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1.  Dietary Intake of Fiber, Fruit, and Vegetables Decrease the Risk of Incident Kidney Stones in Women: A Women's Health Initiative (WHI) Report 
The Journal of urology  2014;192(6):1694-1699.
We evaluated the relationship between dietary fiber, fruit, and vegetable intake, and the risk of kidney stone formation.
Overall, 83,922 postmenopausal women from the WHI Observational Study were included and followed prospectively. Cox proportional hazards regression analyses evaluated the associations between total dietary fiber, fruits, and vegetable intake, and the risk of incident kidney stone formation adjusting for nephrolithiasis risk factors (age, race/ethnicity, geographic region, diabetes mellitus, calcium supplementation, hormone therapy use, body mass index, calibrated caloric intake, and dietary water, sodium, animal protein, and calcium intake). Women with a prior history of kidney stones (3,471 women) were analyzed separately.
Mean age was 64±7 years, 85% of women were Caucasian and 2,937 women (3.5%) experienced a kidney stone occurrence in 8 years median follow-up. In women with no history of kidney stones, higher total dietary fiber (6-26% decreased risk, p<0.001), higher fruit intake (12-25% decreased risk, p<0.001), and higher vegetable intake (9-22% decreased risk, p=0.002) were associated with a decreased risk of incident kidney stone formation in separate adjusted models. In women with a history of stones, there were no significant protective effects of fiber, fruits, or vegetable intake on the risk of kidney stone recurrence.
Greater dietary intake of fiber, fruits and vegetables were each associated with a reduced risk of incident kidney stones in postmenopausal women. The protective effects were independent of other known risk factors for kidney stones. In contrast, there was no reduction in risk in women with a history of stones.
PMCID: PMC4241174  PMID: 24859445
nutrition; diet; fiber; fruit; vegetables; healthy lifestyle; kidney stones; nephrolithiasis; urinary calculi; dietary fiber
2.  Usual dietary isoflavone intake and reproductive function across the menstrual cycle 
Fertility and sterility  2013;100(6):10.1016/j.fertnstert.2013.08.002.
To assess the association of total isoflavone intake with ovulatory function, including sporadic anovulation in healthy premenopausal women.
Prospective cohort study.
Participants included 259 healthy regularly menstruating women aged 18–44 years.
Main Outcome Measure(s)
Serum concentrations of E2, free E2, P, LH, FSH, and SHBG and sporadic anovulation in healthy premenopausal women.
Isoflavone intake was not associated with E2, free E2, P, LH, and FSH concentrations. Consumption in the highest quartile (Q4: 1.6–78.8 mg/d) was significantly associated with greater SHBG concentrations (β = 0.09; 95% confidence interval [CI] 0.02–0.16), compared with the first quartile (Q1: 0.0–0.3 mg/d).
Isoflavone intake was not associated with sporadic anovulation (Q4 vs. Q1: odds ratio 0.87, 95% CI 0.32–1.66). Dietary isoflavone intake among young premenopausal women was not related to sex hormone concentrations or anovulation, but was associated with minimally increased SHBG concentrations. These results suggest potential endocrine effects with no subsequent effects on ovulation, easing concerns regarding their impacts on fertility.
PMCID: PMC3867935  PMID: 23998910
Isoflavone; anovulation; sex hormones; nutrition
3.  All-Cause, Cardiovascular, and Cancer Mortality Rates in Postmenopausal White, Black, Hispanic, and Asian Women With and Without Diabetes in the United States 
American Journal of Epidemiology  2013;178(10):1533-1541.
Using data from the Women's Health Initiative (1993–2009; n = 158,833 participants, of whom 84.1% were white, 9.2% were black, 4.1% were Hispanic, and 2.6% were Asian), we compared all-cause, cardiovascular, and cancer mortality rates in white, black, Hispanic, and Asian postmenopausal women with and without diabetes. Cox proportional hazard models were used for the comparison from which hazard ratios and 95% confidence intervals were computed. Within each racial/ethnic subgroup, women with diabetes had an approximately 2–3 times higher risk of all-cause, cardiovascular, and cancer mortality than did those without diabetes. However, the hazard ratios for mortality outcomes were not significantly different between racial/ethnic subgroups. Population attributable risk percentages (PARPs) take into account both the prevalence of diabetes and hazard ratios. For all-cause mortality, whites had the lowest PARP (11.1, 95% confidence interval (CI): 10.1, 12.1), followed by Asians (12.9, 95% CI: 4.7, 20.9), blacks (19.4, 95% CI: 15.0, 23.7), and Hispanics (23.2, 95% CI: 14.8, 31.2). To our knowledge, the present study is the first to show that hazard ratios for mortality outcomes were not significantly different between racial/ethnic subgroups when stratified by diabetes status. Because of the “amplifying” effect of diabetes prevalence, efforts to reduce racial/ethnic disparities in the rate of death from diabetes should focus on prevention of diabetes.
PMCID: PMC3888272  PMID: 24045960
diabetes; health disparities; menopause; mortality; obesity; women's health
4.  A randomised trial to evaluate the Effects of low dose Aspirin in Gestation and Reproduction (EAGeR): Design and baseline characteristics 
Paediatric and perinatal epidemiology  2013;27(6):10.1111/ppe.12088.
Low dose aspirin (LDA) has been proposed to improve pregnancy outcomes in couples experiencing recurrent pregnancy loss. However, results from studies of LDA on pregnancy outcomes have been inconsistent, perhaps because most studies evaluated LDA-initiated post-conception. The purpose of the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial was to determine whether preconception-initiated LDA improves live-birth rates in women with 1–2 prior losses.
We performed a multicenter, block randomised, double-blind, placebo-controlled trial. Study participants were recruited using community-based advertisements and physician referral to four university medical centers in the US (2006–12). Eligible women were aged 18–40 years actively trying to conceive with 1–2 prior losses. Participants were randomised to receive daily LDA (81 mg/day) or a matching placebo, and all were provided with daily 400 mcg folic acid. Follow-up continued for ≤six menstrual cycles while attempting to conceive. For those that conceived, treatment was continued until 36 weeks gestation. The primary outcome was the cumulative live birth rate over the trial period.
1228 women were randomised (615 LDA, 613 placebo). Participants had a mean age of 28.7, were mostly white (95%), well educated (86% >high school education), and employed (75%) with a household income >$100,000 annually (40%). Characteristics of those in the treatment and placebo arms were well-balanced.
We describe the study design, recruitment, data collection, and baseline characteristics of participants enrolled in EAGeR, which aimed to determine the effect of LDA on live birth and other pregnancy outcomes in these women.
PMCID: PMC3821875  PMID: 24118062
Low-dose aspirin; conception; pregnancy; miscarriage; sub-fertility
5.  Calcium Plus Vitamin D Supplementation and Health Outcomes Five Years After Active Intervention Ended: The Women's Health Initiative 
Journal of Women's Health  2013;22(11):915-929.
Clinical outcomes of the Women's Health Initiative (WHI) calcium plus vitamin D supplementation trial have been reported during 7.0 years of active intervention. We now report outcomes 4.9 years after the intervention stopped and cumulative findings.
Postmenopausal women (N=36,282) were randomized; postintervention follow-up continued among 29,862 (86%) of surviving participants. Primary outcomes were hip fracture and colorectal cancer. Breast cancer, all cancers, cardiovascular disease (CVD), and total mortality were predetermined major study outcomes.
Hip fracture incidence was comparable in the supplement and the placebo groups, postintervention hazard ratio (HR)=0.95, 95% confidence interval (95% CI: 0.78, 1.15) and overall HR=0.91 (95% CI: 0.79, 1.05). Overall, colorectal cancer incidence did not differ between randomization groups, HR=0.95 (95% CI: 0.80, 1.13). Throughout, there also was no difference in invasive breast cancer, CVD, and all-cause mortality between groups. In subgroup analyses, the invasive breast cancer effect varied by baseline vitamin D intake (p=0.03 for interaction). Women with vitamin D intakes >600 IU/d, had an increased risk of invasive breast cancer, HR=1.28 (95% CI; 1.03, 1.60). Over the entire study period, in post hoc analyses, the incidence of vertebral fractures, HR=0.87 (95% CI: 0.76, 0.98) and in situ breast cancers, HR=0.82 (95% CI: 0.68, 0.99) were lower among women randomized to supplementation.
After an average of 11 years, calcium and vitamin D supplementation did not decrease hip fracture or colorectal cancer incidence. Exploratory analyses found lower vertebral fracture and in situ breast cancer incidence in the supplement users. There was no effect on CVD or all-cause mortality.
PMCID: PMC3882746  PMID: 24131320
6.  Genetic Predictors of Circulating 25-Hydroxyvitamin D and Risk of Colorectal Cancer 
Experimental evidence has demonstrated an anti-neoplastic role for vitamin D in the colon and higher circulating 25-hydroxyvitamin D (25[OH]D) levels are consistently associated with a lower risk of colorectal cancer (CRC). Genome-wide association studies have identified loci associated with levels of circulating 25(OH)D. The identified SNPs from four gene regions, collectively explain approximately 5% of the variance in circulating 25(OH)D.
We investigated whether six polymorphisms in GC, CYP2R1, CYP24A1 and DHCR7/NADSYN1, genes previously shown to be associated with circulating 25(OH)D levels, were associated with CRC risk in 10,061 cases and 12,768 controls drawn from 13 studies included in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and Colon Cancer Family Registry (CCFR). We performed a meta-analysis of crude and multivariate-adjusted logistic regression models to calculate odds ratios and associated confidence intervals for SNPs individually, SNPs simultaneously, and for a vitamin D additive genetic risk score (GRS).
We did not observe a statistically significant association between the 25(OH)D associated SNPs and CRC marginally, conditionally, or as a GRS, or for colon or rectal cancer separately or combined.
Our findings do not support an association between SNPs associated with circulating 25(OH)D and risk of CRC. Additional work is warranted to investigate the complex relationship between 25(OH)D and CRC risk.
There was no association observed between genetic markers of circulating 25(OH)D and CRC. These genetic markers account for a small proportion of the variance in 25(OH)D.
PMCID: PMC3818310  PMID: 23983240
7.  The Women’s Health Initiative Hormone Therapy Trials: Update and Overview of Health Outcomes During the Intervention and Post-Stopping Phases 
Menopausal hormone therapy continues in clinical use but questions remain regarding its risks and benefits for chronic disease prevention.
To provide a comprehensive, integrated overview of findings from the two Women’s Health Initiative (WHI) hormone therapy (HT) trials with extended post-intervention follow up.
27,347 postmenopausal women, age 50–79 years, were enrolled at 40 US centers. Interventions were conjugated equine estrogens (CEE, 0.625 mg/day) with medroxyprogesterone acetate (MPA, 2.5 mg/day) for women with an intact uterus (N = 16,608) and CEE alone for women with hysterectomy (N= 10,739), or their placebos. Intervention continued for 5.6 and 7.2 years (median), respectively, with cumulative follow-up of 13 years through September 30, 2010.
The primary efficacy and safety outcomes were coronary heart disease (CHD) and invasive breast cancer, respectively. A global index also included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and deaths. Secondary and quality-of-life outcomes were also assessed.
During the intervention phase for CEE+MPA, the hazard ratio (HR) for CHD was 1.18 (95% confidence interval [CI] 0.95–1.45) and overall risks outweighed benefits, with increases in invasive breast cancer, stroke, pulmonary embolism, and the global index. Other risks included increased dementia (in women >65 years), gallbladder disease, and urinary incontinence, while benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Post-intervention, most risks and benefits dissipated, although some elevation in breast cancer risk persisted (cumulative hazard ratio [HR] =1.28; 95% confidence interval, 1.11–1.48). During intervention for CEE alone, risks and benefits were more balanced, with a HR for CHD of 0.94 (0.78–1.14), increased stroke and venous thrombosis, decreased hip fractures and diabetes, and over cumulative follow-up, decreased breast cancer (HR=0.79 [0.65–0.97]). Neither regimen affected all-cause mortality. With CEE, younger women (50–59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index (nominal P values for trend by age <0.05), but not for stroke and venous thrombosis. Absolute risks of adverse events (measured by the global index) per 10,000 women per year on CEE+MPA ranged from 12 excess cases for age 50–59 to 38 for age 70–79 and, for CEE, from 19 fewer cases for age 50–59 to 51 excess cases for age 70–79. Results for quality of life outcomes in both trials were mixed.
Menopausal hormone therapy has a complex pattern of risks and benefits. While appropriate for symptom management in some women, its use for chronic disease prevention is not supported by the WHI randomized trials.
clinical Identifier: NCT00000611
PMCID: PMC3963523  PMID: 24084921
8.  OPG and sRANKL serum levels and incident hip fracture in postmenopausal Caucasian women in the Women's Health Initiative Observational Study 
Bone  2013;56(2):10.1016/j.bone.2013.05.018.
The osteoprotogerin/receptor activator of NF-kappa β/receptor activator of NF-kappa β ligand (OPG/RANK/RANKL) pathway plays a critical role in bone remodeling. This study investigated associations between serum levels of OPG, soluble RANKL (sRANKL), and the ratio of OPG/sRANKL to risk of incident hip fracture.
A nested case–control study was conducted among postmenopausal, Caucasian women aged 50–79 at baseline (1993–1998), followed for hip fracture through March 2005 in the Women's Health Initiative Observational Study. 400 incident hip fracture cases were selected and individually matched to 400 controls with noprior fracture or incident hip fracture. Matching factors were baseline age, enrollment date and hormone therapy (HT) exposure. Baseline serum OPG and sRANKL levels were measured using high sensitivity ELISA. Odds ratios were computed for quartiles of each biomarker adjusting for matching factors and hip fracture risk factors.
Serum OPG was significantly associated with older age, low physical activity and poorer physical function in control women. sRANKL was inversely associated with total calcium intake in control women, but not associated with age or other fracture risk factors. The odds ratio for hip fracture comparing the highest to lowest quartiles of OPG was 2.28 (95% confidence interval (CI), 1.45–3.61) after adjusting for the matching variables (p-value for linear trend <0.001), and 1.87 (95% CI, 1.15–3.04; p for linear trend = 0.02) after adjusting for self-rated health status, physical activity and physical functioning. No significant associations between sRANKL or the ratio of OPG/sRANKL and hip fracture risk were observed.
Serum OPG levels were independently associated with a nearly twofold increased risk of hip fracture in postmenopausal women.
PMCID: PMC3832355  PMID: 23735608
RANKL; Osteoprotogerin; Hip fracture; Osteoporosis; Postmenopausal women
9.  Calcium plus vitamin D supplementation and joint symptoms in postmenopausal women in the Women's Health Initiative randomized trial 
Low vitamin D intake and levels have been associated with increased joint symptoms in some observational studies but the findings are mixed and evidence from randomized trials sparse.
To evaluate the influence of supplemental calcium and vitamin D on joint symptoms in the Women's Health Initiative randomized, placebo-controlled, clinical trial.
In post hoc analyses, the results of the WHI randomized clinical trial in which 36,282 postmenopausal women were randomized to calcium carbonate (1000 mg as elemental calcium) with vitamin D3 (400 IU) daily or placebo were examined in the 6% subgroup of 1911 participants, over-sampled for minorities, who had serial joint symptom assessment. Qualitative information on joint pain and joint swelling was collected by questionnaire before entry and 2 years after randomization. Logistic regression models were used to compare the occurrence and severity of joint symptoms across randomization groups.
At baseline, total calcium and vitamin D intakes from diet and supplements were similar in the two randomization groups. In addition, both joint pain (reported by 73%) and joint swelling (reported by 34%) were commonly reported and comparable in the supplement and placebo groups. Two years after randomization, no statistically significant differences between supplement and placebo groups were seen for joint pain frequency (74.6% compared to 75.1%, [P=0.79] for supplement and placebo groups, respectively) or joint swelling frequency (34.6% compared to 32.4%, [P=0.29], respectively) or in severity scores for either outcome. Subgroup analyses suggested study participants also using non-protocol calcium supplements at study entry may have less joint pain with supplement group randomization (interaction P-value=0.02)..
Joint symptoms are relatively common in postmenopausal women. However, daily supplementation with 1000 mg of calcium carbonate and 400 IU of vitamin D3 in a randomized, placebo-controlled clinical trial setting did not reduce the self-reported frequency or severity of joint symptoms.
PMCID: PMC4108192  PMID: 23954097
10.  Prospective Analysis of Association between Statin Use and Breast Cancer Risk in the Women's Health Initiative 
Statins are a class of cholesterol-lowering drugs that affect many intracellular pathways that may have implications for chemoprevention against cancer. Epidemiologic data on statins and breast cancer are conflicting. We analyzed updated data from the Women’s Health Initiative (WHI) to assess the relationship between statins and breast cancer risk.
The population included 154,587 postmenopausal women ages 50 to 79 years, with 7,430 pathologically confirmed cases of breast cancer identified over an average of 10.8 (SD, 3.3) years. Information on statins was collected at baseline and years one, three, six, and nine. Self- and interviewer-administered questionnaires were used to collect information on risk factors. Cox proportional hazards regression was used to calculate HRs with 95% confidence intervals (CI) to evaluate the relationship between statin use and cancer risk. Statistical tests were two-sided.
Statins were used by 11,584 (7.5%) women at baseline. The annualized rate of breast cancer was 0.42% among statin users and 0.42% among nonusers. The multivariable adjusted HR of breast cancer for users versus nonusers was 0.94 (95% CI, 0.83–1.06). In the multivariable-adjusted, time-dependent model, the HR for simvastatin was 0.87 (95% CI, 0.71–1.07). There was no significant trend by overall duration of use (P value for trend 0.68). There was no effect of tumor stage, grade, or hormone receptor status.
Overall, statins were not associated with breast cancer risk.
Our study is one of the largest prospective observational studies on this topic, and substantially adds to the literature suggesting no relationship between statins and breast cancer risk.
PMCID: PMC3889164  PMID: 23975947
11.  Impact of Nutritional Factors on Incident Kidney Stone Formation: A Report From the WHI OS 
The Journal of urology  2012;187(5):1645-1649.
Increased fluid intake, and decreased dietary sodium and animal protein intake are thought to reduce the risk of kidney stones but the role of calcium intake is controversial. We evaluated the relationship between dietary factors and incident kidney stone formation.
Materials and Methods
Secondary analysis was done of 78,293 women from the prospective WHI OS (Women’s Health Initiative Observational Study) with no history of nephrolithiasis who completed the validated food frequency questionnaire. Multivariate logistic regression was used to determine demographic and dietary factors, and supplement use independently associated with incident kidney stones.
Overall 1,952 women (2.5%) reported an incident kidney stone in 573,575 person-years of followup. The risk of incident kidney stones was decreased by 5% to 28% (p = 0.01) with higher dietary calcium intake and by 13% to 31% (p = 0.002) with higher water intake after adjusting for nephrolithiasis risk factors. Conversely higher dietary sodium intake increased the risk of nephrolithiasis by 11% to 61% (p <0.001) after adjustment with the most pronounced effect in women with the highest intake. Higher body mass index independently increased the risk of incident nephrolithiasis (adjusted OR 1.19–2.01, p <0.001). Animal protein intake was not associated with nephrolithiasis on multivariate analysis.
This study adds to the growing evidence underscoring the importance of maintaining adequate fluid and dietary calcium intake. Greater dietary calcium intake significantly decreased the risk of incident kidney stones. In contrast, excess sodium intake increased the risk of incident nephrolithiasis, especially in women with the highest intake. Animal protein intake was not independently associated with nephrolithiasis.
PMCID: PMC4165387  PMID: 22425103
kidney; kidney calculi; sodium; dietary; calcium; dietary; nutrition disorders
12.  Long Term Effects on Cognitive Function of Postmenopausal Hormone Therapy Prescribed to Women Aged 50–55 Years 
JAMA internal medicine  2013;173(15):10.1001/jamainternmed.2013.7727.
Postmenopausal hormone therapy with conjugated equine estrogens (CEE) may adversely affect older women’s cognitive function. It is not known whether this extends to younger women.
1,326 postmenopausal women, who had begun treatment in two randomized placebo-controlled clinical trials of hormone therapy when aged 50–55 years, were assessed with an annual telephone-administered cognitive battery that included measures of global (primary outcome) and domain-specific cognitive functions (verbal memory, attention, executive function, verbal fluency, and working memory). The clinical trials in which they participated had compared 0.625 mg CEE with or without 2.5 mg medroxyprogesterone acetate (MPA) over an average of 7.0 years. Cognitive testing was conducted an average of 7.2 years following the end of the trials, when women had mean age 67.2 years, and repeated one year later.
Global cognitive function scores from women who had been assigned to CEE-based therapies were similar to those from women assigned to placebo: mean [95% confidence interval] intervention effect of 0.02 [−0.08,0.12]standard deviation units (p=0.66). Similarly, no overall differences were found for any individual cognitive domain (all p>0.15). Pre-specified subgroup analyses found some evidence that CEE-based therapies may have adversely affected verbal fluency among women who had prior hysterectomy or prior use of hormone therapy: mean treatment effects of −0.17 [−0.33, −0.02] and −0.25 [−0.42, −0.08], respectively, however this may be a chance finding. We are not able to address whether initiating hormone therapy during the menopause and maintaining therapy until any symptoms are passed affects cognitive function, either in the short or longer term.
CEE-based therapies produced no overall sustained benefit or risk to cognitive function when administered to postmenopausal women aged 50–55 years.
PMCID: PMC3844547  PMID: 23797469
13.  Polymorphisms in genes related to one-carbon metabolism are not related to pancreatic cancer in PanScan and PanC4 
Cancer causes & control : CCC  2013;24(3):595-602.
The evidence of a relation between folate intake and one-carbon metabolism (OCM) with pancreatic cancer (PanCa) is inconsistent. In this study, the association between genes and single-nucleotide polymorphisms (SNPs) related to OCM and PanCa was assessed.
Using biochemical knowledge of the OCM pathway, we identified thirty-seven genes and 834 SNPs to examine in association with PanCa. Our study included 1,408 cases and 1,463 controls nested within twelve cohorts (PanScan). The ten SNPs and five genes with lowest p values (<0.02) were followed up in 2,323 cases and 2,340 controls from eight case-control studies (PanC4) that participated in PanScan2. The correlation of SNPs with metabolite levels was assessed for 649 controls from the European Prospective Investigation into Cancer and Nutrition.
When both stages were combined, we observed suggestive associations with PanCa for rs10887710 (MAT1A) (OR 1.13, 95%CI 1.04-1.23), rs1552462 (SYT9) (OR 1.27, 95%CI 1.02-1.59), and rs7074891 (CUBN) (OR 1.91, 95%CI 1.12-3.26). After correcting for multiple comparisons, no significant associations were observed in either the first or second stage. The three suggested SNPs showed no correlations with one-carbon biomarkers.
This is the largest genetic study to date to examine the relation between germline variations in OCM-related genes polymorphisms and the risk of PanCa. Suggestive evidence for an association between polymorphisms and PanCa was observed among the cohort-nested studies, but this did not replicate in the case-control studies. Our results do not strongly support the hypothesis that genes related to OCM play a role in pancreatic carcinogenesis.
PMCID: PMC4127987  PMID: 23334854
Pancreatic cancer; One-carbon metabolism; Polymorphisms; Biomarkers; Epidemiology
14.  Nutrition and Physical Activity Cancer Prevention Guidelines, Cancer Risk, and Mortality in the Women's Health Initiative 
Healthy lifestyle behaviors are recommended to reduce cancer risk and overall mortality. Adherence to cancer-preventive health behaviors and subsequent cancer risk has not been evaluated in a diverse sample of postmenopausal women. We examined the association between the American Cancer Society (ACS) Nutrition and Physical Activity Cancer Prevention Guidelines score and risk of incident cancer, cancer-specific mortality, and all-cause mortality in 65,838 postmenopausal women enrolled in the Women’s Health Initiative Observational Study. ACS guidelines scores (0–8 points) were determined from a combined measure of diet, physical activity, body mass index (current and at age 18 years), and alcohol consumption. After a mean follow-up of 12.6 years, 8,632 incident cancers and 2,356 cancer deaths were identified. The highest ACS guidelines scores compared with the lowest were associated with a 17% lower risk of any cancer [HR, 0.83; 95% confidence interval (CI), 0.75–0.92], 22% lower risk of breast cancer (HR, 0.78; 95% CI, 0.67–0.92), 52% lower risk of colorectal cancer (HR, 0.48; 95% CI, 0.32–0.73), 27% lower risk of all-cause mortality, and 20% lower risk of cancer-specific mortality (HR, 0.80; 95% CI, 0.71–0.90). Associations with lower cancer incidence and mortality were generally strongest among Asian, black, and Hispanic women and weakest among non-Hispanic whites. Behaviors concordant with Nutrition and Physical Activity Cancer Prevention Guidelines were associated with lower risk of total, breast, and colorectal cancers and lower cancer-specific mortality in postmenopausal women.
PMCID: PMC4090781  PMID: 24403289
15.  Serum uric acid in relation to endogenous reproductive hormones during the menstrual cycle: findings from the BioCycle study 
Human Reproduction (Oxford, England)  2013;28(7):1853-1862.
Do uric acid levels across the menstrual cycle show associations with endogenous estradiol (E2) and reproductive hormone concentrations in regularly menstruating women?
Mean uric acid concentrations were highest during the follicular phase, and were inversely associated with E2 and progesterone, and positively associated with FSH.
E2 may decrease serum levels of uric acid in post-menopausal women; however, the interplay between endogenous reproductive hormones and uric acid levels among regularly menstruating women has not been elucidated.
The BioCycle study was a prospective cohort study conducted at the University at Buffalo research centre from 2005 to 2007, which followed healthy women for one (n = 9) or 2 (n = 250) menstrual cycle(s).
Participants were healthy women aged 18–44 years. Hormones and uric acid were measured in serum eight times each cycle for up to two cycles. Marginal structural models with inverse probability of exposure weights were used to evaluate the associations between endogenous hormones and uric acid concentrations.
Uric acid levels were observed to vary across the menstrual cycle, with the lowest levels observed during the luteal phase. Every log-unit increase in E2 was associated with a decrease in uric acid of 1.1% (β = −0.011; 95% confidence interval (CI): −0.019, −0.004; persistent-effects model), and for every log-unit increase in progesterone, uric acid decreased by ∼0.8% (β = −0.008; 95% CI: −0.012, −0.004; persistent-effects model). FSH was positively associated with uric acid concentrations, such that each log-unit increase was associated with a 1.6% increase in uric acid (β = 0.016; 95% CI: 0.005, 0.026; persistent-effects model). Progesterone and FSH were also associated with uric acid levels in acute-effects models. Of 509 cycles, 42 were anovulatory (8.3%). Higher uric acid levels were associated with increased odds of anovulation (odds ratio 2.39, 95% CI: 1.25, 4.56).
The change in uric acid levels among this cohort of healthy women was modest, and analysis was limited to two menstrual cycles. The women in this study were healthy and regularly menstruating, and as such there were few women with high uric acid levels and anovulatory cycles.
These findings demonstrate the importance of taking menstrual cycle phase into account when measuring uric acid in premenopausal women, and confirm the hypothesized beneficial lowering effects of endogenous E2 on uric acid levels. These findings suggest that there could be an underlying association affecting both sporadic anovulation and high uric acid levels among young, regularly menstruating women. Further studies are needed to confirm these findings and elucidate the connection between uric acid and reproductive and later cardiovascular health.
This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (contract # HHSN275200403394C). No competing interests declared.
PMCID: PMC3685334  PMID: 23562957
anovulation; estradiol; menstrual cycle; premenopausal women; uric acid
16.  Realignment and multiple imputation of longitudinal data: an application to menstrual cycle data 
Reproductive hormone levels are highly variable among premenopausal women during the menstrual cycle. Accurate timing of hormone measurement is essential, especially when investigating day- or phase-specific effects. The BioCycle Study used daily urine home fertility monitors to help detect the luteinising hormone (LH) surge in order to schedule visits with biologically relevant windows of hormonal variability. However, as the LH surge is brief and cycles vary in length, relevant hormonal changes may not align with scheduled visits even when fertility monitors are used. Using monitor data, measurements were reclassified according to biological phase of the menstrual cycle to more accurate cycle phase categories. Longitudinal multiple imputation methods were applied after reclassification if no visit occurred during a given menstrual cycle phase. Reclassified cycles had more clearly defined hormonal profiles, with higher mean peak hormones (up to 141%) and reduced variability (up to 71%). We demonstrate the importance of realigning visits to biologically relevant windows when assessing phase- or day-specific effects and the feasibility of applying longitudinal multiple imputation methods. Our method has applications in settings where missing data may occur over time, where daily blood sampling for hormonal measurements is not feasible, and in other areas where timing is essential.
PMCID: PMC4059763  PMID: 21819426
menstrual cycle; multiple imputation; statistical methodology; oestradiol 2; luteinising hormone; diet; fibre; missing data
17.  Self-report of Fruit and Vegetable Intake that meets the 5 A Day Recommendation is Associated with Reduced Levels of Oxidative Stress Biomarkers and Increased Levels of Antioxidant Defense in Premenopausal Women 
Oxidative stress has been associated with a variety of chronic diseases and reproductive disorders. Fruits and vegetables may contribute to antioxidant vitamin and micronutrient levels and reduce oxidative stress.
To investigate the effect of meeting the 5 A Day recommendation for fruit and vegetable consumption on biomarkers of oxidative damage and antioxidant defense.
In this longitudinal study, healthy premenopausal women (n=258) were followed for ≤2 menstrual cycles with ≤16 oxidative stress measures timed to cycle phase.
Main outcome measures
Plasma concentrations of F2-isoprostane, 9-hydroxyoctadecadieneoic acid (9-HODE), and 13-hydroxyoctadecadieneoic acid (13-HODE), erythrocyte activity of superoxide dismutase (SOD), glutathione reductase (GSHR), and glutathione peroxidase (GPx), as well as blood micronutrient concentrations were measured. Dietary intake was assessed by Food Frequency Questionnaires (FFQ, 1/cycle) and 24-hour recalls (≤4/cycle).
Statistical analyses performed
Fruit and vegetable servings were dichotomized based on the 5 A Day recommendation. Linear mixed models with repeated measures were used to analyze lipid peroxidation markers, antioxidant vitamins, and antioxidant enzymes by cycle phase and in association with usual fruit and vegetable intake.
For both 24-hour recall (timed to cycle phase) and cycle-specific FFQ, meeting the 5 A Day recommendation was associated with decreased F2-isoprostanes (24-hour recall β= −0.10 (95% CI: −0.12, −0.07); FFQ β= −0.14 (95% CI: −0.18, −0.11)). GSHR was lower in association with typical 5A Day consumption by FFQ but not in the phase-specific analysis. Higher levels of ascorbic acid, lutein, β-carotene and β-cryptoxanthin were observed with both 5 A Day measures.
Meeting the 5 A Day recommendation was associated with lower oxidative stress and improved antioxidant status in analyses of typical diet (FFQ) and in menstrual cycle phase-specific analyses using 24-hour recalls. Green salads were commonly eaten and increasing intake of salads may be a useful strategy to impact oxidation in reproductive aged women.
PMCID: PMC3660508  PMID: 23522825
Fruit and vegetable intake; oxidative stress; premenopausal women; antioxidant
18.  Estrogen Alone and Joint Symptoms in the Women’s Health Initiative Randomized Trial 
Menopause (New York, N.Y.)  2013;20(6):10.1097/GME.0b013e31828392c4.
While joint symptoms are commonly reported after menopause, observational studies examining exogenous estrogen influence on joint symptoms provide mixed results. Against this background, estrogen alone effects on joint symptoms were examined in post hoc analyses in the Women’s Health Initiative randomized, placebo-controlled clinical trial.
10,739 postmenopausal women with prior hysterectomy were randomized to receive daily oral conjugated equine estrogen (0.625 mg/d) or matching placebo. The frequency and severity of joint pain and joint swelling were assessed by questionnaire at entry and year 1 from all participants and in a random 9.9% subsample (n=1062) following years 3 and 6. Logistic regression models were used to compare frequency and severity of symptoms by randomization group. Sensitivity analyses evaluated adherence influence on symptoms.
At baseline, joint pain and swelling were closely comparable in the randomization groups (about 77% with joint pain and 40% with joint swelling). After one year, joint pain frequency was significantly lower in the estrogen alone compared to the placebo group (76.3% vs 79.2%, P=0.001) as was joint pain severity and the difference in pain between randomization groups persisted through year 3. However, joint swelling frequency was higher in the estrogen alone group (42.1% vs 39.7%, P=0.02). Adherence adjusted analyses strengthen the estrogen association with reduced joint pain but attenuated the estrogen association with increased joint swelling.
The current findings suggest that estrogen alone use in postmenopausal women results in a modest but sustained reduction in the frequency of joint pain.
PMCID: PMC3855295  PMID: 23511705
Estrogen; joint pain; joint swelling; Women’s Health Initiative; postmenopausal women; randomized clinical trial
19.  Effect of Daily Fiber Intake on Luteinizing Hormone Levels in Reproductive-Aged Women 
European journal of nutrition  2011;51(2):249-253.
To evaluate whether the association between fiber intake and LH levels is driven by the association between fiber and estradiol, or whether there is an independent association.
A prospective cohort of 259 premenopausal women were followed for up to 2 menstrual cycles. Estrogen and LH were measured ≤ 8 times per cycle at visits scheduled using fertility monitors. Diet was assessed ≤ 4 times per cycle by 24-hour recall. Linear mixed models on the log scale of hormones were utilized to evaluate the total effects of fiber intake. Inverse probability weights were utilized to estimate the independent effect of fiber on LH levels.
In unweighted analyses, we observed a significant, inverse association between fiber intake (in 5g/day increments) and log LH levels (β, −0.051, 95% Confidence Interval (CI), −0.100, −0.002). No association was observed in the weighted analyses, after estradiol levels were taken into account (β, −0.016, 95% CI, −0.060, 0.027).
The decreased levels of LH associated with high fiber intake were attenuated after taking estradiol levels into account, suggesting that the association between fiber and LH is most likely a consequence of fiber’s impact on estradiol and not due to an independent mechanism.
PMCID: PMC4025915  PMID: 21667182
dietary fiber; luteinizing hormone; estradiol; women
20.  Estrogen Plus Progestin and Breast Cancer Incidence and Mortality in the Women’s Health Initiative Observational Study 
In the Women’s Health Initiative (WHI) randomized trial, estrogen plus progestin increased both breast cancer incidence and mortality. In contrast, most observational studies associate estrogen plus progestin with favorable prognosis breast cancers. To address differences, a cohort of WHI observational study participants with characteristics similar to the WHI clinical trial was studied.
We identified 41 449 postmenopausal women with no prior hysterectomy and mammogram negative within 2 years who were either not hormone users (n = 25 328) or estrogen and progestin users (n = 16 121). Multivariable-adjusted Cox proportional hazard regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CI). All statistical tests were two-sided.
After a mean of 11.3 (SD = 3.1) years, with 2236 breast cancers, incidence was higher in estrogen plus progestin users than in nonusers (0.60% vs 0.42%, annualized rate, respectively; HR = 1.55, 95% CI = 1.41 to 1.70, P < .001). Women initiating hormone therapy closer to menopause had higher breast cancer risk with linear diminishing influence as time from menopause increased (P < .001). Survival after breast cancer, measured from diagnosis, was similar in combined hormone therapy users and nonusers (HR = 1.03, 95% CI = 0.79 to 1.35). On a population basis, there were somewhat more deaths from breast cancer, measured from cohort entry (HR = 1.32, 95% CI = 0.90 to 1.93, P = .15), and more all-cause deaths after breast cancer (HR = 1.65, 95% CI = 1.29 to 2.12, P < .001) in estrogen plus progestin users than in nonusers.
Consistent with WHI randomized trial findings, estrogen plus progestin use is associated with increased breast cancer incidence. Because prognosis after diagnosis on combined hormone therapy is similar to that of nonusers, increased breast cancer mortality can be expected.
PMCID: PMC3691942  PMID: 23543779
21.  Validation of Different Instruments for Caffeine Measurement Among Premenopausal Women in the BioCycle Study 
American Journal of Epidemiology  2013;177(7):690-699.
Effects of caffeine on women's health are inconclusive, in part because of inadequate exposure assessment. In this study we determined 1) validity of a food frequency questionnaire compared with multiple 24-hour dietary recalls (24HDRs) for measuring monthly caffeine and caffeinated beverage intakes; and 2) validity of the 24HDR compared with the prior day's diary record for measuring daily caffeinated coffee intake. BioCycle Study (2005–2007) participants, women (n = 259) aged 18–44 years from western New York State, were followed for 2 menstrual cycles. Participants completed a food frequency questionnaire at the end of each cycle, four 24HDRs per cycle, and daily diaries. Caffeine intakes reported for the food frequency questionnaires were greater than those reported for the 24HDRs (mean = 114.1 vs. 92.6mg/day, P = 0.01) but showed high correlation (r = 0.73, P < 0.001) and moderate agreement (К = 0.51, 95% confidence interval: 0.43, 0.57). Women reported less caffeinated coffee intake in their 24HDRs compared with their corresponding diary days (mean = 0.51 vs. 0.80 cups/day, P < 0.001) (1 cup = 237 mL). Although caffeine and coffee exposures were highly correlated, absolute intakes differed significantly between measurement tools. These results highlight the importance of considering potential misclassification of caffeine exposure.
PMCID: PMC3657531  PMID: 23462965
beverages; caffeine; diet; mental recall; nutrition assessment; questionnaires; validation studies; women
22.  Association of Cadmium, Lead and Mercury with Paraoxonase 1 Activity in Women 
PLoS ONE  2014;9(3):e92152.
The activity of paraoxonase 1 (PON1), an antioxidant enzyme whose polymorphisms have been associated with cancer risk, may be associated with metals exposure.
To evaluate PON1 activity in relation to cadmium, lead, and mercury levels in healthy, premenopausal women.
Women from upstate New York were followed for ≥ two menstrual cycles. Repeated measures linear mixed models estimated the association between cadmium, lead, and mercury levels (by tertile: T1, T2, T3) and PON1 arylesterase (PON1A) and PON1 paraoxonase (PON1P) activity, separately. Analyses were stratified by PON1 Q192R phenotype and un-stratified.
Median blood cadmium, lead, and mercury concentrations were 0.30 µg/L, 0.87 µg/dL, and 1.15 µg/L. In un-stratified analyses cadmium and mercury were associated with decreased PON1A activity (T2 vs. T1; not T3 vs. T1) but metals were not associated with PON1P. Phenotypes were distributed between QQ (n = 99), QR (n = 117), and RR (n = 34). Cadmium was associated with decreased PON1A activity for QR and RR phenotypes comparing T2 vs. T1 (−14.4% 95% confidence interval [CI] [−20.1, −8.4] and −27.9% [−39.5, −14.0],). Lead was associated with decreased PON1A (RR phenotype, T3 vs. T1 −18.9% [−32.5, −2.5]; T2 vs. T1 −19.6% [−32.4, −4.4]). Cadmium was associated with lower PON1P comparing T2 vs. T1 for the RR (−34.9% [−51.5, −12.5]) and QR phenotypes (−9.5% [−18.1, 0.0]) but not comparing T3 vs. T1. Cadmium was associated with increases in PON1P levels (QQ phenotype, T3 vs. T1 24.5% [7.0, 44.9]) and mercury was associated with increased PON1A levels (QQ phenotype, T3 vs. T1 6.2% [0.2, 12.6]). Mercury was associated with decreased PON1P (RR phenotype, T2 vs. T1 −22.8 [−37.8, −4.1]).
Blood metals were associated with PON1 activity and these effects varied by phenotype. However, there was not a linear dose-response and these findings await replication.
PMCID: PMC3969354  PMID: 24682159
23.  The association of red blood cell n-3 and n-6 fatty acids to dietary fatty acid intake, bone mineral density and hip fracture risk in The Women’s Health Initiative 
Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFA) in red blood cells (RBC) are an objective indicator of PUFA status and may be related to hip fracture risk.
The primary objective of this study was to examine RBC PUFAs as predictors of hip fracture risk in postmenopausal women.
A nested case-control study (n=400 pairs) was completed within the Women’s Health Initiative (WHI) using 201 incident hip fracture cases from the Bone Mineral Density (BMD) cohort, along with 199 additional incident hip fracture cases randomly selected from the WHI Observational Study. Cases were 1:1 matched on age, race, and hormone use with non-hip fracture controls. Stored baseline RBCs were analyzed for fatty acids using gas chromatography. After removing degraded samples, 324 matched pairs were included in statistical analyses. Stratified Cox proportional hazard models were constructed according to case-control pair status; risk of fracture was estimated for tertiles of RBC PUFA.
In adjusted hazard models, lower hip fracture risk was associated with higher RBC α-linolenic acid [Hazard ratio (HR) Tertile 3 (T3): 0.44; 95% CI: 0.23-0.85; p for linear trend 0.0154)], eicosapentaenoic acid (HR T3: 0.46; 95% CI: 0.24-0.87; p for linear trend 0.0181) and total n-3 PUFAs (HR T3: 0.55; 95% CI: 0.30-1.01; p for linear trend 0.0492). Conversely, hip fracture nearly doubled with the highest RBC n-6/n-3 ratio (HR T3: 1.96; 95% CI: 1.03-3.70; p for linear trend 0.0399). RBC PUFAs were not associated with BMD. RBC PUFAs were indicative of dietary intake of marine n-3 PUFAs (Spearman’s rho=0.45, p<0.0001), total n-6 PUFAs (rho=0.17, p<0.0001) and linoleic acid (rho= 0.09, p<0.05).
These results suggest that higher RBC α-linolenic acid, as well as eicosapentaenoic acid and total n-3 PUFAs, may predict lower hip fracture risk. Contrastingly, a higher RBC n-6/n-3 ratio may predict higher hip fracture risk in postmenopausal women.
PMCID: PMC3785326  PMID: 23018646
Hip fracture; polyunsaturated fatty acids; omega-3 (n-3) fatty acids; omega-6 (n-6) fatty acids; bone mineral density
24.  Body mass index, physical activity, and survival after endometrial cancer diagnosis: Results from the Women’s Health Initiative 
Gynecologic oncology  2012;128(2):181-186.
While low physical activity and high body mass index (BMI) have been associated with higher endometrial cancer incidence, no previous studies have evaluated the association between physical activity and survival after endometrial cancer diagnosis, and studies on BMI and survival have not been performed in a prospective cohort.
We examined pre-diagnosis BMI and moderate- to vigorous-intensity physical activity in relation to overall and disease-specific survival among 983 postmenopausal women who were diagnosed with endometrial cancer in the Women’s Health Initiative Observational Study and Clinical Trials.
Over a median 5.2 (max 14.1) years from diagnosis to death or end of follow-up, 163 total deaths were observed, 66 of which were due to endometrial cancer. We observed a higher all-cause mortality hazard ratio (HR)=1.85 (95% CI 1.19–2.88) comparing women with a BMI ≥35 kg/m2 to women with BMI <25 kg/m2. For endometrial cancer-specific mortality the HR=2.23 (95% CI 1.09–4.54) comparing extreme BMI categories. To examine histologic subtypes we analyzed type I endometrial tumors separately and found a HR=1.20 (95% CI 1.07–1.35) associated with all-cause mortality for each 5-unit change in BMI. Moderate- to vigorous-intensity physical activity was not associated with all-cause or endometrial cancer-specific mortality.
Pre-diagnosis BMI, but not physical activity, was associated with survival among women with endometrial cancer. Future studies should investigate mechanisms and timing of BMI onset to better understand the burden of disease attributable to BMI.
PMCID: PMC3552067  PMID: 23127972
endometrial carcinoma; survivorship; body mass index; physical activity
25.  Sleep Disturbance and Incidence of Thyroid Cancer in Postmenopausal Women The Women's Health Initiative 
American Journal of Epidemiology  2012;177(1):42-49.
Sleep disturbance has been found to be associated with numerous adverse health outcomes, including cancers. However, no epidemiologic study has examined the relation between sleep disturbance and thyroid cancer risk. A total of 142,933 postmenopausal women who were 50–79 years of age and enrolled in the Women's Health Initiative between September 1, 1993, and December 31, 1998, were followed up for a mean of 11 years. Cox proportional-hazard regression models were used to estimate hazard ratios and 95% confidence intervals for sleep disturbance (insomnia and sleep duration) and risk of thyroid cancer. Insomnia score was measured using a validated 5-item Women's Health Initiative Insomnia Rating Scale. Overall, a total of 295 thyroid cancer cases were identified. After adjustment for potential confounders, women with greater insomnia scores had a significantly higher risk of thyroid cancer than did women with low scores (hazard ratio = 1.44, 95% confidence interval: 1.01, 2.05). The significant association between insomnia score and thyroid cancer was confined to nonobese women (hazard ratio = 1.71, 95% confidence interval: 1.12, 2.62) and was not seen in obese women (hazard ratio = 0.94 95% confidence interval: 0.48, 1.84) (P for interaction = 0.07). In conclusion, postmenopausal women with greater insomnia scores, especially nonobese women, had a significantly increased risk of thyroid cancer. More studies are needed to confirm these findings.
PMCID: PMC3590038  PMID: 23221728
insomnia; sleep disorder; sleep disturbance; risk factors; thyroid cancer

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