 2731) groups at years 1, 3, and 6 were compared. By using generalized estimating equations, we calculated overall differences between groups and tested for interactions with age, diabetes, race-ethnicity (white, black, and Hispanic), body mass index (BMI), and hormone therapy (HT). Results: The intervention women experienced significantly greater reductions in percentage body fat, FM, and LM at years 1 and 3 than did women in the comparison group (all P < 0.05). At year 6, only the FM change was significantly different between groups. Overall, the intervention was associated with reductions in percentage body fat (−0.8%; 95% CI: −1.0%, −0.6%), FM (−1.1 kg; 95% CI: −1.3, −0.8 kg), and LM (−0.17 kg; 95% CI: −0.28, −0.06 kg) during follow-up (all P < 0.003). Intervention associations varied by race-ethnicity, BMI, diabetes, and HT and remained significant after adjustment for physical activity. Conclusion: This intervention was associated with modest long-term body-composition changes; the findings were more robust in years 1 and 3. This trial was registered at clinicaltrials.gov as {"type":"clinical-trial","attrs":{"text":"NCT00000611","term_id":"NCT00000611"}}NCT00000611.

Introduction: Low 25-hydroxyvitamin D (25(OH) D) concentrations have been associated with radiologic worsening of osteoarthritis in some reports. However, the results are mixed and few studies have evaluated associations between 25(OH) D concentrations and both total vitamin D intake and clinical joint symptoms. Study design: Cross-sectional analyses of information from a subset of 1993 postmenopausal women obtained at baseline entry in the Women’s Health Initiative Calcium plus Vitamin D clinical trial. Main Outcome Measures: 25(OH) D concentration, total vitamin D intake (diet plus supplements), presence and severity of joint pain and joint swelling. Results: The 25(OH) D levels were commonly low with 53% having deficient ( 72 nmol/L) levels. Joint pain (reported by 74%) and joint swelling (reported by 34%) were also commonly reported. 25(OH) D concentrations were modestly correlated with total vitamin D intake (R = 0.29, p < 0.0001); however, considerable variability in 25(OH) D concentrations for a given vitamin D intake was seen. In adjusted linear regression models, lower serum 25(OH) D concentrations were associated with higher average joint pain score (P = 0.01 for trend) with differences most apparent in the lowest 25(OH) D levels sextile. Conclusions: Relatively low 25(OH) D levels and a high frequency of joint symptoms were common in this population of postmenopausal women. Total vitamin D intake was only modestly associated with 25(OH) D. Low serum 25(OH) D concentrations were associated with higher joint pain scores. These findings can inform the design of future intervention trials. © 2010 Published by Elsevier Ireland Ltd.

Background: Fatty acids (FAs) may be important dietary components that modulate osteoporotic fracture risk. Objective: The objective was to examine FA intake in relation to osteoporotic fractures. Design: The participants were postmenopausal women enrolled in the Women's Health Initiative (n = 137,486). Total fractures were identified by self-report; hip fractures were confirmed by medical record review. FA intake was estimated from baseline food-frequency questionnaires and standardized to total caloric intake. No data on omega-3 (n−3) FA supplements were available. Cox proportional hazard models were constructed to estimate risk of fracture. Results: Higher saturated FA consumption was associated with higher hip fracture risk [quartile 4 multivariate-adjusted hazard ratio (HR): 1.31; 95% CI: 1.11, 1.55; P for trend = 0.001]. Lower total fracture risk was associated with a higher monounsaturated FA intake (quartile 3 HR: 0.94; 95% CI: 0.89, 0.98; P for trend = 0.050) and polyunsaturated FA intake (quartile 4 HR: 0.95; 95% CI: 0.90, 0.99; P for trend = 0.019). Unexpectedly, higher consumption of marine n−3 FAs was associated with greater total fracture risk (quartile 4 HR: 1.07; 95% CI: 1.02, 1.12; P for trend = 0.010), whereas a higher n−6 FA intake was associated with a lower total fracture risk (quartile 4 HR: 0.94; 95% CI: 0.89, 0.98; P for trend 0.009). Conclusions: These results suggest that saturated FA intake may significantly increase hip fracture risk, whereas monounsaturated and polyunsaturated FA intakes may decrease total fracture risk. In postmenopausal women with a low intake of marine n−3 FAs, a higher intake of n−6 FAs may modestly decrease total fracture risk. This trial was registered at clinicaltrials.gov as NCT00000611.

Background: A Mediterranean diet has been associated with a reduced risk of cardiovascular disease and mortality. A possible mechanism is through a decrease in lipid peroxidation (LPO); however, evidence linking the Mediterranean diet with lower LPO in premenopausal women is sparse. Objective: We investigated whether adherence to a Mediterranean diet was associated with lower LPO concentrations in premenopausal women. Design: Two hundred fifty-nine healthy women aged 18–44 y were followed for ≤2 menstrual cycles. Plasma concentrations of F2-isoprostane (8-iso-PGF2α), 9-hydroxyoctadecadieneoic acid (9-HODE), and thiobarbituric acid reactive substances (TBARS) were measured ≤8 times per cycle at visits scheduled by using fertility monitors. Diet was assessed ≤4 times per cycle by using 24-h dietary recalls. The alternate Mediterranean Diet Score (aMED) (range: 0–9) was calculated on the basis of intake of vegetables, legumes, fruit, nuts, whole grains, red and processed meat, fish, and alcohol and the ratio of monounsaturated to saturated fat. Results: A 1-unit increase in aMED was associated with a 4.50% decrease in 8-iso-PGF2α concentrations (95% CI: −6.32%, −2.65%) and a 14.01% decrease in 9-HODE concentrations (95% CI: −17.88%, −9.96%) after adjustment for energy intake, age, race, body mass index, plasma ascorbic acid, and serum cholesterol. No significant association was observed between aMED and TBARS. A 1-unit increase in aMED was associated with a 1.39% increase (95% CI: 0.07%, 2.72%) in plasma ascorbic acid concentrations. Conclusions: Adherence to a Mediterranean diet is associated with lower LPO and higher ascorbic acid concentrations. These results confirm that decreased LPO is a plausible mechanism linking a Mediterranean diet to reduced cardiovascular disease risk.

Background: It is unclear how well surrogate markers for vitamin D exposure (eg, oral intake of vitamin D and estimates of sunlight exposure), with and without consideration of other potential predictors of 25-hydroxyvitamin D [25(OH)D] concentrations, similarly rank individuals with respect to 25(OH)D blood concentrations. Objective: The objective was to determine how much variation in serum 25(OH)D concentrations (nmol/L) could be explained by a predictive model with the use of different vitamin D surrogate markers (latitude of residence, mean annual regional solar irradiance estimates, and oral sources) and other individual characteristics that might influence vitamin D status. Design: A random sample of 3055 postmenopausal women (aged 50–70 y) participating in 3 nested case-control studies of the Women's Health Initiative Calcium plus Vitamin D Clinical Trial was used. Serum 25(OH)D values, assessed at year 1 (1995–2000), and potential predictors of 25(OH)D concentrations, assessed at year 1 or Women's Health Initiative baseline (1993–1998), were used. Results: More than half of the women (57.1%) had deficient (

Background The immune and blood coagulation systems have been implicated in the pathophysiology of the geriatric syndrome of frailty, but limited prospective data examining the relationship of clotting/inflammation biomarkers to risk of incident frailty exist. Methods This prospective analysis was derived from a nested case-control study within the Women's Health Initiative. Among women 65 to 79 years free of frailty at enrollment, we randomly selected 900 incident cases from those developing frailty within 3 years; 900 non-frail controls were individually matched on age, ethnicity, and blood collection date. Biomarkers assessed for risk of incident frailty included fibrinogen, factor VIII, D-dimer, C-reactive protein, interleukin-6, and tissue plasminogen activator (t-PA). Results When examined by quartiles in multivariable adjusted models, higher D-dimer and t-PA levels were each associated with increased risk of frailty ( P trend=.04). Relative to the lowest quartile, the odds ratios for frailty compared with the upper quartile were 1.52 (95% confidence interval, 1.05-2.22) for t-PA and 1.57 (95% confidence interval, 1.11-2.22) for D-dimer. For women having high t-PA and high D-dimer compared with women having lower levels of both biomarkers, the odds of frailty was 2.20 (1.29-3.75). There was little evidence for association between coagulation factor VIII, fibrinogen, C-reactive protein, or interleukin-6 levels and incident frailty. Conclusion This prospective analysis supports the role of markers of fibrin turnover and fibrinolysis as independent predictors of incident frailty in postmenopausal women.

Background: The effects of dietary changes on osteoporosis, low bone density, and frequent falls are unestablished. Objective: We assessed the effect of the Women's Health Initiative Dietary Modification low-fat and increased fruit, vegetable, and grain intervention on incident hip, total, and site-specific fractures and self-reported falls, and, in a subset, on bone mineral density (BMD). Design: Postmenopausal women (n = 48,835) aged 50–79 y (18.6% of minority race-ethnicity) were randomly assigned to receive the Dietary Modification intervention (40%, n = 19,541) (daily goal: ≤20% of energy as fat, ≥5 servings of vegetables and fruit, and ≥6 servings of grains) or to a comparison group that received no dietary changes (60%; n = 29,294). Results: After a mean 8.1 y of follow-up, 215 women in the intervention group and 285 women in the comparison group (annualized rate: 0.14% and 0.12%, respectively) experienced a hip fracture (hazard ratio: 1.12; 95% CI: 0.94, 1.34; P = 0.21). The intervention group (n = 5423; annualized rate: 3.44%) had a lower rate of reporting ≥2 falls than did the comparison group (n = 8695; annualized rate: 3.67%) (HR: 0.92; 95% CI: 0.89, 0.96; P < 0.01). There was a significant interaction according to hormone therapy use; those in the comparison group receiving hormone therapy had the lowest incidence of hip fracture. In a subset of 3951 women, hip BMD at years 3, 6, and 9 was 0.4–0.5% lower in the intervention group than in the comparison group (P = 0.003). Conclusions: A low-fat and increased fruit, vegetable, and grain diet intervention modestly reduced the risk of multiple falls and slightly lowered hip BMD but did not change the risk of osteoporotic fractures. This trial was registered at clinicaltrials.gov as NCT00000611.

Purpose The Buffalo Cardio-Metabolic Occupational Police Stress (BCOPS) study is one of the first population-based studies to integrate psychological, physiological, and subclinical measures of stress, disease, and mental dysfunction. This pilot study was undertaken to establish a methodology and descriptive results for a larger police study. Methods A stratified sample of 100 officers was randomly selected from the Buffalo, NY Police Department. Salivary cortisol served as a stress biomarker. Flow mediated dilation (FMD) and carotid intima-media thickness (IMT) were performed with ultrasound. Dual Energy X-Ray Absorptiometry (DEXA) and anthropometric measures assessed body composition. Self-report measures of depression and posttraumatic stress disorder (PTSD) were obtained. Results Recruitment attained for the study was 100%. Seventy-five percent showed a cortisol increase upon awakening, 90% a negative diurnal slope, and 77% an increased cortisol response after a high protein lunch challenge. Dexamethasone suppression was evident. FMD showed an increase in mean brachial artery diameter of 3.2% in men and 3.9% in women, and mean IMT was lower (male = 0.67 mm; female = 0.62 mm) compared to populations of similar age. For males, the mean body-mass index (BMI) was 29.8 kg/m 2 and total body fat 23.4%. For females, the mean BMI was 26.7 kg/m 2 and total body fat 31.5%. For all officers, 16% met criteria for depression; 36% reported elevated PTSD symptoms. Conclusions Compared to populations of similar age, police officers had slightly lower FMD, lower carotid IMT, elevated BMI, and higher reported rates of depression and PTSD. Standardized physiological and psychological data collection and descriptive results confirmed that the methodology of the study is feasible in a working police population.

Objectives: Hormone oral contraceptives affected ascorbic acid status adversely in young women. In vitro, estrogens and progesterone inhibited ascorbic acid accumulation in intestinal cells. This is a pilot study to examine the relation between hormone replacement therapy (HRT) and plasma ascorbic acid levels among a group of healthy non-smoking postmenopausal women. Methods: Healthy non-smoking postmenopausal women aged 48–72 years, 34 with HRT and 21 without HRT, were recruited in summer, 1997. Their fasting plasma ascorbic acid levels were measured and information on ascorbic acid intakes (diet and supplements) was collected through questionnaires. Results: Women taking HRT in this study did not have significantly lower plasma ascorbic acid levels compared with non-HRT users. When subjects were further divided into groups based on ascorbic acid supplementation, HRT users without supplement had a lower mean plasma ascorbic acid level (54±16 μM, n=10) compared with non-HRT users (66±14 μM, n=12) (P=0.08 for the effect of therapy). HRT users and non-users taking ascorbic acid supplement had similar plasma levels (66±10 μM, n=24; 66±12 μM, n=9, respectively). Conclusion: HRT does not affect ascorbic acid status of healthy well-nourished non-smoking postmenopausal women that are using ascorbic acid supplement. Future larger case-control or supplement intervention study is needed.

The purpose of this study was to investigate the role of leptin on reproductive hormones and ovulation.The BioCycle Study (2005-2007) followed 259 healthy premenopausal women not using hormonal contraceptives for ≤2 menstrual cycles (n = 509 cycles). Serum leptin, estradiol, progesterone, luteinizing hormone (LH), follicle-stimulating hormone, and testosterone were measured ≤8 times per cycle. The association of time-varying leptin and reproductive hormones over the cycle was estimated with the use of linear mixed models that were adjusted for percent body fat and age with inverse probability weighting for time-varying physical activity, caloric intake, and other reproductive hormones. The odds ratio for sporadic anovulation (n = 42 cycles) was estimated with the use of generalized linear models that were adjusted for percent body fat and age.Geometric mean serum leptin levels increased from menses to the late luteal phase (16.7-20.4 ng/mL; P.01), with a mid-cycle peak (21.7 ng/mL) at the time of the LH surge (P.01). A 10% higher leptin level across the menstrual cycle was associated with higher estradiol levels (2.2%; 95% CI, 1.5-3.0), luteal progesterone levels (2.1%; 95% CI, 0.5-3.7), ovulatory LH levels (1.2%; 95% CI, 0-2.3), testosterone levels (0.6%; 95% CI, 0.3-0.9), and lower follicle-stimulating hormone levels (-0.7%; 95% CI, -1.1 to -0.4). Leptin at the time of the expected LH surge was moderately inversely associated with sporadic anovulation (per log increase in leptin; adjusted odds ratio, 0.58; 95% CI, 0.28-1.22).The association that was observed between leptin level and reproductive function points to a possible relationship between serum leptin level and enhanced fertility.