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BackgroundWhether greater leisure time physical activity (LTPA) is associated with less bone mineral density (BMD) loss during the menopause transition (MT) remains an open question. We hypothesized that: 1) larger increases in LTPA from pre-/early perimenopause (period 1) to late perimenopause/postmenopause (period 2) would be associated with a slower period 2 BMD loss rate; and 2) greater entire-study LTPA levels would be associated with better final absolute BMD (g/cm2).MethodsData were from of the Study of Women's Health Across the Nation (1996-2017). Exclusions were: bone beneficial medications, inability to identify start of the MT, and extreme BMD change rates. LTPA measures were a validated ordinal scale and number of metabolic equivalents per hour per week (MET hr wk-1) from sport/exercise. Multiply adjusted, linear regression models estimated: 1) BMD decline rate (annualized %) as a function of LTPA change; and 2) final BMD as a function of entire-study LTPA.FindingsMedian [p25, p75] MET hr wk-1 were 4.2 [0.9, 10.1] and 4.9 [1.4, 11.2] in periods 1 and 2, respectively; walking was the commonest activity. In adjusted models (N = 875), greater increases in LTPA ordinal score and MET hr wk-1 were statistically significantly associated with a slower decline in femoral neck (FN) BMD. Larger entire-study averages of each LTPA measure were statistically significantly related to better final FN and lumbar spine BMD levels.InterpretationFindings suggest that LTPA, at modest levels, mitigate MT-related BMD decline and even small increases in intensity, duration or frequency of common activities may lessen bone loss at the population level.FundingUS-NIH.

In pre- and early perimenopausal women, prediabetes (with blood glucose ≥ 110 mg/dL) and greater insulin resistance are associated with worse trabecular bone quality (as assessed by trabecular bone score).PurposeDiabetes mellitus (DM) is associated with lower trabecular bone score (TBS) and fracture; less certain is whether the precursor states of prediabetes and increased insulin resistance are also related to adverse bone outcomes. We examined, in women who do not have DM, the associations of glycemic status (prediabetes vs. normal) and insulin resistance with TBS.MethodsThis was a cross-sectional analysis of baseline data collected from 42- to 52-year-old, pre- and perimenopausal participants in the Study of Women's Health Across the Nation (SWAN) TBS Study. Women with prediabetes were categorized as having either high prediabetes if their fasting glucose was between 110 and 125 mg/dL or low prediabetes if their fasting glucose was between 100 and 109 mg/dL. Normoglycemia was defined as a fasting glucose below 100 mg/dL.ResultsIn multivariable linear regression, adjusted for age, race/ethnicity, menopause transition stage, cigarette use, calcium and vitamin D supplementation, lumbar spine bone mineral density, and study site, women with high prediabetes had 0.21 (p

PurposeWe compared trajectories of vasomotor symptoms (VMS) and their risk factors in women with breast cancer (BrCa) to those of cancer-free controls.MethodsData were from 15 nearly annual follow-up visits (1996-2017) of the multi-racial/ethnic cohort of midlife women enrolled in the Study of Women's Health Across the Nation (SWAN). We compared women with incident BrCa to controls for patterns of VMS, controlling for risk factors identified in bivariate analyses using multivariable longitudinal analyses.ResultsCharacteristics at study entry largely did not differ between cases (n = 151) and controls (n = 2161). Adjusted prevalence of any VMS increased significantly among cases from diagnosis to 2.75 years post diagnosis [per-year adjusted odds ratio (aOR) = 1.76, 95% confidence interval (CI) 1.39-2.24], peaking at 2.75 years post diagnosis, whereas prevalence was stable among controls in this interval [aOR = 1.04, 95% CI 0.99-1.11]. Beyond 2.75 years post diagnosis, prevalence declined significantly in cases [aOR = 0.72, 95% CI 0.61-0.84] and less in controls [aOR = 0.96, 95% CI 0.92-1.00]. Patterns were similar for frequent VMS. Adjustment for tamoxifen use slightly reduced the per-year OR for any prevalent VMS post diagnosis, partially explaining excess VMS in cases. Other treatments were unassociated with VMS.ConclusionsPatterns of prevalent VMS reporting differed significantly between cases and controls, particularly post diagnosis, the latter only partially explained by tamoxifen use among cases. Risk factors for VMS largely did not differ between cases and controls.

IntroductionCardiovascular risk factors in midlife have been linked to late life risk for Alzheimer's disease and related dementias (ADRD). The relation of vascular risk factors on cognitive decline within midlife has been less studied.MethodsUsing data from the Study of Women's Health Across the Nation, we examined associations of midlife hypertension, elevated lipid levels, diabetes, fasting glucose, central adiposity, and Framingham heart age with rates of cognitive decline in women who completed multiple cognitive assessments of processing speed, and working and verbal memory during midlife.ResultsDiabetes, elevated fasting glucose, central obesity, and heart age greater than chronological age were associated with rate of decline in processing speed during midlife. Vascular risk factors were not related to rate of decline in working or verbal memory.DiscussionMidlife may be a critical period for intervening on cardiovascular risk factors to prevent or delay later life cognitive impairment and ADRD.

ObjectiveThe menopausal transition is characterized by progressive changes in ovarian function and increasing circulating levels of gonadotropins, with some women having irregular menstrual cycles well before their final menstrual period. These observations indicate a progressive breakdown of the hypothalamic-pituitary-ovarian axis often associated with an increase in menopausal symptoms. Relationships between vasomotor symptoms (VMS) and depressed mood and sleep as well as a bidirectional association between VMS and depressed mood in mid-life women have been reported, but the endocrine foundations and hormone profiles associated with these symptoms have not been well described. Our objective was to determine the relationship between daily urinary hormone profiles and daily logs of affect and VMS during the early perimenopausal transition.Study designSWAN, the Study of Women's Health Across the Nation, is a large, mutli-ethnic, multisite cohort study of 3302 women aged 42-52 at baseline, designed to examine predictors of health and disease in women as they traversed the menopause. Inclusion criteria were: an intact uterus and at least one ovary present, at least one menstrual period in the previous three months, no use of sex steroid hormones in the previous three months, and not pregnant or lactating. A subset (n = 849) of women aged 43-53 years from all study sites in the first Daily Hormone Study collection were evaluated for this substudy.Outcome measuresWe measured daily VMS, and urinary hormones: follicle stimulating hormone (FSH), luteinizing hormone (LH), pregnanediol glucuronide (PdG) and estradiol (estrone conjugate, E1C).ResultsA variable pattern of LH and negative LH feedback were the hormone patterns most strongly associated with increased VMS. In contrast, no hormone pattern was significantly related to negative mood.ConclusionFluctuations of LH associated with low progesterone production were associated with VMS but not negative mood, suggesting different endocrine patterns may be related to increased negative mood than to the occurrence of VMS.

BACKGROUNDInflammation is implicated in many aging-related disorders. In animal models, menopause leads to increased gut permeability and inflammation. Our primary objective was to determine if gut permeability increases during the menopause transition (MT) in women. Our exploratory objectives were to examine whether greater gut permeability is associated with more inflammation and lower bone mineral density (BMD).METHODSWe included 65 women from the Study of Women's Health Across the Nation (SWAN). Key measures were markers of gut permeability (gut barrier dysfunction, fatty acid binding protein 2 [FABP2]) and immune activation secondary to gut microbial translocation (LPS binding protein [LBP], soluble CD14 [sCD14]), inflammation (high-sensitivity CRP), and lumbar spine (LS) or total hip (TH) BMD.RESULTSIn our primary analysis, FABP2, LBP, and sCD14 increased by 22.8% (P = 0.001), 3.7% (P = 0.05), and 8.9% (P = 0.0002), respectively, from pre- to postmenopause. In exploratory, repeated measures, mixed-effects linear regression (adjusted for BMI, age at the premenopausal visit, race/ethnicity, and study site), greater gut permeability was associated with greater inflammation, along with lower LS and TH BMD.CONCLUSIONGut permeability increases during the MT. Greater gut permeability is associated with more inflammation and lower BMD. Future studies should examine the longitudinal associations of gut permeability, inflammation, and BMD.FUNDINGFunding for this research was provided by NIH, Department of Health and Human Services, through the National Institute on Aging, National Institute of Nursing Research, and NIH Office of Research on Women's Health (U01NR004061, U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, and U01AG012495).

ObjectiveOur initial understanding of the menopause transition (MT) has been framed by clinical samples of women seeking treatment rather than by population-based studies. The Study of Women's Health Across the Nation (SWAN) initiated in 1996 with an overall goal to define the MT, to characterize its biological and psychosocial antecedents and sequelae in an ethnically and racially diverse sample of midlife women.MethodsThis review summarizes the central findings of SWAN to date that can inform women and their healthcare providers about the impact of the MT and midlife aging on overall health and well-being.ResultsSWAN characterized changes in reproductive axis and menstrual cycle patterns that informed the development of the reproductive aging staging system Staging of Reproductive Aging Workshop+10; MT-related symptoms and mental health (vasomotor symptoms, sleep complaints, psychological symptoms, cognitive performance, and urogenital and sexual health); and physiological systems and functions (cardiovascular and cardiometabolic health, bone health, physical function performance) that are influenced by the MT. SWAN demonstrated substantial interrelations among these changes and significant racial/ethnic differences in the rate and magnitude of change in multiple health indictors in midlife women. The findings point to midlife as a critical stage for adopting healthy behavior and preventive strategies.ConclusionsOver the past 23 years, SWAN has advanced our understanding of the impact of the MT and midlife aging on health and well-being in women. SWAN will be instrumental to determine whether MT-related changes during midlife are related to unfavorable health and well-being in early old age.

ObjectiveTo evaluate factors associated with incident self-reported vaginal dryness and the consequences of this symptom across the menopausal transition in a multiracial/ethnic cohort of community-dwelling women.MethodsWe analyzed questionnaire and biomarker data from baseline and 13 approximately annual visits over 17 years (1996-2013) from 2,435 participants in the Study of Women's Health Across the Nation, a prospective cohort study. We used discrete-time Cox proportional-hazards regression to identify predictors of incident vaginal dryness and to evaluate vaginal dryness as a predictor of pain during intercourse and changes in sexual intercourse frequency.ResultsThe prevalence of vaginal dryness increased from 19.4% among all women at baseline (ages 42-53 years) to 34.0% at the 13th visit (ages 57-69 years). Advancing menopausal stage, surgical menopause, anxiety, and being married were positively associated with developing vaginal dryness, regardless of partnered sexual activity. For women not using hormone therapy, higher concurrent levels of endogenous estradiol were inversely associated (multivariable-adjusted hazard ratio: 0.94 per 0.5 standard deviation increase, 95% confidence interval: 0.91-0.98). Concurrent testosterone levels, concurrent dehydroepiandrosterone sulfate levels, and longitudinal change in any reproductive hormone were not associated with developing vaginal dryness. Both vaginal dryness and lubricant use were associated with subsequent reporting of pain during intercourse, but not with a decline in intercourse frequency.ConclusionIn these longitudinal analyses, our data support many clinical observations about the relationship between vaginal dryness, menopause, and pain during intercourse, and suggest that reporting of vaginal dryness is not related to androgen level or sexual intercourse frequency.

ObjectiveThe aim of the study was to identify whether there is a decline in sexual functioning related to the menopausal transition or to hysterectomy.MethodsIn a cohort of 1,390 women aged 42 to 52, with intact uterus and at least one ovary, not using hormone therapy, and pre- or early perimenopausal at baseline, we fit piecewise linear growth curves to 5,798 repeated measurements (seven visits spanning 14.5 y) of a sexual functioning score (range, 5-25) as a function of time relative to date of final menstrual period (FMP) or hysterectomy.ResultsMean sexual functioning at baseline in women with a dateable FMP was 18.0 (SD, 3.4). There was no change in sexual function until 20 months before the FMP. From 20 months before until 1 year after the FMP, sexual function decreased by 0.35 annually (95% CI, -0.44 to -0.26) and continued to decline more than 1 year after the FMP, but at a slower rate (-0.13 annually, 95% CI, -0.17 to -0.10). The decline was smaller in African Americans and larger in Japanese than whites. Vaginal dryness, lubricant use, depressive symptoms, or anxiety did not explain decline in sexual function. Women who had a hysterectomy before the FMP did not show a decline in sexual function before hysterectomy, but scores declined afterward (0.21 annually, 95% CI, -0.28 to -0.14).ConclusionsDecline in sexual function became apparent 20 months before FMP and slowed 1 year after FMP through 5 years afterward. A decline in sexual function was observed immediately after hysterectomy and persisted for the 5 years of observation.

ObjectiveThe menopausal transition (MT) is a critical period associated with physiologic changes that influence women's long-term health and longevity. Information is, however, limited regarding factors that influence age at the onset of the MT and its duration (ie, time from MT onset to the final menstrual period).MethodsWe analyzed data for 1,145 women from four sites of the Study of Women's Health Across the Nation who participated in the menstrual calendar substudy, had the start of the MT identified, and had no missing covariate information. Participants included from four racial/ethnic groups: African American, white, Chinese, and Japanese. Women completed daily menstrual calendars from 1996 to 2006 and questions on hormone therapy use monthly. Baseline measures included education, economic strain, and menstrual cycle characteristics. Annual measures included height, weight, and smoking status. Cox proportional hazards models were used to analyze the data.ResultsThe adjusted median duration of the MT ranged from 4.37 years among the oldest age-at-onset quartile to 8.57 years among the youngest age-at-onset quartile (P

Context Collagen type I C-telopeptide (CTX) and procollagen type I N-terminal propeptide (PINP) are reference bone resorption and formation markers, respectively. Objective To characterize CTX and PINP trajectories across the menopause transition (MT). Methods This 18-year longitudinal analysis of a community-based cohort from the Study of Women's Health Across the Nation included 541 women (126 Black, 90 Chinese, 87 Japanese, 238 White) who transitioned from pre- to postmenopause. Multivariable mixed effects regression fit piecewise linear models of CTX or PINP relative to years from final menstrual period (FMP); covariates were race/ethnicity, body mass index (BMI), and age at FMP. In the referent participant (White, 52.46 years at FMP, BMI 27.12 kg/m2), CTX and PINP were stable until 3 years pre-FMP (premenopause). During the MT (3 years before to 3 years after the FMP), CTX and PINP increased 10.3% (P <.0001) and 7.5% (P <.0001) per year, respectively; MT-related gains totaled 61.9% for CTX and 45.2% for PINP. Starting 3 years post-FMP (postmenopause), CTX and PINP decreased 3.1% (P <.0001) and 2.9% (P <.0001) per year, respectively. Compared with the White participants, during the MT, Chinese participants had larger gains in CTX (P =.01), and Japanese women experienced greater increases in CTX (P <.0001) and PINP (P =.02). In postmenopause, CTX (P =.01) and PINP (P =.01) rose more in Japanese relative to White women. Conclusion CTX and PINP are stable in premenopause, increase during the MT, and decrease in postmenopause. During the MT and postmenopause, bone turnover change rates vary by race/ethnicity. [ABSTRACT FROM AUTHOR]

BackgroundStudies have reported associations between long-term air pollution exposures and cardiovascular mortality. The biological mechanisms connecting them remain uncertain.MethodsWe examined associations of fine particles (PM2.5) and ozone with serum markers of cardiovascular disease risk in a cohort of midlife women. We obtained information from women enrolled at six sites in the multi-ethnic, longitudinal Study of Women's Health Across the Nation, including repeated measurements of high-sensitivity C-reactive protein, fibrinogen, tissue-type plasminogen activator antigen, plasminogen activator inhibitor type 1, and factor VIIc (factor VII coagulant activity). We obtained residence-proximate PM2.5 and ozone monitoring data for a maximum five annual visits, calculating prior year, 6-month, 1-month, and 1-day exposures and their relations to serum markers using longitudinal mixed models.ResultsFor the 2,086 women studied from 1999 to 2004, PM2.5 exposures were associated with all blood markers except factor VIIc after adjusting for age, race/ethnicity, education, site, body mass index, smoking, and recent alcohol use. Adjusted associations were strongest for prior year exposures for high-sensitivity C-reactive protein (21% increase per 10 μg/m³ PM2.5, 95% confidence interval [CI]: 6.6, 37), tissue-type plasminogen activator antigen (8.6%, 95% CI: 1.8, 16), and plasminogen activator inhibitor (35%, 95% CI: 19, 53). An association was also observed between year prior ozone exposure and factor VIIc (5.7% increase per 10 ppb ozone, 95% CI: 2.9, 8.5).ConclusionsOur findings suggest that prior year exposures to PM2.5 and ozone are associated with adverse effects on inflammatory and hemostatic pathways for cardiovascular outcomes in midlife women.

ObjectivesThis research sought to assess racial and socioeconomic status (SES) differences in level and change in allostatic load (AL) over time in midlife women and to test whether psychosocial factors mediate these relationships. These factors were discrimination, perceived stress, and hostility.MethodsLongitudinal data obtained from the Study of Women's Health Across the Nation were used (n = 2063; mean age at baseline = 46.0 years). Latent growth curve models evaluated the impact of demographic, menopausal, and psychosocial variables on level and change in AL for 8 years.ResultsDirect effects: high levels of discrimination and hostility significantly predicted higher AL (path coefficients = 0.05 and 0.05, respectively). High perceived stress significantly predicted a faster rate of increase of AL (path coefficient = 0.06). Racial and SES differentials were present, with African American race (path coefficient = 0.23), low income (path coefficient = -0.15), and low education (path coefficient = -0.08) significantly predicting high AL level. Indirect effects: significant indirect effects were found for African American race, less income, and lower education through higher discrimination, perceived stress, and hostility on level and rate of AL.ConclusionsThis was one of the first studies that investigated AL over multiple periods, and results supported AL as a cumulative phenomenon, affected by multiple psychosocial and demographic factors. The results suggest the complex ways in which race, SES, and psychosocial factors operate to influence AL.

Our objective was to examine the associations of lifetime parity and accumulated length of lactation with bone strength in women prior to the menopause transition and fracture risk during and after the transition. Participants were 2239 pre- or early peri-menopausal women from the Study of Women's Health Across the Nation (SWAN), ages 42-53 years at baseline, who had no childbirths after age 42. Bone mineral density (BMD) was measured in the femoral neck and the lumbar spine at the baseline SWAN visit using dual-energy x-ray absorptiometry, and the composite indices of femoral neck strength relative to load (in three failure modes: compression, bending, and impact) were calculated from femoral neck BMD, femoral neck size, and body size. Data on fractures after age 42 were collected for a median follow-up of 15.7 years (interquartile range, 11.4-18.5 years). In multiple linear regressions adjusted for covariates, lifetime parity was associated positively with femoral neck strength relative to load (0.024 standard deviation (SD) increment in impact strength index per childbirth, p=0.049), but accumulated length of lactation was associated negatively with lumbar spine BMD (0.018 SD decrement per every additional 6 months of lactation, p=0.040). In Cox proportional hazards regressions adjusted for covariates, neither parity nor lactation was associated with fracture hazard after age 42. In conclusion, parity and lactation have little impact on peak bone strength prior to menopause, and do not affect fracture risk after age 42 over 16-year follow-up.

ObjectiveThis study aims to examine cross-sectional and longitudinal relations between dietary intake of isoflavones and bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN) in black, white, Chinese, and Japanese women during the menopausal transition.MethodsWe tested whether tertiles of isoflavone intake were associated with baseline BMD when all women were premenopausal or early perimenopausal. To analyze whether isoflavone intake was associated with longitudinal BMD, we fitted piecewise linear models to repeated measurements of baseline-normalized LS or FN BMD as functions of time before or after the final menstrual period (FMP) date.ResultsMultiply adjusted mean FN BMD values of premenopausal Japanese women were monotonically positively related to isoflavone consumption (P for trend = 0.0003). Otherwise, no statistically significant baseline associations were observed. During the period of 1 year before the FMP through 5 years after the FMP, all participants lost LS and FN BMD. Loss was unrelated to isoflavone intake, except for Japanese women during the period of 1 year before the FMP to 2 years after the FMP: higher tertiles of isoflavone intake were associated with greater annual LS BMD loss rates (P for trend = 0.01) and FN loss rates (P for trend = 0.04).ConclusionsIn Japanese women, higher isoflavone intake is associated with higher peak FN BMD but also with greater rates of LS and FN BMD loss during the menopausal transition. Results for the other racial/ethnic groups did not support a relation between dietary intake of isoflavones and either peak BMD or BMD loss during the menopausal transition.

ObjectiveFew studies have evaluated factors that influence menstrual cycle length (MCL) during the menopausal transition (MT), a life stage during which very long cycles become more likely to occur. The objective of this article was to assess how body mass index and race/ethnicity--factors associated with MCL in young women--influence MCL during the MT.MethodsStudy of Women's Health Across the Nation menstrual calendar substudy data of African-American, white, Chinese, and Japanese women were available for three sites (southeastern Michigan, Los Angeles, and northern California). Self-recorded monthly menstrual calendars with end-of-the-month questions on hormone therapy use and smoking were collected from 1996 to 2006. Height and weight were measured at annual study visits. We used quantile regression to model MCL at the 25th, 50th, 75th, and 90th percentiles with bootstrap sampling to construct 95% CIs. Models evaluated MCL with time indexed to the start of the MT (n = 963) and to the final menstrual period (n = 431).ResultsDuring the MT, increases in MCL occurred mostly at the right tail of the distribution, reflecting a lengthening of long menstrual cycles, not of the median MCL. After adjustment for smoking, education, physical activity, and time, Chinese and Japanese women had 1 day to 6 days longer MCLs compared with white women. Obese women had 1 day to 5 days longer MCLs compared with nonobese women.ConclusionsAs occurs in younger women, menstrual characteristics during the MT are influenced by race/ethnicity and obesity. The long menstrual cycles characteristic of the MT are longer in obese women and in Chinese and Japanese women.

Proton pump inhibitors (PPIs) have been associated with diminished bone mineral density (BMD) and an increased risk of fracture; however, prior studies have not yielded consistent results, and many have suboptimal ascertainment of both PPI use and BMD. We used data from the Study of Women's Health Across the Nation (SWAN), a multicenter, multi-ethnic, community-based longitudinal cohort study of women across the menopause transition to examine the association between annualized BMD changes and new use of PPIs. We compared changes in BMD in new PPI users with changes in BMD in new users of histamine 2 receptor antagonists (H2RAs) and with changes in BMD in subjects who did not use either class of medications. Mixed linear regression models included recognized risk factors for osteoporosis, including demographics, menopausal transition stage, body mass index (BMI), lifestyle factors, as well as comorbidities and concomitant medications. To provide further evidence for the validity of our analytic approach, we also examined the effects of hormone-replacement therapy (HT), a class of medications that should reduce bone loss, on changes in BMD as an internal positive control group. We identified 207 new users of PPIs, 185 new users of H2RAs, and 1,676 non-users. Study subjects had a mean age of 50 years and were followed for a median of 9.9 years. Adjusted models found no difference in the annualized BMD change at the lumbar spine, femoral neck, or total hip in PPI users compared with H2RA users or non-users. These results were robust to sensitivity analyses. BMD increased as expected in HT users, supporting the validity of our study design. These longitudinal analyses plus similar prior studies argue against an association between PPI use and BMD loss.

Some aspects of an obese body habitus may protect against fracture risk (higher bone mineral density [BMD] and greater tissue padding), while others may augment that risk (greater impact forces during a fall). To examine these competing pathways, we analyzed data from a multisite, multiethnic cohort of 1924 women, premenopausal or early perimenopausal at baseline. Obesity was defined as baseline body mass index (BMI) > 30 kg/m(2) . Composite indices of femoral neck strength relative to fall impact forces were constructed from DXA-derived bone size, BMD and body size. Incident fractures were ascertained annually during a median follow-up of 9 years. In multivariable linear regression adjusted for covariates, higher BMI was associated with higher BMD but with lower composite strength indices, suggesting that although BMD increases with greater skeletal loading, the increase is not sufficient to compensate for the increase in fall impact forces. During the follow-up, 201 women had fractures. In Cox proportional hazard analyses, obesity was associated with increased fracture hazard adjusted for BMD, consistent with greater fall impact forces in obese individuals. Adjusted for composite indices of femoral neck strength relative to fall impact forces, obesity was associated with decreased fracture hazard, consistent with a protective effect of soft tissue padding. Further adjustment for hip circumference, a surrogate marker of soft tissue padding, attenuated the obesity-fracture association. Our findings support that there are at least three major mechanisms by which obesity influences fracture risk: increased BMD in response to greater skeletal loading, increased impact forces, and greater absorption of impact forces by soft tissue padding.

BackgroundSeveral cohort studies report associations between chronic exposure to ambient fine particles (PM2.5) and cardiovascular mortality. Uncertainty exists about biological mechanisms responsible for this observation, but systemic inflammation has been postulated. In addition, the subgroups susceptible to inflammation have not been fully elucidated.MethodsWe investigated whether certain subgroups are susceptible to the effects of long-term exposure to PM2.5 on C-reactive protein (CRP), a marker of inflammation directly linked to subsequent cardiovascular disease. We used data from the SWAN cohort of 1923 mid-life women with up to five annual repeated measures of CRP. Linear mixed and GEE models accounting for repeated measurements within an individual were used to estimate the effects of prior-year PM2.5 exposure on CRP. We examined CRP as a continuous and as binary outcome for CRP greater than 3mg/l, a level of clinical significance.ResultsWe found strong associations between PM2.5 and CRP among several subgroups. For example a 10 µg/m(3) increase in annual PM2.5 more than doubled the risk of CRP greater than 3mg/l in older diabetics, smokers and the unmarried. Larger effects were also observed among those with low income, high blood pressure, or who were using hormone therapy, with indications of a protective effects for those using statins or consuming moderate amounts of alcohol.ConclusionsIn this study, we observed significant associations between long-term exposure to PM2.5 and CRP in several susceptible subgroups. This suggests a plausible pathway by which exposure to particulate matter may be associated with increased risk of cardiovascular disease.

BackgroundYoga is a popular mind-body therapy that has demonstrated beneficial effects on psychological, behavioral, and functional outcomes. However, few studies have investigated effects on inflammatory processes. This study tested the hypothesis that an Iyengar yoga intervention specifically designed for fatigued breast cancer survivors would lead to decreases in inflammation-related gene expression and circulating markers of proinflammatory cytokine activity.MethodsBreast cancer survivors with persistent cancer-related fatigue were randomized to a 12-week Iyengar yoga intervention (n=16) or a 12-week health education control condition (n=15). Blood samples were collected at baseline, post-intervention, and at a 3-month follow-up for genome-wide transcriptional profiling and bioinformatic analyses. Plasma inflammatory markers and salivary cortisol were also assessed.ResultsIn promoter-based bioinformatics analyses, the yoga group showed reduced activity of the pro-inflammatory transcription factor nuclear factor kappa B (NF-κB), increased activity of the anti-inflammatory glucocorticoid receptor, and reduced activity of cAMP response element-binding protein (CREB) family transcription factors relative to controls (all ps

Abstract Background The number of older adults participating in yoga has increased dramatically in recent years; yet, the physical demands associated with yoga performance have not been reported. The primary aim of the Yoga Empowers Seniors Study (YESS) was to use biomechanical methods to quantify the physical demands associated with the performance of 7 commonly-practiced standing yoga poses in older adults. Methods 20 ambulatory older adults (70.7 + − 3.8 yrs) attended 2 weekly 60-minute Hatha yoga classes for 32 weeks. The lower-extremity net joint moments of force (JMOFs), were obtained during the performance of the following poses: Chair, Wall Plank, Tree, Warrior II, Side Stretch, Crescent, and One-Legged Balance. Repeated-measure ANOVA and Tukey’s post-hoc tests were used to identify differences in JMOFs among the poses. Electromyographic analysis was used to support the JMOF findings. Results There was a significant main effect for pose, at the ankle, knee and hip, in the frontal and sagittal planes (p = 0.00 – 0.03). The Crescent, Chair, Warrior II, and One-legged Balance poses generated the greatest average support moments. Side Stretch generated the greatest average hip extensor and knee flexor JMOFs. Crescent placed the highest demands on the hip flexors and knee extensors. All of the poses produced ankle plantar-flexor JMOFs. In the frontal plane, the Tree generated the greatest average hip and knee abductor JMOFs; whereas Warrior II generated the greatest average hip and knee adductor JMOFs. Warrior II and One-legged Balance induced the largest average ankle evertor and invertor JMOFs, respectively. The electromyographic findings were consistent with the JMOF results. Conclusions Musculoskeletal demand varied significantly across the different poses. These findings may be used to guide the design of evidence-based yoga interventions that address individual-specific training and rehabilitation goals in seniors. Clinical trial registration This study is registered with NIH Clinicaltrials.gov #NCT 01411059

The opposing carcinogenic and antiestrogenic properties of tobacco smoke may explain why epidemiologic studies have not consistently reported positive associations for active smoking and breast cancer risk. A negative relation between mammographic density, a strong breast cancer risk factor, and active smoking would lend support for an antiestrogenic mechanism.We used multivariable linear regression to assess the associations of active smoking and secondhand smoke (SHS) exposure with mammographic density in 799 pre- and early perimenopausal women in the Study of Women’s Health Across the Nation (SWAN).We observed that current active smoking was associated with 7.2% lower mammographic density, compared to never active smoking and no SHS exposure (p = 0.02). Starting to smoke before 18 years of age and having smoked ≥20 cigarettes/day were also associated with statistically significantly lower percent densities. Among nulliparous women having smoked ≥20 cigarettes/day was associated with 23.8% lower density, compared to having smoked ≤9 cigarettes/day (p

Abstract Introduction We examined the association between mammographic density and single-nucleotide polymorphisms (SNPs) in genes encoding CYP1A1, CYP1B1, aromatase, 17β-HSD, ESR1, and ESR2 in pre- and early perimenopausal white, African-American, Chinese, and Japanese women. Methods The Study of Women's Health Across the Nation is a longitudinal community-based cohort study. We analyzed data from 451 pre- and early perimenopausal participants of the ancillary SWAN Mammographic Density study for whom we had complete information regarding mammographic density, genotypes, and covariates. With multivariate linear regression, we examined the relation between percentage mammographic breast density (outcome) and each SNP (primary predictor), adjusting for age, race/ethnicity, parity, cigarette smoking, and body mass index (BMI). Results After multivariate adjustment, the CYP1B1 rs162555 CC genotype was associated with a 9.4% higher mammographic density than the TC/TT genotype (P = 0.04). The CYP19A1 rs936306 TT genotype was associated with 6.2% lower mammographic density than the TC/CC genotype (P = 0.02). The positive association between CYP1A1 rs2606345 and mammographic density was significantly stronger among participants with BMI greater than 30 kg/m2 than among those with BMI less than 25 kg/m2 (Pinteraction = 0.05). Among white participants, the ESR1 rs2234693 CC genotype was associated with a 7.0% higher mammographic density than the CT/TT genotype (P = 0.01). Conclusions SNPs in certain genes encoding sex steroid metabolism enzymes and ESRs were associated with mammographic density. Because the encoded enzymes and ESR1 are expressed in breast tissue, these SNPs may influence breast cancer risk by altering mammographic density.

Single nucleotide polymorphism (SNP) genotype frequencies were examined to determine whether variation in 6 estrogen-related genes was associated with differences in cognitive functioning in women at midlife. DNA from a multiracial/multiethnic sample of 875 African American, Caucasian, Chinese, and Japanese women aged 45 to 56 years participating in the Study of Women’s Health Across the Nation (SWAN) was genotyped. Gene markers from the sex steroid hormone pathway were linked to measures of cognitive functioning including the Digit Span Backward Test (DSB), a measure of working memory; the Symbol Digit Modalities Test (SDMT), a measure of perceptual speed; and the East Boston Memory Test (EBMT), a measure of episodic memory. Statistical models were fit using logistic regression and general linear models to estimate the strength of association of estrogen-related polymorphisms with DSB, SDMT, and EBMT scores. On the EBMT, African American women and Caucasian women with ESR1 rs9340799 GG genotypes had about 1.5 to 2.0 times greater odds of remembering story elements on the EBMT-immediate recall test. Caucasian women with ESR1 rs2234693 CC genotypes had 1.3 to 1.5 times greater odds of remembering story elements on the EBMTdelayed recall test. Chinese women with 17HSD rs615942 GG genotypes, 17HSD rs592389 TT genotypes, and 17HSD rs2830 GG genotypes had about 1.7 times greater odds of remembering story elements on the EBMT-immediate recall test. African American women with CYP 19 rs936306 CC genotypes had about 0.25 to 0.40 lower odds of remembering story elements on the EBMT-immediate recall test, whereas Chinese women with CYP 19 rs936306 CC genotypes had about 2.3 times greater odds of remembering story elements on both the EBMT-immediate and -delayed recall tests. On the DSB, African American women with CYP 19 rs749292 GG genotype had a higher mean score. On the SDMT, Japanese women with ESR1 rs728524 GG genotypes had a higher mean score. On the 3 tests of cognitive functioning, there was 1 significant finding for CYP1A1 and none for the YP1B1 or ESR2 SNPs. We conclude that selected genes involved in estrogen synthesis and metabolism may be associated with performance differences on cognitive function tests. Also, the relevant estrogen-related polymorphisms may vary by race/ethnicity.

OBJECTIVES: We investigated whether vasomotor symptom reporting or patterns of change in symptom reporting over the perimenopausal transition among women enrolled in a national study differed according to race/ethnicity. We also sought to determine whether racial/ethnic differences were explained by sociodemographic, health, or lifestyle factors. METHODS: We followed 3198 women enrolled in the Study of Women's Health Across the Nation during 1996 through 2002. We analyzed frequency of vasomotor symptom reporting using longitudinal multiple logistic regressions. RESULTS: Rates of vasomotor symptom reporting were highest among African Americans (adjusted odds ratio [OR]=1.63; 95% confidence interval [CI]=1.21, 2.20). The transition to late perimenopause exhibited the strongest association with vasomotor symptoms (adjusted OR = 6.64; 95% CI = 4.80, 9.20). Other risk factors were age (adjusted OR=1.17; 95% CI=1.13, 1.21), having less than a college education (adjusted OR = 1.91; 95% CI = 1.40, 2.61), increasing body mass index (adjusted OR=1.03 per unit of increase; 95% CI=1.01, 1.04), smoking (adjusted OR=1.63; 95% CI=1.25, 2.12), and anxiety symptoms at baseline (adjusted OR=3.10; 95% CI=2.33, 4.12). CONCLUSIONS: Among the risk factors assessed, vasomotor symptoms were most strongly associated with menopausal status. After adjustment for covariates, symptoms were reported most often in all racial/ethnic groups in late perimenopause and nearly as often in postmenopause.

To examine the combined influence of alcohol use and comorbidity on 20-year mortality in older adults (average age 66 at the time of the baseline survey). DESIGN: Longitudinal analysis of a national probability sample-based cohort study. SETTING: Data sources were the National Health and Nutrition Examination Survey I (NHANES I), 1971-1974, and the NHANES Epidemiologic Followup Survey, 1992. PARTICIPANTS: Four thousand six hundred ninety-one adults aged 60 and older who provided data on alcohol use. MEASUREMENTS: The prevalence of at-risk drinking in older adults in the United States and the 20-year all-cause mortality risk associated with it. At-risk drinking status was determined from amount of alcohol consumed and comorbidities, using a previously validated method. RESULTS: The prevalence of at-risk drinking in the United States between 1971 and 1974 in older adults was 10% (18% of men, 5% of women). The majority of at-risk drinkers were identified as such because of their use of alcohol in amounts deemed risky in the presence of relevant comorbidities (69%) (e.g., drinking 2-3 drinks per day and having gout or anxiety or taking a medication for pain). In men, at-risk drinking was associated with higher mortality rates than not-at-risk drinking (hazard ratio=1.20, 95% confidence interval=1.01-1.41); abstinence was not associated with greater mortality. In women, neither abstinence nor at-risk drinking was associated with greater mortality rates. CONCLUSION: In this first, large population-based study of older adults examining the mortality risks of alcohol use and comorbidity, at-risk drinking was associated with greater mortality rates in men. These findings suggest that a lower threshold of alcohol use should be recommended for older adults with specific comorbidities to reduce mortality risks.

Vitamin D (25(OH)D) increases the efficiency of intestinal calcium absorption. Low levels of serum calcium stimulate the secretion of parathyroid hormone (PTH), which maintains serum calcium levels at the expense of increased bone turnover, bone loss and increased risk of fractures. We studied the association between 25(OH)D and PTH levels, and their associations with bone mineral density (BMD), bone loss, and prevalence of hip fractures in 615 community-dwelling postmenopausal aged 50 - 97 years. Mean level of 25(OH)D and PTH were 102.0 nmol/l +/- 35.0 nmol/l and 49.4 ng/l +/- 23.2 nmol/l, respectively; 49% of women were current hormone therapy users. The overall prevalence of vitamin D insuficiency (25(OH) 65 ng/l) was 17.4%. In multiple linear regression analyses hip BMD was negatively and independently associated with PTH levels (p = 0.04), and positively and independently associated with 25(OH)D levels (p = 0.03). There were only 23 women (3.7%) who experienced a hip fracture. In age-adjusted analyses there were no signifcant differences of 25(OH)D and PTH levels by hip fracture status. Across the entire range of values, the overall correlation between 25(OH)D and PTH was moderate (r = -0.20). However, after the threshold vitamin D level of 120 nmol/l, all PTH values were below 65 ng/l. Further studies are necessary to identify the optimal vitamin D levels necessary to prevent secondary hyperparathyroidism.

Introduction Mammographic breast density is a strong independent risk factor for breast cancer. We hypothesized that demonstration of an association between mammographic breast density and bone mineral density (BMD) would suggest a unifying underlying mechanism influencing both breast density and BMD. Methods In a cross-sectional analysis of baseline data from the Postmenopausal Estrogen/Progestin Interventions Study (PEPI), participants were aged 45 to 64 years and were at least 1 year postmenopausal. Mammographic breast density ( percentage of the breast composed of dense tissue), the outcome, was assessed with a computer-assisted percentage-density method. BMD, the primary predictor, was measured with dual-energy X-ray absorptiometry. Women quitting menopausal hormone therapy to join PEPI were designated recent hormone users. Results The mean age of the 594 women was 56 years. The average time since menopause was 5.6 years. After adjustment for age, body mass index, and cigarette smoking, in women who were not recent hormone users before trial enrollment ( n = 415), mammographic density was positively associated with total hip ( P = 0.04) and lumbar ( P = 0.08) BMD. Mammographic density of recent hormone users ( n = 171) was not significantly related to either total hip ( P = 0.51) or lumbar ( P = 0.44) BMD. In participants who were not recent hormone users, mammographic density was 4% greater in the highest quartile of total hip BMD than in the lowest. In participants who were not recent hormone users, mammographic density was 5% greater in the highest quartile of lumbar spine BMD than in the lowest. Conclusion Mammographic density and BMD are positively associated in women who have not recently used postmenopausal hormones. A unifying biological mechanism may link mammographic density and BMD. Recent exogenous postmenopausal hormone use may obscure the association between mammographic density and BMD by having a persistent effect on breast tissue.