Colorectal cancer in relation to postmenopausal estrogen and estrogen plus progestin in the Women’s Health Initiative clinical trial and observational study

Background: Colorectal cancer incidence was reduced among women assigned to active treatment in the Women’s Health Initiative (WHI) estrogen plus progestin randomized trial, but the interpretation was obscured by an associated later stage of diagnosis. In contrast the estrogen-alone trial showed no incidence reduction or differential stage at diagnosis. Here, data from the WHI observational study are considered, in conjunction with colorectal cancer mortality data from the hormone therapy trials, in an attempt to clarify postmenopausal hormone therapy effects. Participants and Methods: Postmenopausal women aged 50-79 at WHI enrollment. Estrogen-alone analyses include 21,552 and 10,739 women who were post-hysterectomy from the observational study and clinical trial respectively. Estrogen plus progestin analyses include 32,084 and 16,608 observational study and clinical trial women with uterus. Colorectal cancers were verified by central medical and pathology report review. Results: Hazard ratios (95% confidence intervals) from the WHI observational study were 0.80 (0.53 to 1.20) for estrogen and 1.15 (0.74 to 1.79) for estrogen plus progestin, with respectively 168 and 175 women diagnosed with colorectal cancer. Delayed diagnosis with estrogen plus progestin is not evident in the observational study. No protective effect on colorectal cancer mortality in the estrogen plus progestin trial is seen over an 8-year intervention and follow-up period. Conclusion: Hazard ratio patterns in the WHI clinical trial and observational study do not provide strong evidence of a clinically important colorectal cancer benefit with either estrogen-alone or estrogen plus progestin over 7-8 years of treatment and follow-up

Breastfeeding History and Risk of Stroke Among Parous Postmenopausal Women in the Women\u27s Health Initiative

Background: Stroke is the third leading cause of death among US Hispanic and non-Hispanic black women aged 65 and older. One factor that may protect against stroke is breastfeeding. Few studies have assessed the association between breastfeeding and stroke and whether this association differs by race and ethnicity. Methods and Results: Data were taken from the Women\u27s Health Initiative Observational Study with follow-up through 2010; adjusted hazard ratios for stroke subsequent to childbirth were estimated with Cox regression models accounting for left and right censoring, overall and stratified by race/ethnicity. Of the 80 191 parous women in the Women\u27s Health Initiative Observational Study, 2699 (3.4%) had experienced a stroke within a follow-up period of 12.6 years. The average age was 63.7 years at baseline. Fifty-eight percent (n=46 699) reported ever breastfeeding; 83% were non-Hispanic white, 8% were non-Hispanic black, 4% were Hispanic, and 5% were of other race/ethnicity. After adjustment for nonmodifiable potential confounders, compared with women who had never breastfed, women who reported ever breastfeeding had a 23% lower risk of stroke (adjusted hazard ratio=0.77; 95% confidence interval 0.70-0.83). This association was strongest for non-Hispanic black women (adjusted hazard ratio=0.52; 95% confidence interval 0.37-0.71). Further, breastfeeding for a relatively short duration (1-6 months) was associated with a 19% lower risk of stroke (adjusted hazard ratios=0.81; 95% confidence interval 0.74-0.89). This association appeared stronger with longer breastfeeding duration and among non-Hispanic white and non-Hispanic black women (test for trend P \u3c 0.01). Conclusions: Study results show an association and dose-response relationship between breastfeeding and lower risk of stroke among postmenopausal women after adjustment for multiple stroke risk factors and lifestyle variables. Further investigation is warranted

Relationship of Sedentary Behavior and Physical Activity to Incident Cardiovascular Disease Results From the Women's Health Initiative

ObjectivesThe aim of this study was to examine the independent and joint associations of sitting time and physical activity with risk of incident cardiovascular disease (CVD).BackgroundSedentary behavior is recognized as a distinct construct beyond lack of leisure-time physical activity, but limited data exist on the interrelationship between these 2 components of energy balance.MethodsParticipants in the prospective Women’s Health Initiative Observational Study (n = 71,018), 50 to 79 years of age and free of CVD at baseline (1993 to 1998), provided information on sedentary behavior, defined as hours of sitting/day, and usual physical activity at baseline and during follow-up through September 2010. First CVD (coronary heart disease or stroke) events were centrally adjudicated.ResultsSitting ≥10 h/day compared with ≤5 h/day was associated with increased CVD risk (hazard ratio: 1.18, 95% confidence interval: 1.09 to 1.29) in multivariable models including physical activity. Low physical activity was also associated with higher CVD risk (p for trend < 0.001). When women were cross-classified by sitting time and physical activity (p for interaction = 0.94), CVD risk was highest in inactive women (≤1.7 metabolic equivalent task-h/week) who also reported ≥10 h/day of sitting. Results were similar for coronary heart disease and stroke when examined separately. Associations between prolonged sitting and risk of CVD were stronger in overweight versus normal weight women and women 70 years of age and older compared with younger women.ConclusionsProlonged sitting time was associated with increased CVD risk, independent of leisure-time physical activity, in postmenopausal women without a history of CVD. A combination of low physical activity and prolonged sitting augments CVD risk

Racial and Ethnic Variations in Lung Cancer Incidence and Mortality: Results From the Women’s Health Initiative

This study aimed to evaluate racial/ethnic differences in lung cancer incidence and mortality in the Women’s Health Initiative Study, a longitudinal prospective cohort evaluation of postmenopausal women recruited from 40 clinical centers

Statin use and all-cancer survival: prospective results from the Women's Health Initiative

Background: This study aims to investigate the association between statin use and all-cancer survival in a prospective cohort of postmenopausal women, using data from the Women's Health Initiative Observational Study (WHI-OS) and Clinical Trial (WHI-CT). Methods: The WHI study enrolled women aged 50–79 years from 1993 to 1998 at 40 US clinical centres. Among 146 326 participants with median 14.6 follow-up years, 23 067 incident cancers and 3152 cancer deaths were observed. Multivariable-adjusted Cox proportional hazards models were used to investigate the relationship between statin use and cancer survival. Results: Compared with never-users, current statin use was associated with significantly lower risk of cancer death (hazard ratio (HR), 0.78; 95% confidence interval (CI), 0.71–0.86, P<0.001) and all-cause mortality (HR, 0.80; 95% CI, 0.74–0.88). Use of other lipid-lowering medications was also associated with increased cancer survival (P-interaction (int)=0.57). The lower risk of cancer death was not dependent on statin potency (P-int=0.22), lipophilicity/hydrophilicity (P-int=0.43), type (P-int=0.34) or duration (P-int=0.33). However, past statin users were not at lower risk of cancer death compared with never-users (HR, 1.06; 95% CI, 0.85–1.33); in addition, statin use was not associated with a reduction of overall cancer incidence despite its effect on survival (HR, 0.96; 95% CI, 0.92–1.001). Conclusions: In a cohort of postmenopausal women, regular use of statins or other lipid-lowering medications was associated with decreased cancer death, regardless of the type, duration, or potency of statin medications used

A genome-wide association study meta-analysis of clinical fracture in 10,012 African American women

Background Osteoporosis is a major public health problem associated with excess disability and mortality. It is estimated that 50–70% of the variation in osteoporotic fracture risk is attributable to genetic factors. The purpose of this hypothesis-generating study was to identify possible genetic determinants of fracture among African American (AA) women in a GWAS meta-analysis. Methods Data on clinical fractures (all fractures except fingers, toes, face, skull or sternum) were analyzed among AA female participants in the Women's Health Initiative (WHI) (N = 8155), Cardiovascular Health Study (CHS) (N = 504), BioVU (N = 704), Health ABC (N = 651), and the Johnston County Osteoarthritis Project (JoCoOA) (N = 291). Affymetrix (WHI) and Illumina (Health ABC, JoCoOA, BioVU, CHS) GWAS panels were used for genotyping, and a 1:1 ratio of YRI:CEU HapMap haplotypes was used as an imputation reference panel. We used Cox proportional hazard models or logistic regression to evaluate the association of ~ 2.5 million SNPs with fracture risk, adjusting for ancestry, age, and geographic region where applicable. We conducted a fixed-effects, inverse variance-weighted meta-analysis. Genome-wide significance was set at P &lt; 5 × 10− 8. Results One SNP, rs12775980 in an intron of SVIL on chromosome 10p11.2, reached genome-wide significance (P = 4.0 × 10− 8). Although this SNP has a low minor allele frequency (0.03), there was no evidence for heterogeneity of effects across the studies (I2 = 0). This locus was not reported in any previous osteoporosis-related GWA studies. We also interrogated previously reported GWA-significant loci associated with fracture or bone mineral density in our data. One locus (SMOC1) generalized, but overall there was not substantial evidence of generalization. Possible reasons for the lack of generalization are discussed. Conclusion This GWAS meta-analysis of fractures in African American women identified a potentially novel locus in the supervillin gene, which encodes a platelet-associated factor and was previously associated with platelet thrombus formation in African Americans. If validated in other populations of African descent, these findings suggest potential new mechanisms involved in fracture that may be particularly important among African Americans

Associations of total and free 25OHD and 1,25(OH)2D with serum markers of inflammation in older men

UnlabelledVitamin D is hypothesized to suppress inflammation. We tested total and free vitamin D metabolites and their association with inflammatory markers. Interleukin-6 levels were lower with higher 25-hydroxyvitamin D. 1,25-dihydroxyvitamin D and free 25OHD associations mirrored those of 25OHD. However, associations for the two metabolites diverged for tumor necrosis factor alpha (TNF-α) soluble receptors.IntroductionVitamin D is hypothesized to suppress inflammation, and circulating 25-hydroxyvitamin D (25OHD) and inflammatory markers are inversely correlated. However, total serum 25OHD may not be the best indicator of biologically active vitamin D.MethodsWe tested serum total 25OHD, total 1,25(OH)2D, vitamin D binding protein (DBP), and estimated free 25OHD and free 1,25(OH)2D associations with inflammatory markers serum interleukin-6 (IL-6), TNF-α and their soluble receptors, interleukin-10 (IL-10), and C-reactive protein (CRP) as continuous outcomes and the presence of ≥2 inflammatory markers in the highest quartile as a dichotomous outcome, in a random subcohort of 679 men in the Osteoporotic Fractures in Men (MrOS) study.ResultsIL-6 was lower in men with higher 25OHD (-0.23&nbsp;μg/mL per standard deviation (SD) increase in 25OHD, 95&nbsp;% confidence intervals (CI) -0.07 to -0.38&nbsp;μg/mL) and with higher 1,25(OH)2D (-0.20&nbsp;μg/mL, 95&nbsp;% CI -0.0004 to -0.39&nbsp;μg/mL); free D associations were slightly stronger. 25OHD and DBP, but not 1,25(OH)2D, were independently associated with IL-6. TNF-α soluble receptors were inversely associated with 1,25(OH)2D but positively associated with 25OHD, and each had independent effects. The strongest association with ≥2 inflammatory markers in the highest quartile was for free 1,25(OH)2D (odds ratios (OR) 0.70, 95&nbsp;% CI 0.54 to 0.89 per SD increase in free 1,25(OH)2D).ConclusionsAssociations of 1,25(OH)2D and free 25OHD with IL-6 mirrored those of 25OHD, suggesting that 1,25(OH)2D and free D do not improve upon 25OHD in population-based IL-6 studies. However, associations for the two metabolites diverged for TNF-α soluble receptor, warranting examination of both metabolites in studies of TNF-α and its antagonists

Association between the metabolic syndrome and its components and gait speed among U.S. adults aged 50 years and older: a cross-sectional analysis

BACKGROUND: To examine the relationship between the metabolic syndrome and its components and gait speed among older U.S. men and women. Whether these associations are independent of physical activity was also explored. METHODS: Eight hundred and thirty-five men and 850 women aged ≥50 years from the continuous National Health and Nutrition Examination Survey 1999–2002 were examined. We used the definition of the metabolic syndrome developed by the U.S. National Cholesterol Education Program Adult Treatment Panel III. Gait speed was measured with a 6.10-meter timed walk examination. RESULTS: The prevalence of the metabolic syndrome was 40.2% in men and 45.6% in women (P = .127). The prevalence of gait speed impairment was 29.3% in men and 12.5% in women (P < .001). No association was found between the metabolic syndrome and gait speed impairment. After including the individual components of the metabolic syndrome in a logistic model adjusted for age and leisure-time physical activity, abdominal obesity, low HDL cholesterol, and high fasting glucose were significantly associated with gait speed impairment among women (adjusted odds ratio [AOR] = 0.48, 95% confidence interval [CI] = 0.26 to 0.89; AOR = 2.26, 95% CI = 1.08 to 4.75; and AOR = 2.05, 95% CI = 1.12 to 3.74, respectively). Further adjustment for race/ethnicity, education, smoking status, alcohol consumption, arthritis status, and use of an assistive device attenuated these associations; among women, abdominal obesity and low HDL cholesterol remained significantly associated with gait speed impairment (AOR = 0.37, 95% CI = 0.18 to 0.76 and AOR = 2.45, 95% CI = 1.07 to 5.63, respectively) while the association between hyperglycemia and impaired gait speed attenuated to nonsignificance. CONCLUSION: Among women, gait speed impairment is associated with low HDL cholesterol and inversely with abdominal obesity. These associations may be sex-dependent and warrant further research

Triacylglycerol Fatty Acid Composition in Diet-Induced Weight Loss in Subjects with Abnormal Glucose Metabolism – the GENOBIN Study

BACKGROUND: The effect of weight loss on different plasma lipid subclasses at the molecular level is unknown. The aim of this study was to examine whether a diet-induced weight reduction result in changes in the extended plasma lipid profiles (lipidome) in subjects with features of metabolic syndrome in a 33-week intervention. METHODOLOGY/PRINCIPAL FINDINGS: Plasma samples of 9 subjects in the weight reduction group and 10 subjects in the control group were analyzed using mass spectrometry based lipidomic and fatty acid analyses. Body weight decreased in the weight reduction group by 7.8+/-2.9% (p<0.01). Most of the serum triacylglycerols and phosphatidylcholines were reduced. The decrease in triacylglycerols affected predominantly the saturated short chain fatty acids. This decrease of saturated short chain fatty acid containing triacylglycerols correlated with the increase of insulin sensitivity. However, levels of several longer chain fatty acids, including arachidonic and docosahexanoic acid, were not affected by weight loss. Levels of other lipids known to be associated with obesity such as sphingolipids and lysophosphatidylcholines were not altered by weight reduction. CONCLUSIONS/SIGNIFICANCE: Diet-induced weight loss caused significant changes in global lipid profiles in subjects with abnormal glucose metabolism. The observed changes may affect insulin sensitivity and glucose metabolism in these subjects. TRIAL REGISTRATION: ClinicalTrials.gov NCT00621205