Health Initiative Hormone Therapy Trials Research Articles

Menopausal hormone therapy reduces the risk of fracture regardless of falls risk or baseline FRAX probability—results from the Women’s Health Initiative hormone therapy trials

SummaryIn a combined analysis of 25,389 postmenopausal women aged 50–79 years, enrolled in the two Women’s Health Initiative hormone therapy trials, menopausal hormone therapy vs. placebo reduced the risk of fracture regardless of baseline FRAX fracture probability and falls history.IntroductionThe aim of this study was to determine if the anti-fracture efficacy of menopausal hormone therapy (MHT) differed by baseline falls history or fracture risk probability as estimated by FRAX, in a combined analysis of the two Women’s Health Initiative (WHI) hormone therapy trials.MethodsA total of 25,389 postmenopausal women aged 50–79 years were randomized to receive MHT (n = 12,739) or matching placebo (n = 12,650). At baseline, questionnaires were used to collect information on falls history, within the last 12 months, and clinical risk factors. FRAX 10-year probability of major osteoporotic fracture (MOF) was calculated without BMD. Incident clinical fractures were verified using medical records. An extension of Poisson regression was used to investigate the relationship between treatment and fractures in (1) the whole cohort; (2) those with prior falls; and (3) those without prior falls. The effect of baseline FRAX probability on efficacy was investigated in the whole cohort.ResultsOver 4.3 ± 2.1 years (mean ± SD), MHT (vs. placebo) significantly reduced the risk of any clinical fracture (hazard ratio [HR] 0.72 [95% CI, 0.65–0.78]), MOF (HR 0.60 [95% CI, 0.53–0.69]), and hip fracture (0.66 [95% CI, 0.45–0.96]). Treatment was effective in reducing the risk of any clinical fracture, MOF, and hip fracture in women regardless of baseline FRAX MOF probability, with no evidence of an interaction between MHT and FRAX (p > 0.30). Similarly, there was no interaction (p > 0.30) between MHT and prior falls.ConclusionIn the combined WHI trials, compared to placebo, MHT reduces fracture risk regardless of FRAX probability and falls history in postmenopausal women.

On the targets of inference with multivariate failure time data.

There are several different topics that can be addressed with multivariate failure time regression data. Data analysis methods are needed that are suited to each such topic. Specifically, marginal hazard rate models are well suited to the analysis of exposures or treatments in relation to individual failure time outcomes, when failure time dependencies are themselves of little or no interest. On the other hand semiparametric copula models are well suited to analyses where interest focuses primarily on the magnitude of dependencies between failure times. These models overlap with frailty models, that seem best suited to exploring the details of failure time clustering. Recently proposed multivariate marginal hazard methods, on the other hand, are well suited to the exploration of exposures or treatments in relation to single, pairwise, and higher dimensional hazard rates. Here these methods will be briefly described, and the final method will be illustrated using the Women's Health Initiative hormone therapy trial data.

Blood Pressure Variability and Heart Failure Hospitalization: Results From the Women's Health Initiative

Little is known about the relationships between annual visit-to-visit blood pressure variability and heart failure subphenotypes. The aim of this analysis was to examine the association between blood pressure variability and incident heart failure with preserved and reduced ejection fraction. Data from 23,918 postmenopausal women enrolled in the Women's Health Initiative Hormone Therapy Trials were analyzed. Blood pressure was measured at baseline (1993‒1998) and then annually through 2005. Variability was defined as the SD of the mean blood pressure across visits or the SD of the participant's regression line for blood pressure across visits. The outcome was the first heart failure hospitalization. Heart failure ascertainment and adjudications were through March 31, 2018. During a mean follow-up of 15.8 years, 913 incident cases of heart failure with preserved ejection fraction and 421 cases of heart failure with reduced ejection fraction were identified. In fully adjusted models, including mean longitudinal systolic and diastolic blood pressure and time-varying coronary events interim to heart failure hospitalization, women in the highest versus in the lowest quartile of SD of the mean systolic blood pressure were at a statistically significantly higher risk of heart failure with preserved ejection fraction (hazard ratio [95% CI]=1.61 [1.12, 2.31]) but not of heart failure with reduced ejection fraction (1.18 [0.70,1.96]). Conversely, the hazard ratio (95% CI) for the highest versus lowest quartile of SD of the mean diastolic blood pressure was 1.56 (0.89, 2.74) for heart failure with reduced ejection fraction and 1.19 (0.85,1.65) for heart failure with preserved ejection fraction. Results attenuated for SD of the participant's regression line when additionally adjusted for the temporal trend of systolic and diastolic blood pressure. Greater systolic blood pressure variability was associated with a higher risk of heart failure with preserved ejection fraction independent of mean blood pressure and coronary events interim to heart failure hospitalization.

Abstract P132: Self-reported Recreational Physical Activity And Incident Venous Thromboembolism Risk In The Women’s Health Initiative

Introduction: The association between physical activity (PA) and incident venous thromboembolism (VTE) is inconsistent and incompletely characterized. Hypothesis: Higher amounts of self-reported total PA will be associated with a lower risk of incident VTE. Methods: Eligible women were Women’s Health Initiative (WHI) Hormone Therapy (HT) trial and Observational Study (OS) participants without prior VTE, able to walk at least one block, with baseline PA data (n=110,631). At multiple timepoints, women reported their current usual frequency and duration of walking and low, moderate, and strenuous intensity recreational PA, which were used to estimate energy expended. VTE, including deep vein thrombosis and pulmonary embolism, were validated in the WHI-HT and self-reported in the WHI-OS. Multivariable-adjusted (Table) Cox Proportional Hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of time-varying total PA and incident VTE risk, with women censored at death, loss to follow-up, and three years after their final PA measure. Results: At baseline, women were 64 years of age on average. Over an average of 9.9 years of follow-up, 1,403 women experienced incident VTE. In primary confounder-adjusted models, compared with women who reported no PA, higher tertiles of total PA were associated with a lower risk of incident VTE (high vs. no PA HR=0.60; 95% CI: 0.51, 0.71; p-trend<0.001) (Table). Further adjustment for potential mediators on the causal pathway (physical function, self-reported health, body mass index [BMI], cardiovascular-related factors) attenuated but did not eliminate this association (high vs. no PA HR=0.81; 95% CI: 0.68, 0.97; p-trend=0.017). Conclusions: Compared to no PA, higher tertiles of total PA were associated with a lower risk of incident VTE, even after adjusting for potential mediators reflecting physical function, health, BMI, and cardiovascular risk. Our results add to the apparent health benefits of even moderate amounts of recreational PA.

Abstract MP60: Blood Pressure Variability And Risk Of Heart Failure In Postmenopausal Women. Results From The Women's Health Initiative.

Introduction: Little is known about the relationships between visit-to-visit BPV and HF sub-phenotypes, HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF). The aim of this analysis was to investigate the relationship of visit-to-visit systolic and diastolic BPV and risk of HF subtypes HFrEF and HFpEF in a large cohort of postmenopausal women. Hypothesis: We hypothesized that greater systolic and diastolic BPV would be associated with a higher risk for HFrEF and HFpEF. Methods: This study consisted of 23,918 postmenopausal women aged 50-79 enrolled in the Women’s Health Initiative Hormone Therapy Trials. Blood pressure (BP) was measured at baseline (1993-1998) and then annually through 2005 by trained clinical staff. Variability was defined as the standard deviation of the mean BP across visits (SDm). The outcome was first HF hospitalization, which was adjudicated by physician review of medical records. Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for HF endpoints with adjustments for demographic, medical history, lifestyle factors, antihypertensive medication use, mean systolic and diastolic BPs, and time-varying coronary events interim to HF hospitalization. Results: During a mean follow-up of 15.8 years, 913 incident cases of HFpEF and 421 cases of HFrEF were identified. In fully adjusted models, women in the highest quartile of SDm for systolic blood pressure were at higher risk of HFpEF [HR (95% CI): 1.61, 95% confidence interval: 1.12, 2.31)], but not HFrEF [1.18 (0.70,1.96)] compared to women in the lowest quartile of SDm. Higher SDm for diastolic blood pressure was not related to HFpEF [1.19 (0.85,1.65)] or HFrEF [1.56 (0.89,2.74)]. Conclusions: Greater systolic BPV was associated with a higher risk of HFpEF independent of mean blood pressure and coronary events interim to HF hospitalization. These findings suggest that control of BPV may be a relevant target for the prevention of HFpEF in postmenopausal women.

Hormone Therapy in Menopause: Concepts, Controversies, and Approach to Treatment.

Hormone therapy (HT) is an effective treatment for menopausal symptoms, including vasomotor symptoms and genitourinary syndrome of menopause. Randomized trials also demonstrate positive effects on bone health, and age-stratified analyses indicate more favorable effects on coronary heart disease and all-cause mortality in younger women (close proximity to menopause) than in women more than a decade past menopause. In the absence of contraindications or other major comorbidities, recently menopausal women with moderate or severe symptoms are appropriate candidates for HT. The Women's Health Initiative (WHI) hormone therapy trials-estrogen and progestin trial and the estrogen-alone trial-clarified the benefits and risks of HT, including how the results differed by age. A key lesson from the WHI trials, which was unfortunately lost in the posttrial cacophony, was that the risk:benefit ratio and safety profile of HT differed markedly by clinical characteristics of the participants, especially age, time since menopause, and comorbidity status. In the present review of the WHI and other recent HT trials, we aim to provide readers with an improved understanding of the importance of the timing of HT initiation, type and route of administration, and of patient-specific considerations that should be weighed when prescribing HT.

Menopausal Hormone Therapy and Risks of First Hospitalized Heart Failure and its Subtypes During the Intervention and Extended Postintervention Follow-up of the Women's Health Initiative Randomized Trials

BackgroundWe assessed whether postmenopausal hormone therapy (HT) was associated with incident heart failure (HF) and its subtypes and examined whether there was a modifying effect of age on the associations. Methods and ResultsPostmenopausal women aged 50–79 enrolled in the Women's Health Initiative HT trials were analyzed. The 16,486 women with a uterus were randomized to receive conjugated equine estrogens (CEE 0.625 mg/day) plus medroxyprogesterone acetate (MPA 2.5 mg/day) or placebo, and 10,739 women with prior hysterectomy were randomized to receive CEE (0.625 mg/day) alone or placebo. Incident HF was defined as the first HF hospitalization. HF with reduced ejection fraction (HFrEF) or preserved EF (HFpEF) was defined as EF < 50% or ≥ 50%. During the intervention phase, median follow-up was 5.6 years in the CEE-plus-MPA trial and 7.2 years in the CEE-alone trial. During the cumulative follow-up of 18.9 years, women randomized to HT vs placebo in the 2 combined trials had incidence rates of 3.90 vs 3.89 per 1000 person-years for total HF; 1.25 vs 1.40 per 1000 person-years for HFrEF, and 1.88 vs 1.79 per 1000 person-years for HFpEF, respectively. There were no significant effects of HT on the risk of total incident HF or its subtypes in either trial, and age at randomization did not significantly modify the results. ConclusionsPostmenopausal HT did not alter the risk of hospitalization for HF or its subtypes during the intervention or cumulative 18.9 years of follow-up, and results did not vary significantly by age at randomization. Trial Registrationclinicaltrials.gov Identifier: NCT0000611 https://clinicaltrials.gov/ct2/show/NCT00000611?cond=women%27s±health±initiative&rank=5

Identifying Metabolomic Profiles of Insulinemic Dietary Patterns.

The food-based empirical dietary index for hyperinsulinemia (EDIH) score assesses the insulinemic potential of diet. This cross-sectional study evaluated associations between EDIH scores from food frequency questionnaires with c-peptide concentrations and with 448 metabolites, from fasting plasma samples, in multivariable linear regression analyses. Metabolites were measured with liquid chromatography tandem mass spectroscopy. Using a robust two-stage study design, discovery of metabolite associations was conducted among 1109 Women’s Health Initiative (WHI) Hormone Therapy (HT) trial participants and results replicated in an independent dataset of 810 WHI Observational Study (OS) participants. In both discovery and replication datasets, statistical significance was based on the false-discovery rate adjusted P < 0.05. In the multivariable-adjusted analyses, EDIH was significantly associated with c-peptide concentrations among 919 women (HT & OS) with c-peptide data. On average, c-peptide concentrations were 18% higher (95% CI, 6%, 32%; P-trend < 0.0001) in EDIH quintile 5 compared to quintile 1. Twenty-six metabolites were significantly associated with EDIH in the discovery dataset, and 19 of these were replicated in the validation dataset. Nine metabolites were found to decrease in abundance with increasing EDIH scores and included: C14:0 CE, C16:1 CE, C18:1 CE, C18:3 CE, C20:3 CE, C20:5 CE, C36:1 PS plasmalogen, trigonelline, and eicosapentanoate, whereas the 10 metabolites observed to increase with increasing EDIH scores were: C18:2 SM, C36:3 DAG, C36:4 DAG-A, C51:3 TAG, C52:3 TAG, C52:4, TAG, C54:3 TAG, C54:4 TAG, C54:6 TAG, and C10:2 carnitine. Cholesteryl esters, phospholipids, acylglycerols, and acylcarnitines may constitute circulating metabolites that are associated with insulinemic dietary patterns.

Identifying metabolomic profiles of inflammatory diets in postmenopausal women

We previously showed that a food-based empirical dietary inflammatory pattern (EDIP) score is associated with circulating inflammatory biomarkers. Metabolomic profiling of inflammatory diets may therefore provide insights on mechanisms contributing to disease etiology and prognosis. We aimed to elucidate metabolites associated with inflammatory diets among postmenopausal women, utilizing a robust study design that incorporates independent discovery and validation datasets. This baseline cross-sectional investigation evaluated associations between continuous EDIP scores calculated from food frequency questionnaires and 448 log-transformed plasma metabolites as outcomes in multivariable-adjusted linear regression analyses. Metabolites were measured with liquid chromatography tandem mass spectroscopy. Metabolite discovery was conducted among 1109 Women's Health Initiative (WHI) Hormone Therapy trial participants and results were replicated in an independent dataset of 810 WHI Observational Study participants. Secondary analyses were stratified by standard body mass index (BMI, kg/m2) categories. In discovery and replication datasets statistical significance was based on false-discovery rate adjusted P<0.05. After adjusting for energy intake, BMI, physical activity, and other confounding variables, 23 metabolites were significantly associated with EDIP score in the discovery dataset. Of these, the following ten were replicated: trigonelline, caffeine, acethylamino-6-amino-3-methyluracil, 7-methylxanthine, 1,7-dimethyluric acid, 3-methylxanthine, C18:3CE, glycine, associated with lower dietary inflammatory potential; whereas C52:3 triacylglycerol and linoleate associated with higher dietary inflammatory potential. Four of the ten were associated [glycine (inversely), caffeine, 1,7-dimethyluric acid, C52:3 triacylglycerol, (positively)], with C-reactive protein levels. In secondary analyses, associations showed differences by BMI category. Four metabolites, related to coffee/caffeine metabolism were inversely associated among normal weight women, and 83 metabolites associated with EDIP among overweight/obese women, including 40 (48%) that were also associated with C-reactive protein. Metabolites associated with coffee/caffeine and lipid metabolism may reflect the inflammatory potential of diet. Potential differences by BMI and the linkage to disease outcomes, require further study.

Identifying Metabolomic Profiles of Insulinemic Dietary Patterns (OR31-03-19)

ObjectivesThe empirical dietary index for hyperinsulinemia (EDIH) is a food-based score derived from correlations with plasma c-peptide. Our aim is to use the EDIH to discover metabolites associated with insulinemic dietary patterns. MethodsThis baseline cross-sectional study evaluated associations between continuous EDIH scores from food frequency questionnaires and 448 log-transformed plasma metabolites as outcomes in multivariable linear regression analyses. Metabolites were measured with liquid chromatography tandem mass spectroscopy. Metabolite discovery was conducted among 1109 Women’s Health Initiative (WHI) Hormone Therapy trial participants and results replicated in an independent dataset of 810 WHI Observational Study participants. In both discovery and replication datasets statistical significance was based on false-discovery rate adjusted P < 0.05. Secondary analyses were conducted in body mass index (BMI: <25, >=25 kg/m2) categories. ResultsAfter adjustment for energy intake, BMI, physical activity, and other confounding variables, 26 metabolites were significantly associated with EDIH in the discovery dataset, and included: trigonelline, C14:0 CE, C16:1 CE, C18:1 CE, C18:3 CE, C20:3 CE. C20:5 CE, C36:1 PS plasmalogen and eicosapentaenoate were associated with lower dietary insulinemic potential, whereas C36:3 DAG, C51:3 TAG, C52:3 TAG, C52:4 TAG, C54:2 TAG, C54:3 TAG, C54:4 TAG, C54:6 TAG, C36:4 DAG-A, cystathionine, isoleucine, N4-acetylcytidine, C10:2 carnitine, cAMP, C18:2 SM, C4-OH carnitine, and myristoleic acid were associated with higher dietary insulinemic potential. 25 out of the 26 metabolites replicated in the validation dataset except myristoleic acid. In secondary analyses within BMI strata, Associations differed by BMI category: 12 metabolites were significant among normal weight women whereas 64 metabolites were associated with EDIH among overweight/obese women. ConclusionsCholesterol esters, triglycerides, carnitines and amino acids may constitute metabolites that are associated with insulinemic dietary patterns. Funding SourcesR00CA207736, NHLBI HHSN268201300008C.

The Timing Hypothesis: Hormone Therapy for Treating Symptomatic Women During Menopause and Its Relationship to Cardiovascular Disease.

The risks and benefits of menopausal hormonal therapy (HT) have been evaluated extensively over the past three decades. While the efficacy of HT for management of menopausal symptoms, including vasomotor symptoms and vaginal dryness is well established, its relationship to cardiovascular outcomes is complex. The timing hypothesis, which posits that the cardiovascular effects of HT depend on the timing of initiation of HT in relation to menopause, has helped shape our understanding of the cardiovascular outcomes related to HT. Based on results from female monkey studies, the timing hypothesis provides a framework to explain discrepancies in results between multiple observation studies and the Women's Health Initiative (WHI) hormone therapy trials. The WHI trials closed early in 2002 in part because of increased cardiovascular events seen in women on treatment. Subanalysis of the WHI results by age group, and more recent randomized control studies, including the Kronos Early Estrogen and Prevention Study (KEEPS) and Early Versus Late Intervention Trial (ELITE), demonstrate that the risk of adverse cardiovascular events for HT are low for women <60 years of age or within 10 year from menopause. Although current data does not support using HT for primary prevention of cardiovascular disease, it does suggest that HT can be safely used to treat symptoms in appropriately selected women close to menopause.

27-Hydroxycholesterol, an Endogenous SERM, and Risk of Fracture in Postmenopausal Women: A Nested Case-Cohort Study in the Women's Health Initiative.

27-Hydroxycholesterol (27HC) is a purported, novel endogenous SERM. In animal models, 27HC has an anti-estrogen effect in bone, and 17β-estradiol mitigates this effect. 27HC in relation to fracture risk has not been investigated in humans. Depending on the level of bioavailable 17β-estradiol (bioE2 ), 27HC may increase fracture risk in postmenopausal women and modify the fracture risk reduction from menopausal hormone therapy (MHT). To test these a priori hypotheses, we conducted a nested case-cohort study of 868 postmenopausal women within the Women's Health Initiative Hormone Therapy (WHI-HT) trials. The WHI-HT tested conjugated equine estrogens versus placebo and separately conjugated equine estrogens plus progestin versus placebo. Fracture cases were 442 women who had an adjudicated incident hip or clinical vertebral fracture during the WHI-HT follow-up. The subcohort included 430 women randomly selected at WHI-HT baseline, four of whom had a subsequent fracture. Of the 868 women, 266 cases and 219 non-cases were assigned to the placebo arms. Cox models estimated hazard ratios for incident fracture in relation to pre-randomization circulating levels of 27HC and 27HC/bioE2 molar ratio. Models adjusted for age, race/ethnicity, total cholesterol, bioE2 , sex hormone-binding globulin, 25-hydroxyvitamin D, diabetes, osteoporosis, prior MHT use, BMI, falls history, and prior fracture. In women assigned to placebo arms, those in the middle and the highest tertiles of 27HC/bioE2 had an up to 1.9-fold (95% confidence intervals, 1.25 to 2.99) greater risk of fracture than women in the lowest tertile. In women assigned to MHT arms, fracture risk increased with continuous 27HC/bioE2 levels but not with categorical levels. 27HC levels alone were not associated with fracture risk. 27HC and 27HC/bioE2 did not modify the fracture risk reduction from MHT. In postmenopausal women, circulating levels of 27HC relative to bioE2 may identify those at increased risk of fracture. © 2018 American Society for Bone and Mineral Research.

Effects of oral conjugated equine estrogens with or without medroxyprogesterone acetate on incident hypertension in the Women's Health Initiative hormone therapy trials.

The aim of the study was to determine the effect of menopausal hormone therapy on incident hypertension in the two Women's Health Initiative hormone therapy trials and in extended postintervention follow-up. A total of 27,347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers. This analysis includes the subsample of 18,015 women who did not report hypertension at baseline and were not taking antihypertensive medication. Women with an intact uterus received conjugated equine estrogens (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) (n = 5,994) or placebo (n = 5,679). Women with prior hysterectomy received CEE alone (0.625 mg/d) (n = 3,108) or placebo (n = 3,234). The intervention lasted a median of 5.6 years in the CEE plus MPA trial and 7.2 years in the CEE-alone trial with 13 years of cumulative follow-up until September 30, 2010. The primary outcome for these analyses was self-report of a new diagnosis of hypertension and/or high blood pressure requiring treatment with medication. During the CEE and CEE plus MPA intervention phase, the rate of incident hypertension was 18% higher for intervention than for placebo (CEE: hazard ratio [HR], 1.18; 95% CI, 1.09-1.29; CEE plus MPA: HR, 1.18; 95% CI, 1.09-1.27). This effect dissipated postintervention in both trials (CEE: HR, 1.06; 95% CI, 0.94-1.20; CEE plus MPA: HR, 1.02; 95% CI, 0.94-1.10). CEE (0.625 mg/d) administered orally, with or without MPA, is associated with an increased risk of hypertension in older postmenopausal women. Whether lower doses, different estrogen formulations, or transdermal route of administration offer lower risks warrant further study.

Abstract 246: An integrative genetic epidemiologic approach to identify susceptibility genes for post-menopausal breast cancer

Abstract Background: Up to 30% of common (peri- and post-menopausal) breast cancer cases in the general population are believed to be due to segregation of mutations and variations with low to medium risk [i.e., 1.5&amp;lt; relative risk &amp;lt;20] for breast cancer. The majority of these genes remain to be identified. We used a hypothesis-driven integrative genetic epidemiologic approach to test the association of post-menopausal breast cancer with Nucleotide Excision Repair (NER) genes using several gene expression microarray and genome-wide association studies (GWAS) datasets. Methods: As per inclusion criteria, all datasets contained Caucasian cases with invasive ductal breast carcinoma diagnosed post-menopause (≥50 years of age) and healthy controls (with no personal history of breast cancer). Raw data from four gene expression microarray datasets (GSE5764, GSE10797, GSE10780, E-TABM-276) were used for pathway and meta-analysis. Raw data from three GWAS datasets, the Cancer Genetic Markers of Susceptibility (CGEMS) (1089 cases, 1093 controls), a nested case-control (351 cases, 884 controls) within National Surgical Adjuvant Breast and Bowel Project (NSABP), and a nested case-control (465 cases and 1394 controls) within the Women's Health Initiative (WHI) Hormone Therapy Trials, were analyzed using logistic regression models adjusting for covariates. Linkage disequilibrium patterns and deviations from Hardy-Weinberg Equilibrium (HWE) were assessed for single nucleotide polymorphisms (SNPs) within all candidate genes. Individual haplotypes and diplotypes were determined for all subjects. Odd ratios (OR) and 95% confidence intervals (CI) were calculated. Results: Individual analysis of gene expression microarray datasets and meta-analysis of GSE10780 and E-TABM-276 identified significant up-regulation of several NER genes including ERCC6 (P=7.95*10-6) and ERCC8 (P=4.67*10-6). Increased risk of breast cancer was found in association with variations in ERCC6 in all GWAS datasets. ERCC6 SNPs were in strong LD in all datasets with no deviations from HWE. In CGEMS, increased risk of breast cancer was found with ERCC6 rs4253082 (OR=1.32, 95%CI: 1.09-1.61, P=0.005), rs3750749 (OR=1.40, 95%CI: 1.07-1.8, P=0.01), and rs3750751 (OR=2.91, 95%CI: 1.05-8.06, P=0.04). In NSABP, increased risk of breast cancer was found with ERCC6 rs2229760 (OR=1.37, 95%CI: 1.02-1.83, P=0.03). In WHI, increased risk of breast cancer was found with ERCC6 rs1012553 (OR=1.35, 95%CI: 1.07-1.71, P=0.01) and rs2228528 (OR=1.29, 95%CI: 1.01-1.66, P=0.04). Gene-gene interaction analysis was significant for interactions between ERCC6 and several NER genes, including between specific diplotypes in ERCC6 and ERCC8 (Pinteraction=0.0009 in CGEMS). Conclusion: Genes involved in the NER pathway, including ERCC6 and ERCC8, may be associated with low to medium risk for susceptibility to post-menopausal breast cancer. Citation Format: Roxana Moslehi, Nur Zeinomar, Cristy Stagnar, Hui-Shien Tsao, Amiran Dzutsev. An integrative genetic epidemiologic approach to identify susceptibility genes for post-menopausal breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 246.

Vasomotor symptoms and the risk of incident venous thrombosis in postmenopausal women

Background Vasomotor symptoms may be markers of changes in cardiovascular risk, but it is unknown whether these symptoms are associated with the risk of venous thrombosis (VT). Objective To evaluate the association of vasomotor symptom presence and severity with incident VT risk among postmenopausal women, independent of potential explanatory variables. Methods This cohort study included participants of the Women's Health Initiative (WHI) Hormone Therapy Trials (n=24508) and Observational Study (n=87783), analyzed separately. At baseline, women reported whether hot flashes or night sweats were present and, if so, their severity. Using Cox proportional hazards models, we estimated the VT risk associated with vasomotor symptom presence and severity, adjusted for potential explanatory variables: age, body mass index, smoking status, race/ethnicity, and time-varying current hormone therapy use. Results At baseline, WHI Hormone Therapy Trial participants were aged 64years and WHI Observational Study participants were aged 63years, on average. In the WHI Hormone Therapy Trials over a median of 8.2years of follow-up, 522 women experienced a VT event. In the WHI Observational Study, over 7.9years of follow-up, 1103 women experienced a VT event. In adjusted analyses, we found no evidence of an association between vasomotor symptom presence (hazard ratio [HR]adj 0.91, 95% confidence interval [CI]0.75-1.1 in the WHI Hormone Therapy Trials; HRadj 1.1, 95%CI0.99-1.3 in the WHI Observational Study) or severity (HRadj for severe versus mild0.99, 95%CI0.53-1.9 in the WHI Hormone Therapy Trials; HRadj 1.3, 95%CI0.89-2.0) in the WHI Observational Study) and the risk of incident VT. Conclusions Although vasomotor symptoms have been associated with the risk of other cardiovascular events in published studies, our findings do not suggest that vasomotor symptoms constitute a marker of VT risk.

Sexual activity and vaginal symptoms in the postintervention phase of the Women's Health Initiative Hormone Therapy Trials.

To assess the impact of discontinuing oral hormone therapy (HT) on sexual activity, vaginal symptoms, and sexual activity components among participants in the estrogen-progestin therapy (EPT) and estrogen therapy (ET) trial of the Women's Health Initiative. Surveys were sent postintervention to those who were still taking study pills and agreed to continue in the study when the trials were stopped. Comparisons between former HT and placebo users were accomplished with chi-square tests for categorical variables and t tests for continuous variables. In all, 13,902 women with mean age at survey 69.9 years (EPT trial, women with intact uterus) and 71.7 years (ET trial, women with history of hysterectomy) responded. Prevalence of sexual activity postintervention was not significantly different between former EPT and placebo users (36.0% vs 34.2%; P = 0.37). Sexual activity of former ET users was 5.6% higher than placebo users (27.6% vs 22.0%; P = 0.001). The majority of sexually active women overall maintained orgasmic capacity and sexual satisfaction. Former EPT users were 10% to 12% more likely than former placebo users to report decreased desire, arousal, intercourse, climax, and satisfaction with sexual activity, and also increased dryness and dyspareunia upon discontinuing study drugs (P < 0.001). Former ET users were more likely than placebo users to report rare to no desire or arousal postintervention (P < 0.001). Postintervention ET trial participants formerly assigned to ET were significantly more likely to report sexual activity than those formerly assigned to placebo. Women who discontinued EPT were significantly more likely to report negative vaginal and sex-related effects.

Case-only approach to identifying markers predicting treatment effects on the relative risk scale.

Retrospectively measuring markers on stored baseline samples from participants in a randomized controlled trial (RCT) may provide high quality evidence as to the value of the markers for treatment selection. Originally developed for approximating gene-environment interactions in the odds ratio scale, the case-only method has recently been advocated for assessing gene-treatment interactions on rare disease endpoints in randomized clinical trials. In this article, the case-only approach is shown to provide a consistent and efficient estimator of marker by treatment interactions and marker-specific treatment effects on the relative risk scale. The prohibitive rare-disease assumption is no longer needed, broadening the utility of the case-only approach. The case-only method is resource-efficient as markers only need to be measured in cases only. It eliminates the need to model the marker's main effect, and can be used with any parametric or nonparametric learning method. The utility of this approach is illustrated by an application to genetic data in the Women's Health Initiative (WHI) hormone therapy trial.

Then and Now: Experts Insights on Understanding the Women's Health Initiative Hormone Therapy Trials [4M

INTRODUCTION: More than a decade following publication of the Women's Health Initiative (WHI) clinical trials for hormone therapy (HT), perception in the medical community remains that HT is unsafe for postmenopausal women. The evidence suggests otherwise for the majority of symptomatic menopausal women under 60 years and within 10 years of menopause. METHODS: A 30-minute expert interview CME program discussed the accurate interpretation of data from the WHI trials. Correct answers were compared between immediate pre- and post-tests, including case-based scenarios. RESULTS: 15,236 participants have engaged with the program to date (July 1–August 31, 2016) with 355 completions. Participants included physicians, 50%, and nurses, 21%, with 31% in women's health, 30% in primary care and the rest distributed among other specialties. Correct responses improved from pre- to post-test for all questions, including outcomes from the WHI trials (22%-52% to 49%-88%), attributes of new menopausal medications (43% to 67%) and appropriate application of clinical guidelines (64% to 90%). For most case-based questions, responses improved from 58%-83% in the pre-test to 78%-96% in the post-test, with one question in older postmenopausal women (aged 62) only improving from 42% to 48%. CONCLUSION: Results demonstrate the negative impact of inappropriate data interpretation, its effect on clinical care and guideline application. Continued uncertainty remains regarding HT risks, interpretation of follow-up studies, and the benefits/risks of newer medications. Future educational efforts must reinforce the need to treat symptomatic menopausal women according to the best available evidence, and how benefits exceed risks for many women with existing/new HT medications.

The cross-sectional association between vasomotor symptoms and hemostatic parameter levels in postmenopausal women.

Vasomotor symptoms (VMS) may be a marker of cardiovascular risk. We aimed to evaluate the cross-sectional association of VMS presence and severity with hemostatic parameter levels measured at baseline among Women's Health Initiative (WHI) Hormone Therapy trial postmenopausal participants. This cross-sectional analysis included 2,148 postmenopausal women with measures of VMS presence and severity reported in the 4 weeks before WHI baseline, who were not using warfarin or hormone therapy and for whom the following baseline hemostatic parameters were measured within the WHI Cardiovascular Disease Biomarker Case-Control Study: antithrombin, plasminogen activator inhibitor-1, protein C antigen, total and free protein S antigen, total and free tissue factor pathway inhibitor, D-dimer, normalized activated protein C sensitivity ratio, and thrombin generation. Using multiple linear regression, we estimated the adjusted average difference in each hemostatic parameter associated with VMS presence and severity. A multiple comparisons-corrected P value was computed using the P-min procedure to determine statistical significance of our smallest observed P value. Women were 67 years of age on average and 33% reported VMS presence at baseline. There was some suggestion that VMS presence may be associated with a -0.34 adjusted difference in normalized activated protein C sensitivity ratio compared with no VMS (95% CI, -0.60 to -0.087; P = 0.009), but this association was not significant after correction for multiple comparisons (P = 0.073). VMS presence or severity was not significantly associated with the other hemostatic parameters. We found no convincing evidence that VMS presence or severity was associated with levels of hemostatic parameters among postmenopausal women.

Admixture mapping of pelvic organ prolapse in African Americans from the Women’s Health Initiative Hormone Therapy trial

Admixture mapping of pelvic organ prolapse in African Americans from the Women’s Health Initiative Hormone Therapy trial