The Women's Health Initiative Randomized Trials and Clinical Practice: A Review.

Importance: Approximately 55 million people in the US and approximately 1.1 billion people worldwide are postmenopausal women. To inform clinical practice about the health effects of menopausal hormone therapy, calcium plus vitamin D supplementation, and a low-fat dietary pattern, the Women's Health Initiative (WHI) enrolled 161 808 postmenopausal US women (N = 68 132 in the clinical trials) aged 50 to 79 years at baseline from 1993 to 1998, and followed them up for up to 20 years. Observations: The WHI clinical trial results do not support hormone therapy with oral conjugated equine estrogens plus medroxyprogesterone acetate for postmenopausal women or conjugated equine estrogens alone for those with prior hysterectomy to prevent cardiovascular disease, dementia, or other chronic diseases. However, hormone therapy is effective for treating moderate to severe vasomotor and other menopausal symptoms. These benefits of hormone therapy in early menopause, combined with lower rates of adverse effects of hormone therapy in early compared with later menopause, support initiation of hormone therapy before age 60 years for women without contraindications to hormone therapy who have bothersome menopausal symptoms. The WHI results do not support routinely recommending calcium plus vitamin D supplementation for fracture prevention in all postmenopausal women. However, calcium and vitamin D are appropriate for women who do not meet national guidelines for recommended intakes of these nutrients through diet. A low-fat dietary pattern with increased fruit, vegetable, and grain consumption did not prevent the primary outcomes of breast or colorectal cancer but was associated with lower rates of the secondary outcome of breast cancer mortality during long-term follow-up. Conclusions and Relevance: For postmenopausal women, the WHI randomized clinical trials do not support menopausal hormone therapy to prevent cardiovascular disease or other chronic diseases. Menopausal hormone therapy is appropriate to treat bothersome vasomotor symptoms among women in early menopause, without contraindications, who are interested in taking hormone therapy. The WHI evidence does not support routine supplementation with calcium plus vitamin D for menopausal women to prevent fractures or a low-fat diet with increased fruits, vegetables, and grains to prevent breast or colorectal cancer. A potential role of a low-fat dietary pattern in reducing breast cancer mortality, a secondary outcome, warrants further study.

Systolic Blood Pressure and Survival to Very Old Age: Results From the Women's Health Initiative.

BACKGROUND: The relationship between systolic blood pressure (SBP) and longevity is not fully understood. We aimed to determine which SBP levels in women ≥65 years of age with or without blood pressure medication were associated with the highest probability of surviving to 90 years of age. METHODS: The study population consisted of 16 570 participants enrolled in the Women's Health Initiative who were eligible to survive to 90 years of age by February 28, 2020, without a history of cardiovascular disease, diabetes, or cancer. Blood pressure was measured at baseline (1993 through 1998) and then annually through 2005. The outcome was defined as survival to 90 years of age with follow-up. Absolute probabilities of surviving to 90 years of age were estimated for all combinations of SBP and age using generalized additive logistic regression modeling. The SBP that maximized survival was estimated for each age, and a 95% CI was generated. RESULTS: During a median follow-up of 19.8 years, 9723 of 16 570 women (59%) survived to 90 years of age. Women with an SBP between 110 and 130 mm Hg at attained ages of 65, 70, 75, and 80 years had a 38% (95% CI, 34%-48%), 54% (52%-56%), 66% (64%-67%), or 75% (73%-78%) absolute probability to survive to 90 years of age, respectively. The probability of surviving to 90 years of age was lower for greater SBP levels. Women at the attained age of 80 years with 0%, 20%, 40%, 60%, 80%, or 100% time in therapeutic range (defined as an SBP between 110 and 130 mm Hg) had a 66% (64%-69%), 68% (67%-70%), 71% (69%-72%), 73% (71%-74%), 75% (72%-77%), or 77% (74%-79%) absolute survival probability to 90 years of age. CONCLUSIONS: For women >65 years of age with low cardiovascular disease and other chronic disease risk, an SBP level <130 mm Hg was found to be associated with longevity. These findings reinforce current guidelines targeting an SBP target <130 mm Hg in older women.

Low physical function Post-Cancer diagnosis is associated with higher mortality risk in postmenopausal women.

BACKGROUND: Postmenopausal women with cancer experience an accelerated physical dysfunction beyond that expected through aging alone due to cancer and its treatments. The aim of this study is to determine whether declines in physical function after cancer diagnosis are associated with all-cause mortality and cancer-specific mortality. METHODS: This prospective cohort study included 8,068 postmenopausal women enrolled in the Women's Health Initiative (WHI) who were diagnosed with cancer and had physical function assessed within 1-year of cancer diagnosis. Self-reported physical function was measured using the 10-item physical function subscale of the RAND 36-Item Health Survey. Cause of death was determined by medical record review with central adjudication and linkage to the National Death Index. Death was adjudicated through February 2022. RESULTS: Over a median follow-up of 7.7 years from cancer diagnosis 3,316 (41.1%) women died. Our results showed that for every 10% decline in the physical function score after cancer diagnosis, all-cause mortality and cancer-specific mortality were significantly reduced by 12% (HR, 0.88; 95% CI, 0.87 to 0.89) and (HR, 0.88; 95%CI, 0.86 to 0.91), respectively. Further categorical analyses showed a significant dose-response relationship between post-diagnosis physical function categories and mortality outcomes (trend test P < .001), where the median survival time for women in the lowest physical function quartile was 9.1 (8.6, 10.6) years compared to 18.4 (15.8, 22.0) years for women in the highest physical function quartile. CONCLUSION: Postmenopausal women with low physical function after cancer diagnosis may be at higher risk of mortality from all causes and cancer-related mortality.

Long-Term Effect of Randomization to Calcium and Vitamin D Supplementation on Health in Older Women : Postintervention Follow-up of a Randomized Clinical Trial.

BACKGROUND: Although calcium and vitamin D (CaD) supplementation may affect chronic disease in older women, evidence of long-term effects on health outcomes is limited. OBJECTIVE: To evaluate long-term health outcomes among postmenopausal women in the Women's Health Initiative CaD trial. DESIGN: Post hoc analysis of long-term postintervention follow-up of the 7-year randomized intervention trial of CaD. (ClinicalTrials.gov: NCT00000611). SETTING: A multicenter (n = 40) trial across the United States. PARTICIPANTS: 36 282 postmenopausal women with no history of breast or colorectal cancer. INTERVENTION: Random 1:1 assignment to 1000 mg of calcium carbonate (400 mg of elemental calcium) with 400 IU of vitamin D3 daily or placebo. MEASUREMENTS: Incidence of colorectal, invasive breast, and total cancer; disease-specific and all-cause mortality; total cardiovascular disease (CVD); and hip fracture by randomization assignment (through December 2020). Analyses were stratified on personal supplement use. RESULTS: For women randomly assigned to CaD versus placebo, a 7% reduction in cancer mortality was observed after a median cumulative follow-up of 22.3 years (1817 vs. 1943 deaths; hazard ratio [HR], 0.93 [95% CI, 0.87 to 0.99]), along with a 6% increase in CVD mortality (2621 vs. 2420 deaths; HR, 1.06 [CI, 1.01 to 1.12]). There was no overall effect on other measures, including all-cause mortality (7834 vs. 7748 deaths; HR, 1.00 [CI, 0.97 to 1.03]). Estimates for cancer incidence varied widely when stratified by whether participants reported supplement use before randomization, whereas estimates on mortality did not vary, except for CVD mortality. LIMITATION: Hip fracture and CVD outcomes were available on only a subset of participants, and effects of calcium versus vitamin D versus joint supplementation could not be disentangled. CONCLUSION: Calcium and vitamin D supplements seemed to reduce cancer mortality and increase CVD mortality after more than 20 years of follow-up among postmenopausal women, with no effect on all-cause mortality. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute of the National Institutes of Health.

Vascular health years after a hypertensive disorder of pregnancy: The EPOCH study.

BACKGROUND: Preeclampsia is associated with a two-fold increase in a woman's lifetime risk of developing atherosclerotic cardiovascular disease (ASCVD), but the reasons for this association are uncertain. The objective of this study was to examine the associations between vascular health and a hypertensive disorder of pregnancy among women ≥ 2 years postpartum. METHODS: Pre-menopausal women with a history of either a hypertensive disorder of pregnancy (cases: preeclampsia or gestational hypertension) or a normotensive pregnancy (controls) were enrolled. Participants were assessed for standard ASCVD risk factors and underwent vascular testing, including measurements of blood pressure, endothelial function, and carotid artery ultrasound. The primary outcomes were blood pressure, ASCVD risk, reactive hyperemia index measured by EndoPAT and carotid intima-medial thickness. The secondary outcomes were augmentation index normalized to 75 beats per minute and pulse wave amplitude measured by EndoPAT, and carotid elastic modulus and carotid beta-stiffness measured by carotid ultrasound. RESULTS: Participants had a mean age of 40.7 years and were 5.7 years since their last pregnancy. In bivariate analyses, cases (N = 68) were more likely than controls (N = 71) to have hypertension (18% vs 4%, P = .034), higher calculated ASCVD risk (0.6 vs 0.4, P = .02), higher blood pressures (systolic: 118.5 vs 111.6 mm Hg, P = .0004; diastolic: 75.2 vs 69.8 mm Hg, P = .0004), and higher augmentation index values (7.7 vs 2.3, P = .03). They did not, however, differ significantly in carotid intima-media thickness (0.5 vs 0.5, P = .29) or reactive hyperemia index (2.1 vs 2.1, P = .93), nor in pulse wave amplitude (416 vs 326, P = .11), carotid elastic modulus (445 vs 426, P = .36), or carotid beta stiffness (2.8 vs 2.8, P = .86). CONCLUSION: Women with a prior hypertensive disorder of pregnancy had higher ASCVD risk and blood pressures several years postpartum, but did not have more endothelial dysfunction or subclinical atherosclerosis.

Traditional Mexican dietary pattern and cancer risk among women of Mexican descent.

PURPOSE: To examine the association of a traditional Mexican diet score with risk of total, breast, and colorectal cancer among women of Mexican ethnic descent in the Women's Health Initiative (WHI). METHODS: Participants were WHI enrollees who self-identified as being of Mexican descent. Data from food frequency questionnaires self-administered at study baseline were used to calculate the MexD score, with higher scores indicating greater adherence to an a priori-defined traditional Mexican diet (high in dietary fiber, vegetables, and legumes). Incident cancers were self-reported by participants from 1993 to 2020 and adjudicated by trained physicians. We used multivariable-adjusted Cox proportional hazards models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Among 2,343 Mexican descent women (median baseline age: 59 years), a total of 270 cancers (88 breast, 37 colorectal) occurred during a mean follow-up of 14.4 years. The highest tertile of MexD score was associated with a lower risk of all-cancer incidence (HR: 0.67; 95% CI 0.49-0.91; p-trend: 0.01) and colorectal cancer (HR: 0.38; 95% CI 0.14-0.998; p-trend < 0.05), with each unit increase in the MexD score associated with a 6% lower risk of all-cancer incidence (HR: 0.94; 95% CI 0.88-0.99). There was no statistically significant association with risk of breast cancer. CONCLUSION: Consumption of a traditional Mexican diet was associated with a significantly lower risk of all-cancer incidence and colorectal cancer. Confirmation of these findings in future studies is important, given the prevalence of colorectal cancer and a growing U.S. population of women of Mexican descent.

Dietary Intervention Favorably Influences Physical Functioning: The Women's Health Initiative Randomized Dietary Modification Trial.

BACKGROUND: In the Women's Health Initiative Dietary Modification randomized trial, the dietary intervention reduced breast cancer mortality by 21% (P = .02) and increased physical activity as well. OBJECTIVE: Therefore, the aim was to examine whether or not these lifestyle changes attenuated age-related physical functioning decline. DESIGN: In a randomized trial, the influence of 8 years of a low-fat dietary pattern intervention was examined through 20 years of cumulative follow-up. PARTICIPANTS AND SETTING: From 1993 to 1998, 48,835 postmenopausal women, ages 50 to 79 years with no prior breast cancer and negative baseline mammogram were randomized at 40 US clinical centers to dietary intervention or usual diet comparison groups (40 out of 60). The intervention significantly reduced fat intake and increased vegetable, fruit, and grain intake. MAIN OUTCOME MEASURES: In post hoc analyses, physical functioning, assessed using the RAND 36-Item Short Form Health Survey, evaluated quality or limitations of 10 hierarchical physical activities. Longitudinal physical functioning, reported against a disability threshold (when assistance in daily activities is required) was the primary study outcome. STATISTICAL ANALYSES PERFORMED: Semiparametric linear mixed effect models were used to contrast physical functioning trajectories by randomization groups. RESULTS: Physical functioning score, assessed 495,317 times with 11.0 (median) assessments per participant, was significantly higher in the intervention vs comparison groups through 12 years of cumulative follow-up (P = .001), representing a reduction in age-related functional decline. The intervention effect subsequently attenuated and did not delay time to the disability threshold. Among women in the dietary intervention vs comparison groups, aged 50 to 59 years, who were physically inactive at entry, a persistent, statistically significant, favorable influence on physical functioning with associated delay in crossing the disability threshold by approximately a year was seen (P value for interaction = .007). CONCLUSIONS: In the Women's Health Initiative Dietary Modification randomized trial, a dietary intervention that significantly reduced breast cancer mortality also significantly reduced age-related functional decline through 12 years, which was attenuated with longer follow-up.

Accelerometer-Measured Physical Activity, Sedentary Time, and Heart Failure Risk in Women Aged 63 to 99 Years.

Importance: Heart failure (HF) prevention is paramount to public health in the 21st century. Objective: To examine incident HF and its subtypes with preserved ejection fraction (HFpEF) and reduced EF (HFrEF) according to accelerometer-measured physical activity (PA) and sedentary time. Design, Setting, and Participants: This was a prospective cohort study, the Objective Physical Activity and Cardiovascular Health (OPACH) in Older Women study, conducted from March 2012 to April 2014. Included in the analysis were women aged 63 to 99 years without known HF, who completed hip-worn triaxial accelerometry for 7 consecutive days. Follow-up for incident HF occurred through February 2022. Data were analyzed from March to December 2023. Exposure: Daily PA (total, light, moderate to vigorous PA [MVPA], steps) and sedentary (total, mean bout duration) behavior. Main Outcomes and Measures: Adjudicated incident HF, HFpEF, and HFrEF. Results: A total of 5951 women (mean [SD] age, 78.6 [6.8] years) without known HF were included in this analysis. Women self-identified with the following race and ethnicity categories: 2004 non-Hispanic Black (33.7%), 1022 Hispanic (17.2%), and 2925 non-Hispanic White (49.2%). There were 407 HF cases (257 HFpEF; 110 HFrEF) identified through a mean (SD) of 7.5 (2.6) years (range, 0.01-9.9 years) of follow-up. Fully adjusted hazard ratios (HRs) for overall HF, HFpEF, and HFrEF associated with a 1-SD increment were 0.85 (95% CI, 0.75-0.95), 0.78 (95% CI, 0.67-0.91), and 1.02 (95% CI, 0.81-1.28) for minutes per day total PA; 0.74 (95% CI, 0.63-0.88), 0.71 (95% CI, 0.57-0.88), and 0.83 (95% CI, 0.62-1.12) for steps per day; and 1.17 (95% CI, 1.04-1.33), 1.29 (95% CI, 1.10-1.51), and 0.94 (95% CI, 0.75-1.18) for minutes per day total sedentary. Cubic spline curves for overall HF and HFpEF were significant inverse for total PA and steps per day and positive for total sedentary. Light PA and MVPA were inversely associated with overall HF (HR per 1 SD: 0.88; 95% CI, 0.78-0.98 and 0.84; 95% CI, 0.73-0.97) and HFpEF (0.80; 95% CI, 0.70-0.93 and 0.85; 95% CI, 0.72-1.01) but not HFrEF. Associations did not meaningfully differ when stratified by age, race and ethnicity, body mass index, physical function, or comorbidity score. Results for sedentary bout duration were inconsistent. Conclusions and Relevance: Higher accelerometer-measured PA (MVPA, light PA, steps per day) was associated with lower risk (and greater total sedentary time with higher risk) of overall HF and HFpEF in a racially and ethnically diverse cohort of older women. Increasing PA and reducing sedentary time for primary HFpEF prevention may have relevant implications for cardiovascular resilience and healthy aging in later life.

Engagement With Remote Delivery Channels in a Physical Activity Intervention for Senior Women in the US.

PURPOSE: Identify the effects of engagement with different intervention delivery channels on physical activity (PA), and the participant subgroups engaging with the different channels, among Women's Health Initiative Strong and Healthy (WHISH) PA trial participants. DESIGN: Secondary analysis of data from WHISH, a pragmatic trial that used passive randomized consent. SETTING: United States (remote intervention in all 50 states). SAMPLE: 18,080 U.S. women, aged 68-99 years, assigned to the WHISH PA intervention arm. MEASURES: 6 dichotomous variables operationalized engagement: Engagement with Targeted Inserts, Email (opened), Email (clicked links), Website (logging in), Website (tracking), Interactive Voice Response (IVR). PA was measured using the CHAMPS PA questionnaire. ANALYSIS: Linear regressions evaluated effects of engagement on PA. Conditional Inference Trees identified subgroups of participants engaging with different channels based on demographic and psychosocial variables. RESULTS: Engagement with each channel, except IVR, was associated with significantly more hours/week of PA (square root coefficients .29 - .13, P values <.001). Consistently across channels, features that identified subgroups of participants with higher engagement included younger age, and higher levels of PA and physical function. Subgroups with the highest engagement differed from those with the lowest in most participant characteristics. CONCLUSIONS: For equitable population-level impact via large-scale remotely-delivered PA programs, it may be necessary to identify strategies to engage and target harder to reach subgroups more precisely. CLINICAL TRIAL REGISTRATION: The WHISH trial is registered at ClinicalTrials.gov (No. NCT02425345).

Prevalence of frequent premature ventricular contractions and nonsustained ventricular tachycardia in older women screened for atrial fibrillation in the Women's Health Initiative.

BACKGROUND: Frequent premature ventricular contractions (PVCs) and nonsustained ventricular tachycardia (NSVT) have been associated with cardiovascular disease and mortality. Their prevalence, especially in ambulatory populations, is understudied and limited by few female participants and the use of short-duration (24- to 48-hour) monitoring. OBJECTIVE: The objective of this study was to report the prevalence of frequent PVCs and NSVT in a community-based population of women likely to undergo electrocardiogram (ECG) screening by sequential patch monitoring. METHODS: Participants from the Women's Health Initiative Strong and Healthy (WHISH) trial with no history of atrial fibrillation (AF) but 5-year predicted risk of incident AF ≥5% by CHARGE-AF score were randomly selected to undergo screening with 7-day ECG patch monitors at baseline, 6 months, and 12 months. Recordings were reviewed for PVCs and NSVT (>5 beats); data were analyzed with multivariate regression models. RESULTS: There were 1067 participants who underwent ECG screening at baseline, 866 at 6 months, and 777 at 12 months. Frequent PVCs were found on at least 1 patch from 4.3% of participants, and 1 or more episodes of NSVT were found in 12 (1.1%) women. PVC frequency directly correlated with CHARGE-AF score and NSVT on any patch. Detection of frequent PVCs increased with sequential monitoring. CONCLUSION: In postmenopausal women at high risk for AF, frequent PVCs were relatively common (4.3%) and correlated with higher CHARGE-AF score. As strategies for AF screening continue to evolve, particularly in those individuals at high risk of AF, the prevalence of incidental ventricular arrhythmias is an important benchmark to guide clinical decision-making.

Association of maternal birth weight and maternal preterm birth with subsequent risk for adverse reproductive outcomes: The Women's Health Initiative.

BACKGROUND: Advancements in medical technology and pharmacologic interventions have drastically improved survival of infants born preterm and low birth weight, but knowledge regarding the long-term health impacts of these individuals is limited and inconsistent. AIM: To investigate whether an individual's birthweight or history of being born preterm increases the risk of an adverse reproductive outcome. STUDY DESIGN: Nested case-control study within the Women's Health Initiative. SUBJECTS: 79,934 individuals who self-reported their personal birthweight category and/or preterm birth status. OUTCOMES MEASURES: Self-reported pregnancy outcomes: subfertility, miscarriage, stillbirth, preeclampsia, gestational diabetes, gestational hypertension, preterm birth, low birthweight infant, high birthweight infant. Logistic regression models were used to estimate unadjusted and adjusted odds ratios (OR). RESULTS: After adjustments, individuals reporting their birthweight <6lbs. were 20 % more likely to have a stillbirth or 70 % more likely to have a low birthweight infant and were less likely to have a full-term birth or high birthweight infant during their pregnancy. Individuals reporting a birthweight ≥10 lbs. were more likely to have a high birthweight infant (OR 3.49, 95 % CI 2.73-4.39) and less likely to have a low birthweight infant (OR 0.64, 95 % CI 0.47-0.82). Individuals born preterm were at increased risk for infertility, miscarriage, preeclampsia, gestational diabetes, and delivering a preterm or low birthweight infant. CONCLUSIONS: As more individuals born preterm and/or low birthweight survive to adulthood, the incidence and prevalence of poor reproductive outcomes may increase. Women born at extremes of birthweight and prematurity may need to be monitored more closely during their own pregnancies.

Association Between Insomnia, Stress Events, and Other Psychosocial Factors and Incident Atrial Fibrillation in Postmenopausal Women: Insights From the Women's Health Initiative.

Background The association between psychosocial factors and atrial fibrillation (AF) is poorly understood. Methods and Results Postmenopausal women from the Women's Health Initiative were retrospectively analyzed to identify incident AF in relation to a panel of validated psychosocial exposure variables, as assessed by multivariable Cox proportional hazard regression and hierarchical cluster analysis. Among the 83 736 women included, the average age was 63.9±7.0 years. Over an average of 10.5±6.2 years follow-up, there were 23 954 cases of incident AF. Hierarchical cluster analysis generated 2 clusters of highly correlated psychosocial variables: the Stress Cluster included stressful life events, depressive symptoms, and insomnia, and the Strain Cluster included optimism, social support, social strain, cynical hostility, and emotional expressiveness. Incident AF was associated with higher values in the Stress Cluster (hazard ratio [HR], 1.07 per unit cluster score [95% CI, 1.05-1.09]) and the Strain Cluster (HR, 1.03 per unit cluster score [95% CI, 1.00-1.05]). Of the 8 individual psychosocial predictors that were tested, insomnia (HR, 1.04 [95% CI, 1.03-1.06]) and stressful life events (HR, 1.02 [95% CI, 1.01-1.04]) were most strongly associated with increased incidence of AF in Cox regression analysis after multivariate adjustment. Subgroup analyses showed that the Strain Cluster was more strongly associated with incident AF in those with lower traditional AF risks (P for interaction=0.02) as determined by the cohorts for heart and aging research in genomic epidemiology for atrial fibrillation score. Conclusions Among postmenopausal women, 2 clusters of psychosocial stressors were found to be significantly associated with incident AF. Further research is needed to validate these associations.

Systolic Blood Pressure and Survival to Very Old Age. Results from the Women's Health Initiative.

Background: The association between systolic blood pressure (SBP) and longevity is not fully understood. We aimed to determine survival probabilities to age 90 for various SBP levels among women aged ≥ 65 years with or without BP medication. Methods: We analyzed blood pressure data from participants in the Women's Health Initiative (n=16,570) who were aged 65 or older and without history of cardiovascular disease, diabetes or cancer. Blood pressure was measured at baseline (1993-1998) and then annually through 2005. The outcome was defined as survival to age 90 with follow-up until February 28, 2020. Results: During a follow-up of 18 years, 9,723 (59%) of 16,570 women survived to age 90. The SBP associated with the highest probability of survival was about 120mmHg regardless of age. Compared to an SBP between 110 and 130 mmHg, women with uncontrolled SBP had a lower survival probability across all age groups and with or without BP medication. A 65-year-old women on BP medication with an interpolated SBP between 110 and 130 mmHg in 80% of the first 5 years of follow-up had a 31% (95% confidence interval, 24%, 38%) absolute survival probability. For those with 20% time in range, the probability was 21% (95% confidence interval, 16%, 26%). Conclusions: An SBP level below 130 mmHg was found to be associated with longevity among older women. The longer SBP was controlled at a level between 110 and 130 mmHg, the higher the survival probability to age 90. Preventing age-related rises in SBP and increasing the time with controlled BP levels constitute important measures for achieving longevity.

Body size over the adult life course and the risk of colorectal cancer among postmenopausal women.

OBJECTIVE: To assess the associations among several anthropometric measures, as well as BMI trajectories and colorectal cancer (CRC) risk in older women. DESIGN: Prospective cohort study. SETTING: Forty clinical centres in the USA. PARTICIPANTS: Totally, 79 034 postmenopausal women in the Women's Health Initiative Observational Study. RESULTS: During an average of 15·8 years of follow-up, 1514 CRC cases were ascertained. Five BMI trajectories over 18-50 years of age were identified using growth mixture model. Compared with women who had a normal BMI at age 18, women with obesity at age 18 had a higher risk of CRC (HR 1·58, 95 % CI 1·02, 2·44). Compared with women who kept relatively low normal body size during adulthood, women who progressed from normal to obesity (HR 1·29, 95 % CI 1·09, 1·53) and women who progressed from overweight to obesity (HR 1·37, 95 % CI 1·13, 1·68) had higher CRC risks. A weight gain > 15 kg from age 18 to 50 (HR 1·20, 95 % CI 1·04, 1·40) and baseline waist circumference > 88 cm (HR 1·33, 95 % CI 1·19, 1·49) were associated with higher CRC risks, compared with stable weight and waist circumference ≤ 88 cm, respectively. CONCLUSION: Women who have a normal weight in early adult life and gain substantial weight later, as well as those who are persistently heavy over adulthood, demonstrated a higher risk of developing CRC. Our study highlights the importance of maintaining a healthy body weight over the life course for reducing the risk of developing CRC in women.

A Review of Hormone and Non-Hormonal Therapy Options for the Treatment of Menopause.

Understanding the role of both menopausal hormone therapy (MHT) along with non-hormonal options for the treatment of vasomotor symptoms, sleep disruption, and genitourinary symptoms after menopause is critical to the health of women during middle and later life. Recent updates to the evidence for the treatment of menopausal symptoms pertaining to both hormonal and non-hormonal therapies as well as updated guidance from specialty societies can help guide clinicians in their treatment of women going through natural menopause or with estrogen deficiencies due to primary ovarian insufficiency or induced menopause from surgery or medications. The objective of this narrative review is to provide clinicians with an overview of MHT for the use of menopausal symptoms in women, incorporating updated primary evidence for risk versus benefit profiles, recent specialty society recommendations, and alternative, non-hormonal options. In this review, we summarize literature on the use of MHT for menopause-related symptomatology including options for formulations and dosages of MHT, non-hormonal treatment options, and the risk-benefit profile of MHT including long-term health consequences (eg, cardiovascular disease, cognitive decline, venous thromboembolism, and fracture risk). Finally, we highlight areas in which future research is needed to advance care of women after menopause. In summary, both hormonal (MHT) and non-hormonal options exist to treat symptoms of menopause. There is strong evidence for safety and effectiveness of MHT for the treatment of vasomotor symptoms among women who are less than 60 years of age, less than 10 years since menopause, and without significant cardiometabolic comorbidities. For others, treatment with hormonal versus non-hormonal therapies can be considered based on individual risk profiles, as well as other factors such as drug formulation, therapeutic goals, and symptom severity.

Quantifying structural racism in cohort studies to advance prospective evidence.

Calls-to-action in health research have described a need to improve research on race, ethnicity, and structural racism. Well-established cohort studies typically lack access to novel structural and social determinants of health (SSDOH) or precise race and ethnicity categorization, contributing to a loss of rigor to conduct informative analyses and a gap in prospective evidence on the role of structural racism in health outcomes. We propose and implement methods that prospective cohort studies can use to begin to rectify this, using the Women's Health Initiative (WHI) cohort as a case study. To do so, we evaluated the quality, precision, and representativeness of race, ethnicity, and SSDOH data compared with the target US population and operationalized methods to quantify structural determinants in cohort studies. Harmonizing racial and ethnic categorization to the current standards set by the Office of Management and Budget improved measurement precision, aligned with published recommendations, disaggregated groups, decreased missing data, and decreased participants reporting "some other race". Disaggregation revealed sub-group disparities in SSDOH, including a greater proportion of Black-Latina (35.2%) and AIAN-Latina (33.3%) WHI participants with income below the US median compared with White-Latina (42.5%) participants. We found similarities in the racial and ethnic patterning of SSDOH disparities between WHI and US women but less disparity overall in WHI. Despite higher individual-level advantage in WHI, racial disparities in neighborhood resources were similar to the US, reflecting structural racism. Median neighborhood income was comparable between Black WHI ($39,000) and US ($34,700) women. WHI SSDOH-associated outcomes may be generalizable on the basis of comparing across race and ethnicity but may quantitatively (but not qualitatively) underestimate US effect sizes. This paper takes steps towards data justice by implementing methods to make visible hidden health disparity groups and operationalizing structural-level determinants in prospective cohort studies, a first step to establishing causality in health disparities research.

Accelerometer-measured physical activity and sitting with incident mild cognitive impairment or probable dementia among older women.

INTRODUCTION: Physical activity (PA) is prospectively inversely associated with dementia risk, but few studies examined accelerometer measures of PA and sitting with rigorously-adjudicated mild cognitive impairment (MCI) and dementia risk. METHODS: We examined the associations of accelerometer measures (PA and sitting) with incident MCI/probable dementia in the Women's Health Initiative (n = 1277; mean age = 82 ± 6 years) RESULTS: Over a median follow-up of 4.2 years, 267 MCI/probable dementia cases were identified. Adjusted Cox regression HRs (95% CI) across moderate-to-vigorous PA (MVPA) min/d quartiles were 1.00 (reference), 1.28 (0.90 to 1.81), 0.79 (0.53 to 1.17), and 0.69 (0.45 to 1.06); P-trend = 0.01. Adjusted HRs (95% CI) across steps/d quartiles were 1.00 (reference), 0.73 (0.51 to 1.03), 0.64 (0.43 to 0.94), and 0.38 (0.23 to 0.61); P-trend < 0.001. The HR (95% CI) for each 1-SD increment in MVPA (31 min/d) and steps/d (1865) were 0.79 (0.67 to 0.94) and 0.67 (0.54 to 0.82), respectively. Sitting was not associated with MCI/probable dementia. DISCUSSION: Findings suggest ≥ moderate intensity PA, particularly stepping, associates with lower MCI and dementia risk. HIGHLIGHTS: Few studies have examined accelerometer-measured physical activity, including steps, and sitting with incident ADRD. Moderate-to-vigorous physical activity and steps, but not light physical activity or sitting, were inversely associated with lower ADRD risk. Among older women, at least moderate intensity physical activity may be needed to reduce ADRD risk.

Genetic evidence for causal relationships between age at natural menopause and the risk of ageing-associated adverse health outcomes.

BACKGROUND: A later age at natural menopause (ANM) has been linked to several ageing-associated traits including an increased risk of breast and endometrial cancer and a decreased risk of lung cancer, osteoporosis and Alzheimer disease. However, ANM is also related to several proxies for overall health that may confound these associations. METHODS: We investigated the causal association of ANM with these clinical outcomes using Mendelian randomization (MR). Participants and outcomes analysed were restricted to post-menopausal females. We conducted a one-sample MR analysis in both the Women's Health Initiative and UK Biobank. We further analysed and integrated several additional data sets of post-menopausal women using a two-sample MR design. We used ≤55 genetic variants previously discovered to be associated with ANM as our instrumental variable. RESULTS: A 5-year increase in ANM was causally associated with a decreased risk of osteoporosis [odds ratio (OR) = 0.80, 95% CI (0.70-0.92)] and fractures (OR = 0.76, 95% CI, 0.62-0.94) as well as an increased risk of lung cancer (OR = 1.35, 95% CI, 1.06-1.71). Other associations including atherosclerosis-related outcomes were null. CONCLUSIONS: Our study confirms that the decline in bone density with menopause causally translates into fractures and osteoporosis. Additionally, this is the first causal epidemiological analysis to our knowledge to find an increased risk of lung cancer with increasing ANM. This finding is consistent with molecular and epidemiological studies suggesting oestrogen-dependent growth of lung tumours.