Relationships of depression and antidepressant use with epigenetic age acceleration and all-cause mortality among postmenopausal women.

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

Psychotropic medication use and Parkinson's disease risk amongst older women.

OBJECTIVE: To examine associations of antidepressant, anxiolytic and hypnotic use amongst older women (≥65 years) with incident Parkinson's Disease (PD), using data from Women's Health Initiative linked to Medicare claims. METHODS: PD was defined using self-report, first diagnosis, medications and/or death certificates and psychotropic medications were ascertained at baseline and 3-year follow-up. Cox regression models were constructed to calculate adjusted hazard ratios (aHR) with 95% confidence intervals (CI), controlling for socio-demographic, lifestyle and health characteristics, overall and amongst women diagnosed with depression, anxiety and/or sleep disorders (DASD). RESULTS: A total of 53,996 WHI participants (1,756 PD cases)-including 27,631 women diagnosed with DASD (1,137 PD cases)-were followed up for ~14 years. Use of hypnotics was not significantly associated with PD risk (aHR = 0.98, 95% CI: 0.82, 1.16), whereas PD risk was increased amongst users of antidepressants (aHR = 1.75, 95% CI: 1.56, 1.96) and anxiolytics (aHR = 1.48, 95% CI: 1.25, 1.73). Compared to non-users of psychotropic medications, those who used 1 type had ~50% higher PD risk, whereas those who used ≥2 types had ~150% higher PD risk. Women who experienced transitions in psychotropic medication use ('use to non-use' or 'non-use to use') between baseline and 3-year follow-up had higher PD risk than those who did not. We obtained similar results with propensity scoring and amongst DASD-diagnosed women. INTERPRETATION: The use of antidepressants, anxiolytics or multiple psychotropic medication types and transitions in psychotropic medication use was associated with increased PD risk, whereas the use of hypnotics was not associated with PD risk amongst older women.

Association of sleep disturbance with Parkinson disease: evidence from the Women's Health Initiative.

OBJECTIVE: To examine the association of sleep disturbance with Parkinson disease (PD) during 10+ years of follow-up among postmenopausal women, 50 to 79 years of age at baseline. METHODS: Longitudinal data on 130,502 study-eligible women (mean ± standard deviation baseline age = 63.16 ±â€Š7.20 y) from the Women's Health Initiative Clinical Trials and Women's Health Initiative Observational Study were analyzed. The cohort was followed for 15.88 ±â€Š6.50 years, yielding 2,829 (2.17%) PD cases. Sleep disturbance (habitual sleep duration, insomnia symptoms, obstructive sleep apnea risk factors, sleep aids among those with WHI Insomnia Rating Scale scores (WHIIRS) > 9) was measured at baseline and one follow-up time by September 12, 2005. Cox proportional hazards models evaluated relationships controlling for sociodemographic, lifestyle, and health characteristics. RESULTS: PD was significantly associated with long sleep duration (≥9 h) versus a benchmark of 7 to 8 hours (hazard ratio [HR] = 1.296, 95% confidence interval [CI]: 1.153-1.456), WHIIRS (>9 vs ≤9) (HR = 1.114, 95% CI:1.023-1.214), and use of sleep aids (yes vs no) (HR = 1.332, 95% CI:1.153-1.539) among those with WHIIRS > 9. Compared with 7 to 8 hours, short (<7 h) sleep duration was unrelated to PD. Finally, the presence of obstructive sleep apnea risk factors was not associated with PD. CONCLUSIONS: Among postmenopausal women, sleep disturbance was associated with approximately 10% to 30% increased PD risk after ∼16 years follow-up. Prospective cohort studies with objective exposures and adjudicated outcomes that include men and women of diverse backgrounds are required to confirm and extend these findings.

Associations of parental ages at childbirth with healthy aging among women.

OBJECTIVE: To examine associations of parental ages at childbirth with healthy survival to age 90 years among older women. STUDY DESIGN: This study included a racially and ethnically diverse sub-cohort of 8,983 postmenopausal women from the larger Women's Health Initiative population, recruited during 1993-1998 and followed for up to 25 years through 2018. MAIN OUTCOME MEASURES: The outcome was categorized as: 1) healthy survival, defined as survival to age 90 without major morbidities (coronary heart disease, stroke, diabetes, cancer, or hip fracture) or mobility disability; 2) usual survival, defined as survival to age 90 without healthy aging (reference category); or 3) death before age 90. Women reported their own and their parents' birth years, and parental ages at childbirth were calculated and categorized as <25, 25-29, 30-34, or ≥35 years. RESULTS: Women were aged on average 71.3 (standard deviation 2.7; range 65-79) years at baseline. There was no significant association of maternal age at childbirth with healthy survival to age 90 or death before age 90. Women born to fathers aged ≥35 compared with 30-34 years at their births were more likely to achieve healthy than usual survival (OR, 1.15; 95% CI, 1.00-1.32). There was no association of paternal age at childbirth with death before age 90. CONCLUSIONS: Findings suggest that being born to older fathers was associated with healthy survival to age 90 among women who had survived to ages 65-79 years at study baseline. There was no association of maternal age at childbirth with healthy survival to age 90 among these older women.

Psychological Traits, Heart Rate Variability, and Risk of Coronary Heart Disease in Healthy Aging Women-The Women's Health Initiative.

OBJECTIVE: Psychological traits such as optimism and hostility affect coronary heart disease (CHD) risk, but mechanisms for this association are unclear. We hypothesized that optimism and hostility may affect CHD risk via changes in heart rate variability (HRV). METHODS: We conducted a longitudinal analysis using data from the Women's Health Initiative Myocardial Ischemia and Migraine Study. Participants underwent 24-hour ambulatory electrocardiogram monitoring 3 years after enrollment. Optimism (Life Orientation Test-Revised), cynical hostility (Cook-Medley), demographics, and coronary risk factors were assessed at baseline. HRV measures included standard deviation of average N-N intervals (SDNN); standard deviation of average N-N intervals for 5 minutes (SDANN); and average heart rate (HR). CHD was defined as the first occurrence of myocardial infarction, angina, coronary angioplasty, and bypass grafting. Linear and Cox regression models adjusted for CHD risk factors were used to examine, respectively, associations between optimism, hostility, and HRV and between HRV and CHD risk. RESULTS: Final analyses included 2655 women. Although optimism was not associated with HRV, hostility was inversely associated with HRV 3 years later (SDANN: adjusted ß = -0.54; 95% CI = -0.97 to -0.11; SDNN: -0.49; 95% CI = -0.93 to -0.05). HRV was inversely associated with CHD risk; for each 10-millisecond increase in SDNN or SDANN, there was a decrease in CHD risk of 9% (p = .023) and 12% (p = .006), respectively. CONCLUSIONS: HRV did not play a major role in explaining why more optimistic women seem to be somewhat protected from CHD risk. Although hostility was inversely associated with HRV, its role in explaining the association between hostility and CHD risk remains to be established.

Parental longevity predicts healthy ageing among women.

Objective: to examine the association of parental longevity with healthy survival to age 90 years. Methods: this was a prospective study among a racially and ethnically diverse cohort of 22,735 postmenopausal women from the Women's Health Initiative recruited from 1993 to 1998 and followed through 2017. Women reported maternal and paternal ages at death and current age of alive parents. Parental survival categories were <70, 70-79 (reference), 80-89 and ≥90 years (longevity). Healthy ageing was defined as reaching age 90 without major chronic conditions (coronary heart disease, stroke, diabetes, cancer, or hip fracture) or physical limitations. Results: women whose mothers survived to ≥90 years were more likely to attain healthy ageing (OR, 1.25; 95% CI, 1.11-1.42) and less likely to die before age 90 (OR, 0.75; 95% CI, 0.68-0.83). Women whose fathers survived to ≥90 years did not have significantly increased odds of healthy ageing but showed 21% (OR, 0.79; 95% CI, 0.70-0.90) decreased odds of death before age 90. Women whose mother and father both lived to 90 had the strongest odds of healthy ageing (OR, 1.38; 95% CI, 1.09-1.75) and decreased odds of death (OR, 0.68; 95% CI, 0.54-0.85). The proportion of healthy survivors was highest among women whose mother and father lived to 90 (28.6%), followed by those whose mother only lived to 90 (23.2%). Conclusions: parental longevity predicted healthy ageing in a national cohort of postmenopausal women, supporting the view that genetic, environmental, and behavioral factors transmitted across generations may influence ageing outcomes among offspring.

The association of sleep duration and quality with all-cause and cause-specific mortality in the Women's Health Initiative.

BACKGROUND/OBJECTIVE: Many studies have shown a U-shaped association of sleep duration with mortality; however, this association is difficult to interpret owing to possible reverse causation, residual confounding, and measurement issues. We used data from the Women's Health Initiative to examine the associations of sleep duration, insomnia, and use of sleep aids with death from cardiovascular disease (CVD), cancer, "other" causes, and all causes combined. METHODS: Cox proportional hazards models were used in the analysis of baseline data and in time-dependent analyses of repeated measures to estimate associations of sleep-related factors with mortality. Among 158,203 women with information regarding sleep, 30,400 total deaths, 8857 CVD deaths, 9284 cancer deaths, and 11,928 other deaths were ascertained over a median of 17.8 years. RESULTS: In both baseline and time-dependent analyses, both short (≤5 h) and long sleep (≥9 h) durations were associated with increased risk of total, CVD, and "other" deaths, but not with cancer deaths. Insomnia showed no association with mortality, whereas use of sleep medications was associated with an increased mortality risk. CONCLUSIONS: While our findings showed a small but robust association of sleep duration with mortality in postmenopausal women, studies including objective measurements of sleep quality and efficiency are needed to clarify these associations.

Comparison of the Simplified sWHI and the Standard CHS Frailty Phenotypes for Prediction of Mortality, Incident Falls, and Hip Fractures in Older Women.

BACKGROUND: We compared the simplified Women's Health Initiative (sWHI) and the standard Cardiovascular Health Study (CHS) frailty phenotypes in predicting falls, hip fracture, and death in older women. METHODS: Participants are from the WHI Clinical Trial. CHS frailty criteria included weight loss, exhaustion, weakness, slowness, and low physical activity. The sWHI frailty score used two items from the RAND-36 physical function and vitality subscales, one item from the WHI physical activity scale plus the CHS weight loss criteria. Specifically, level of physical function was the capacity to walk one block and scored as severe (2-points), moderate (1-point), or no limitation (0). Vitality was based on feeling tired most or all of the time (1-point) versus less often (0). Low physical activity was walking outside less than twice a week (1-point) versus more often (0). A total score of 3 resulted in a frailty classification, a score of 1 or 2 defined pre-frailty, and 0 indicated nonfrailty. Outcomes were modeled using Cox regression and Harrell C-statistics were used for comparisons. RESULTS: Approximately 5% of the participants were frail based on the CHS or sWHI phenotype. The sWHI frailty phenotype was associated with higher rates of mortality (hazard ratio [HR] = 2.36, p ≤ .001) and falls (HR = 1.45, p = .005). Comparable HRs in CHS-phenotype were 1.97 (p < .001) and 1.36 (p = .03), respectively. Neither phenotype predicted hip fracture. Harrell C-statistics revealed nonsignificant differences in HRs between the CHS and sWHI frailty phenotypes. CONCLUSION: The sWHI phenotype, which is self-reported and brief, might be practical in settings with limited resources.

Comparison of Frailty Phenotypes for Prediction of Mortality, Incident Falls, and Hip Fracture in Older Women.

OBJECTIVES: To compare the ability of the commonly used Women's Health Initiative (WHI) and Cardiovascular Health Study (CHS) frailty phenotypes to predict falls, hip fracture, and death in WHI Clinical Trial participants aged 65 and older. DESIGN: Longitudinal cohort study. SETTING: WHI Clinical Trial. PARTICIPANTS: Participants with data for WHI and CHS frailty phenotypes (N = 3,558). MEASUREMENTS: Frailty was operationally defined in the CHS as the presence of three or more of weight loss, poor energy, weakness, slowness, and low physical activity. WHI operationalized frailty similarly but with the RAND-36 physical function scale substituted for slowness and weakness (RAND-36 physical function scale score <13 = 2 points, 13-78 = 1 point, >78 = 0 points). Frailty was defined as a summary score of 3 or greater, prefrailty as a score of 2 or 1, and nonfrailty as a score of 0. Outcomes were modeled using Cox regression. Harrell C-statistics were compared for models containing alternative instruments. RESULTS: Approximately 5% of participants were frail based on the CHS or WHI phenotype. The WHI frailty phenotype was associated with higher rates of falls (hazard ratio (HR) = 1.48, P = .003), hip fracture (HR = 1.87, P = .04), and death (HR = 2.32, P < .001). Comparable HRs in CHS-phenotype frail women were 1.32 (P = .04), 1.08 (P = .83), and 1.91 (P < .001), respectively. Harrell C-statistics revealed marked but insignificant differences in predicting abilities between CHS and WHI phenotype models (P > .50 for all). CONCLUSION: The WHI phenotype, which does not require direct measurements of physical performance, might offer a practical advantage for epidemiological and clinical needs.

The Relationship of Cardiovascular Disease to Physical Functioning in Women Surviving to Age 80 and Above in the Women's Health Initiative.

BACKGROUND: Cardiovascular disease (CVD) is highly prevalent at ages 80 and above. The association of physical functioning (PF), a key to an optimal aging trajectory, with CVD and specific CVD diagnosis in women who survive to age 80 and above has not been described previously and has important public health significance given our aging population. METHODS: Women's Health Initiative participants aged 80 years or older at the time of self-reporting PF (RAND SF-36) were studied in relationship to CVD diagnosis, whether present at study baseline (1993-1998) or diagnosed during follow-up through 2012. Cross-sectional analyses utilized demographic, medical, lifestyle, and psycho-social questionnaire data from baseline or updated at the time of self-reported PF. RESULTS: Among 27,145 older Women's Health Initiative participants, 22.0% (N = 5,959) had been diagnosed with CVD, specifically: 11.3% (N = 3,071) with coronary heart disease; 4.7% (N = 1,279), stroke; 5.2% (N = 1,397), venous thromboembolism; 2.7% (N = 737), peripheral arterial disease; and 2.7% (N = 725), congestive heart failure. PF scores (mean ± SE) were significantly (p < .0001) higher without CVD (60.0 ± 26.9), compared with any CVD (47.9 ± 27.3), and for each specific CVD diagnosis: coronary heart disease (48.8 ± 27.1); stroke (44.8 ± 27.9); venous thromboembolism (48.9 ± 27.4); peripheral arterial disease (41.9 ± 2.2); and congestive heart failure (38.8 ± 26.1). Regardless of CVD diagnosis, higher PF was associated with: younger age at the time of PF assessment; lower body mass index; higher recreational physical activity; better self-reported general health; fewer hip fractures after age 55; no history of arthritis; and no recent use of non-steroidal anti-inflammatory drugs. CONCLUSIONS: Older women with any CVD, and particularly women with congestive heart failure or peripheral arterial disease, reported significantly lower PF compared to women with no CVD. Regardless of CVD diagnosis, higher PF was strongly associated with a more active lifestyle and lower body mass index, suggesting potential intervention targets for more optimal aging.

Global Quality of Life Among WHI Women Aged 80 Years and Older.

BACKGROUND: The number of older adults living to age 80 and older is increasing rapidly, particularly among women. Correlates of quality of life (QOL) in very advanced ages are not known. We examined the association of demographic, social-psychological, lifestyle, and physical health variables with global QOL in a Women's Health Initiative (WHI) cohort of women aged 80 and older. METHODS: 26,299 WHI participants, who had completed a recent psychosocial and medical update, were included in these analyses. Global QOL was assessed by a single item, asking the women to rate their overall QOL on a scale from 0 to 10. Characteristics of the women were examined by the level of their transformed global QOL scores (≤50, 50-70, ≥70), and multiple regression was used to examine which demographic, social-psychological, lifestyle and health variables were independently associated with higher global QOL. RESULTS: Social-psychological and current health variables were more strongly associated with global QOL than a history of selected comorbid conditions. In particular, higher self-rated health and fewer depressive symptoms were the most strongly associated with better global QOL in WHI women ≥80 years. CONCLUSIONS: Interventions to reduce depressive symptoms and improve health may lead to better self-reported health and global QOL among older women. Physical and mental health screenings followed by evidence-based interventions are imperative in geriatric care.

Low-Fat Dietary Pattern Intervention and Health-Related Quality of Life: The Women's Health Initiative Randomized Controlled Dietary Modification Trial.

BACKGROUND: Intensive dietary intervention programs may lead to benefits in vitality and other components of health quality. The Women's Health Initiative Dietary Modification (DM) intervention includes a large randomized controlled trial of an intensive intervention. OBJECTIVE: To evaluate whether the intervention is associated with improved health-related quality of life (HRQoL) subscales, overall self-reported health, depression symptoms, cognitive functioning, and sleep quality. DESIGN: This randomized controlled trial was analyzed as intent to treat. PARTICIPANTS: Between 1993 and 1998, 48,835 women aged 50 to 79 years were recruited by 40 clinical centers across the United States. Eligibility included having fat intake at baseline ≥32% of total calories, and excluded women with any prior colorectal or breast cancer, recent other cancers, type 1 diabetes, or medical conditions with predicted survival <3 years. INTERVENTION: Goals were to reduce calories from fat to 20%, increase vegetables and fruit to 5+ servings, and increase grain servings to 6+ servings a day. During the first year, 18 group sessions were held, with quarterly sessions thereafter. MAIN OUTCOME MEASURES: The RAND 36-Item Health Survey was used to assess HRQoL at baseline, Year 1, and close-out (about 8 years postrandomization), and estimate differential HRQoL subscale change scores. STATISTICAL ANALYSES PERFORMED: Mean change in HRQoL scores (Year 1 minus baseline) were compared by randomization group using linear models. RESULTS: At 1 year, there was a differential change between intervention and comparison group of 1.7 units (95% CI 1.5, 2.0) in general health associated with the intervention. DM intervention improved physical functioning by 2.0 units (95% CI 1.7, 2.3), vitality by 1.9 units (95% CI 1.6, 2.2), and global quality of life by 0.09 units (95% CI 0.07, 0.12). With the exception of global quality of life, these effects were significantly modified by body mass index at baseline. CONCLUSIONS: DM intervention was associated with small, but significant improvements in three HRQoL subscales: general health, physical functioning, and vitality at 1 year follow-up, with the largest improvements seen in the women with the greatest baseline body mass index.

Sleep duration, cognitive decline, and dementia risk in older women.

INTRODUCTION: Consistent evidence linking habitual sleep duration with risks of mild cognitive impairment (MCI) and dementia is lacking. METHODS: We conducted a prospective study on 7444 community-dwelling women (aged 65-80 y) with self-reported sleep duration, within the Women's Health Initiative Memory Study in 1995-2008. Incident MCI/dementia cases were ascertained by validated protocols. Cox models were used to adjust for multiple sociodemographic and lifestyle factors, depression, cardiovascular disease (CVD), and other clinical characteristics. RESULTS: We found a statistically significant (P = .03) V-shaped association with a higher MCI/dementia risk in women with either short (≤6 hours/night) or long (≥8 hours/night) sleep duration (vs. 7 hours/night). The multicovariate-adjusted hazard for MCI/dementia was increased by 36% in short sleepers irrespective of CVD, and by 35% in long sleepers without CVD. A similar V-shaped association was found with cognitive decline. DISCUSSION: In older women, habitual sleep duration predicts the future risk for cognitive impairments including dementia, independent of vascular risk factors.

Intraindividual variability in domain-specific cognition and risk of mild cognitive impairment and dementia.

Intraindividual variability among cognitive domains may predict dementia independently of interindividual differences in cognition. A multidomain cognitive battery was administered to 2305 older adult women (mean age 74 years) enrolled in an ancillary study of the Women's Health Initiative. Women were evaluated annually for probable dementia and mild cognitive impairment (MCI) for an average of 5.3 years using a standardized protocol. Proportional hazards regression showed that lower baseline domain-specific cognitive scores significantly predicted MCI (N = 74), probable dementia (N = 45), and MCI or probable dementia combined (N = 101) and that verbal and figural memory predicted each outcome independently of all other cognitive domains. The baseline intraindividual standard deviation across test scores (IAV Cognitive Domains) significantly predicted probable dementia and this effect was attenuated by interindividual differences in verbal episodic memory. Slope increases in IAV Cognitive Domains across measurement occasions (IAV Time) explained additional risk for MCI and MCI or probable dementia, beyond that accounted for by interindividual differences in multiple cognitive measures, but risk for probable dementia was attenuated by mean decreases in verbal episodic memory slope. These findings demonstrate that within-person variability across cognitive domains both at baseline and longitudinally independently accounts for risk of cognitive impairment and dementia in support of the predictive utility of within-person variability.

Vitamin D supplementation and depression in the women's health initiative calcium and vitamin D trial.

While observational studies have suggested that vitamin D deficiency increases risk of depression, few clinical trials have tested whether vitamin D supplementation affects the occurrence of depression symptoms. The authors evaluated the impact of daily supplementation with 400 IU of vitamin D(3) combined with 1,000 mg of elemental calcium on measures of depression in a randomized, double-blinded US trial comprising 36,282 postmenopausal women. The Burnam scale and current use of antidepressant medication were used to assess depressive symptoms at randomization (1995-2000). Two years later, women again reported on their antidepressant use, and 2,263 completed a second Burnam scale. After 2 years, women randomized to receive vitamin D and calcium had an odds ratio for experiencing depressive symptoms (Burnam score ≥0.06) of 1.16 (95% confidence interval: 0.86, 1.56) compared with women in the placebo group. Supplementation was not associated with antidepressant use (odds ratio = 1.01, 95% confidence interval: 0.92, 1.12) or continuous depressive symptom score. Results stratified by baseline vitamin D and calcium intake, solar irradiance, and other factors were similar. The findings do not support a relation between supplementation with 400 IU/day of vitamin D(3) along with calcium and depression in older women. Additional trials testing higher doses of vitamin D are needed to determine whether this nutrient may help prevent or treat depression.

Toward a positive aging phenotype for older women: observations from the women's health initiative.

BACKGROUND: To develop a positive aging phenotype, we undertook analyses to describe multiple dimensions of positive aging and their relationships to one another in women 65 years of age and older and evaluate the performance of individual indicators and composite factors of this phenotype as predictors of time to death, years of healthy living, and years of independent living. METHODS: Data from Women's Health Initiative clinical trial and observational study participants ages 65 years and older at baseline, including follow-up observations up to 8 years later, were analyzed using descriptive statistics and principal components analysis to identify the factor structure of a positive aging phenotype. The factors were used to predict time to death, years of healthy living (without hospitalization or diagnosis of a serious health condition), and years of independent living (without nursing home admission or use of special services). RESULTS: We identified a multidimensional phenotype of positive aging that included two factors: Physical-Social Functioning and Emotional Functioning. Both factors were predictive of each of the outcomes, but Physical-Social Functioning was the strongest predictor. Each standard deviation of increase in Physical-Social Functioning was accompanied by a 23.7% reduction in mortality risk, a 19.4% reduction in risk of major health conditions or hospitalizations, and a 26.3% reduction in risk of dependent living. CONCLUSIONS: Physical-Social Functioning and Emotional Functioning constitute important components of a positive aging phenotype. Physical-Social Functioning was the strongest predictor of outcomes related to positive aging, including years of healthy living, years of independent living, and time to mortality.

Vitamin D intake from foods and supplements and depressive symptoms in a diverse population of older women.

BACKGROUND: Vitamin D may plausibly reduce the occurrence of depression in postmenopausal women; however, epidemiologic evidence is limited, and few prospective studies have been conducted. OBJECTIVE: We conducted a cross-sectional and prospective analysis of vitamin D intake from foods and supplements and risk of depressive symptoms. DESIGN: Study participants were 81,189 members of the Women's Health Initiative (WHI) Observational Study who were aged 50-79 y at baseline. Vitamin D intake at baseline was measured by food-frequency and supplement-use questionnaires. Depressive symptoms at baseline and after 3 y were assessed by using the Burnam scale and current antidepressant medication use. RESULTS: After age, physical activity, and other factors were controlled for, women who reported a total intake of ≥800 IU vitamin D/d had a prevalence OR for depressive symptoms of 0.79 (95% CI: 0.71, 0.89; P-trend < 0.001) compared with women who reported a total intake of <100 IU vitamin D/d. In analyses limited to women without evidence of depression at baseline, an intake of ≥400 compared with <100 IU vitamin D/d from food sources was associated with 20% lower risk of depressive symptoms at year 3 (OR: 0.80; 95% CI: 0.67, 0.95; P-trend = 0.001). The results for supplemental vitamin D were less consistent, as were the results from secondary analyses that included as cases women who were currently using antidepressant medications. CONCLUSIONS: Overall, our findings support a potential inverse association of vitamin D, primarily from food sources, and depressive symptoms in postmenopausal women. Additional prospective studies and randomized trials are essential in establishing whether the improvement of vitamin D status holds promise for the prevention of depression, the treatment of depression, or both.

The effect of calcium plus vitamin D on risk for invasive cancer: results of the Women's Health Initiative (WHI) calcium plus vitamin D randomized clinical trial.

In the Women's Health Initiative (WHI) trial of calcium plus vitamin D (CaD), we examined the treatment effect on incidence and mortality for all invasive cancers. Postmenopausal women (N = 36,282) were randomized to 1,000 mg of elemental calcium with 400 IU vitamin D3 or placebo. Cox models estimated risk of cancer incidence and mortality. After 7.0 yr, 1,306 invasive cancers were diagnosed in the supplement and 1,333 in the placebo group [hazard ratio (HR) = 0.98; CI = 0.90, 1.05, unweighted P = 0.54]. Mortality did not differ between supplement (315, annualized% = .26) and placebo [(347, 0.28%; P = 0.17; HR = 0.90 (0.77, 1.05)]. Significant treatment interactions on incident cancer were found for family history of cancer, personal total intake of vitamin D, smoking, and WHI dietary trial randomized group. Calcium/vitamin D supplementation did not reduce invasive cancer incidence or mortality. Supplementation lowered cancer risk in the WHI healthy diet trial arm and in women without a first-degree relative with cancer. The interactions are only suggestive given multiple testing considerations. The low vitamin D dose provided, limited adherence, and lack of serum 25(OH)D values should be considered when interpreting these findings.

Application of machine learning methods to describe the effects of conjugated equine estrogens therapy on region-specific brain volumes.

Use of conjugated equine estrogens (CEE) has been linked to smaller regional brain volumes in women aged ≥65 years; however, it is unknown whether this results in a broad-based characteristic pattern of effects. Structural magnetic resonance imaging was used to assess regional volumes of normal tissue and ischemic lesions among 513 women who had been enrolled in a randomized clinical trial of CEE therapy for an average of 6.6 years, beginning at ages 65-80 years. A multivariate pattern analysis, based on a machine learning technique that combined Random Forest and logistic regression with L(1) penalty, was applied to identify patterns among regional volumes associated with therapy and whether patterns discriminate between treatment groups. The multivariate pattern analysis detected smaller regional volumes of normal tissue within the limbic and temporal lobes among women that had been assigned to CEE therapy. Mean decrements ranged as high as 7% in the left entorhinal cortex and 5% in the left perirhinal cortex, which exceeded the effect sizes reported previously in frontal lobe and hippocampus. Overall accuracy of classification based on these patterns, however, was projected to be only 54.5%. Prescription of CEE therapy for an average of 6.6 years is associated with lower regional brain volumes, but it does not induce a characteristic spatial pattern of changes in brain volumes of sufficient magnitude to discriminate users and nonusers.

Long-term effects of conjugated equine estrogen therapies on domain-specific cognitive function: results from the Women's Health Initiative study of cognitive aging extension.

OBJECTIVES: To determine whether small decrements in global cognitive function that conjugated equine estrogen (CEE) therapies have been shown to produce in older women persist after cessation and extend to specific cognitive domains. DESIGN: Randomized controlled clinical trial. SETTING: Fourteen clinical centers of the Women's Health Initiative. PARTICIPANTS: Two thousand three hundred four women aged 65 to 80 free of probable dementia at enrollment. INTERVENTION: CEE 0.625 mg/d with or without medroxyprogesterone acetate (MPA, 10 mg/d) and matching placebos. MEASUREMENTS: Annual administrations of a battery of cognitive tests during and after the trial. RESULTS: Assignment to CEE-based therapies was associated with small mean relative decrements in global cognitive function and several domain-specific cognitive functions during the trial, which largely persisted through up to 4 years after the trial. The strongest statistical evidence was for global cognitive function (0.07-standard deviation decrements during (P=.007) and after (P=.01) the trial. For domain-specific scores, the mean decrements were slightly smaller, were less significant, and tended to be larger for CEE-alone therapy. CONCLUSION: CEE-based therapies, when initiated after the age of 65, produce a small broad-based decrement in cognitive function that persists after their use is stopped, but the differences in cognitive function are small and would not be detectable or have clinical significance for an individual woman. Differences in effects between cognitive domains suggest that more than one mechanism may be involved.