The purpose of this study is to quantify cancer mortality in relationship to organ-specific radiation dose among women irradiated for benign gynecologic disorders. Included in this study are 12,955 women treated for benign gynecologic disorders at hospitals in the Northeastern U.S. between 1925 and 1965; 9,770 women treated by radiation and 3,186 women treated by other methods. The average age at treatment was 45.9 years (range, 13–88 years), and the average follow-up period was 30.1 years (maximum, 69.9 years). Radiation doses to organs and active bone marrow were reconstructed by medical physicists using original radiotherapy records. The highest doses were received by the uterine cervix (median, 120 Gy) and uterine corpus (median, 34 Gy), followed by the bladder, rectum and colon (median, 1.7–7.2 Gy), with other abdominal organs receiving median doses ≤1 Gy and organs in the chest and head receiving doses <0.1 Gy. Standardized mortality rate ratios relative to the general U.S. population were calculated. Radiation-related risks were estimated in internal analyses using Poisson regression models. Mortality was significantly elevated among irradiated women for cancers of the uterine corpus, ovary, bladder, rectum, colon and brain, as well as for leukemia (exclusive of chronic lymphocytic leukemia) but not for cancer of the cervix, Hodgkin or non-Hodgkin lymphoma, multiple myeloma, or chronic lymphocytic leukemia. Evidence of a dose-response was seen for cancers of the ovary [excess relative risk (ERR) 0.31/Gy, P < 0.001], bladder (ERR = 0.21/Gy, P = 0.02) and rectum (ERR = 0.23/Gy, P = 0.05) and suggested for colon (ERR = 0.09/Gy, P = 0.10), but not for cancers of the uterine corpus or brain nor for non-chronic lymphocytic leukemia. Relative risks of mortality due to cancers of the stomach, pancreas, liver and kidney were close to 1.0, with no evidence of dose-response over the range of 0–1.5 Gy. Breast cancer was not significantly associated with dose to the breast or ovary. Mortality due to cancers of heavily irradiated organs remained elevated up to 40 years after irradiation. Significantly elevated radiation-related risk was seen for cancers of organs proximal to the radiation source or fields (bladder, rectum and ovary), as well as for non-chronic lymphocytic leukemia. Our results corroborate those from previous studies that suggest that cells of the uterine cervix and lymphopoietic system are relatively resistant to the carcinogenic effects of radiation. Studies of women irradiated for benign gynecologic disorders, together with studies of women treated with higher doses of radiation for uterine cancers, provide quantitative information on cancer risks associated with a broad range of pelvic radiation exposures.
Adherence to the Mediterranean Diet (MD) high in fruits, vegetables and monounsaturated fats, has been associated with lower body mass index. Associations with measured body fat, including regional adiposity, have not been previously investigated. We examined the associations between the alternate Mediterranean Diet Score (aMED), anthropometry and measured adiposity by dual energy x-ray absorptiometry.
This study included 248 healthy females, aged 18–44 years from the BioCycle Study. Each woman’s aMED (range 0–9) was calculated from up to eight 24-hr dietary recalls over 1–2 menstrual cycles (>97% had ≥7 recalls). Multiple linear regression was used to determine whether aMED and its specific components were associated with total and regional adiposity after adjusting for age, race, education, physical activity and energy intake.
Participants had an average (SD) aMED of 4.2 (1.7) and percent body fat of 29.5 (6.0)%. Significant inverse associations were found between aMED and all the examined adiposity measures except waist to hip ratio. Among the DXA measures, a 1-unit increment in aMED was associated with a 0.06 (95% CI:−0.09,−0.02) lower trunk-to-leg fat ratio (T/L), a measure of upper to lower body fat. In an analysis examining T/L as an outcome with the separate components of the aMED, T/L was lower with increased legume consumption (β=−0.280, 95% CI:−0.550,−0.010) but was higher with increased consumption of red and processed meat (β=0.060, 95% CI:0.002,0.117).
Adherence to the aMED was associated with lower total and regional adiposity, adding to the mounting evidence of the health benefits of the MD.
Mediterranean Diet; body fat; trunk fat; regional adiposity; obesity; body mass index; DXA
Vitamin D has anti-inflammatory and anti-microbial properties that, together with its influence on bone health, may confer periodontal benefit.
We investigated cross-sectional associations (1997–2000) between plasma 25-hydroxyvitamin D concentrations [25(OH)D] and periodontal measure among 920 postmenopausal women. Chronic measures of disease were defined based on: 1) alveolar crestal height (ACH) measures from intraoral radiographs and tooth loss, and the 2) Center for Disease Control and Prevention (CDC)/American Academy of Periodontology (AAP) criteria using measures of clinical attachment level (CAL) and probing pocket depth (PD). Acute oral inflammation was assessed by the % of gingival sites that bled upon assessment with a probe. Logistic regression was used to estimate the odds ratios (OR) and 95% confidence intervals (CIs) for periodontal disease among participants with adequate ([25(OH)D]≥50 nmol/L) compared to deficient/inadequate ([25(OH)D]<50 nmol/L) vitamin D status adjusted for age, dental visit frequency, and body mass index.
No association was observed between vitamin D status and periodontal disease defined by ACH and tooth loss (adjusted OR=0.96, 95% CI: 0.68–1.35). In contrast, women with adequate compared to deficient/inadequate vitamin D status had a 33% lower odds (95% CI: 5%–53%) of periodontal disease defined using the CDC/AAP definition and a 42% lower odds (95% CI: 21%-58%) of having ≥50% of gingival sites that bled.
Vitamin D status was inversely associated with gingival bleeding, an acute measure of oral health and inflammation and inversely associated with clinical categories of chronic periodontal disease that incorporated PD, an indicator of oral inflammation. However, vitamin D was not associated with chronic periodontal disease based on measures of ACH in combination with tooth loss.
vitamin D; 25-hydroxyvitamin D; periodontal diseases; postmenopausal period; epidemiology; women
The aim of this study was to investigate how serum retinol and carotenoids (β-carotene, β-cryptoxanthin, lutein/zeaxanthin, lycopene) are associated with biomarkers of insulin resistance.
Research Methods and Procedures
The BioCycle Study (2005–2007) is a prospective cohort of 259 healthy premenopausal women. Fasting serum samples were collected at up to sixteen clinic visits, from which retinol, carotenoids, insulin, glucose, and sex hormone-binding globulin (SHBG) were measured. Insulin resistance was estimated by the homeostasis model assessment (HOMA-IR). Linear mixed models were used to determine associations adjusting for age, race, body mass index (BMI), education, smoking, physical activity, triglycerides, and energy intake.
Retinol was positively associated with HOMA-IR (β = 0.19 (95% CI: 0.07, 0.32)) units per ug/mL increase in retinol; the relationship was driven by insulin (β = 0.20 (95% CI: 0.08, 0.31)). Retinol was inversely associated with SHBG (β = −0.22 (95% CI: −0.28, −0.16)). Although no significant associations were found between serum carotenoids and HOMA-IR, β-carotene was positively associated with SHBG and β-cryptoxanthin inversely with fasting plasma glucose.
Results indicate a possible role for serum retinol in the pathogenesis of type 2 diabetes. However, they do not support a strong association between individual or total serum carotenoids and insulin resistance.
To investigate the influence of adiposity on patterns of sex hormones across the menstrual cycle among regularly menstruating women.
The BioCycle Study followed 239 healthy women for 1–2 menstrual cycles, with up to 8 visits per cycle timed using fertility monitors.
Serum estradiol (E2), progesterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and sex hormone binding globulin (SHBG) were measured at each visit. Adiposity was measured by anthropometry and by dual energy x-ray absorptiometry. Differences in hormonal patterns by adiposity measures were estimated using nonlinear mixed models, which allow for comparisons in overall mean levels, amplitude (i.e. lowest to highest level within each cycle), and shifts in timing of peaks while adjusting for age, race, energy intake, and physical activity.
Compared to normal weight women (n=154), obese women (BMI≥30 kg/m2, n=25) averaged lower levels of progesterone (−15%, P=0.003), LH (−17%, P=0.01), FSH (−23%, P=0.001) and higher free E2 (+22%, p=0.001) across the cycle. To lesser magnitudes, overweight women (BMI: 25–30, n=60) also exhibited differences in the same directions for mean levels of free E2, FSH, and LH. Obese women experienced greater changes in amplitude of LH (9%, p=0.002), and FSH (8%, p=0.004), but no differences were observed among overweight women. Higher central adiposity by top compared to bottom tertile of trunk-to-leg fat ratio by DXA was associated with lower total E2 (−14%, p=0.005) and FSH (−15%, p=0.001). Peaks in FSH and LH occurred later (~0.5 day) in the cycle among women with greater central adiposity.
Greater total and central adiposity were associated with changes in mean hormone levels. The greater amplitudes observed among obese women suggest compensatory mechanisms at work to maintain hormonal homeostasis. Central adiposity may be more important in influencing timing of hormonal peaks than total adiposity.
adiposity; body mass index; body composition; sex hormones; menstrual cycle; progesterone; estradiol
Epidemiological evidence of diabetes as a lung cancer risk factor is limited and conflicting. Therefore, we assessed associations among diabetes, diabetes therapy, and lung cancer risk in postmenopausal women participating in the Women’s Health Initiative (WHI) study.
RESEARCH DESIGN AND METHODS
Postmenopausal women (n = 145,765), ages 50–79 years, including 8,154 women with diabetes at study entry were followed for a mean of 11 years with 2,257 lung cancers diagnosed. Information on diabetes therapy was collected via two methods (self-reported information on treatment history collected on a questionnaire at baseline and a face-to-face review of current medication containers that participants brought to the baseline visit). Lung cancers were confirmed by central medical record and pathology report review. Cox proportional hazards regression models adjusted for lung cancer risk factors were used to estimate hazard ratios (HRs) (95% CI) for diagnosis of diabetes and treatment of disease as risk factors for lung cancer.
Compared with women without diabetes, women with self-reported treated diabetes had a significantly higher risk of lung cancer (HR 1.27 [95% CI 1.02–1.59]), with risks increasing for women with diabetes requiring insulin treatment (1.71 [1.15–2.53]). However, we did not observe a significant association between lung cancer risk and diabetes not treated with medication or with duration of diabetes.
Postmenopausal women with treated diabetes, especially those using insulin, have a significantly higher risk of lung cancer. The influence of diabetes severity and specific classes of therapy for diabetes on lung cancer risk require future study.
We examined the association between new-onset breast tenderness and change in mammographic density after initiation of conjugated equine estrogens (CEE).
We analyzed baseline, year 1, and year 2 data from 695 participants of the Women's Health Initiative Estrogen + Progestin (daily CEE 0.625 mg + medroxyprogesterone acetate 2.5 mg [MPA] or placebo) and Estrogen-Alone (CEE 0.625 mg or placebo) trials who participated in the Mammogram Density Ancillary Study. Using multivariable repeated measures models, we analyzed the association between new-onset breast tenderness (i.e. absence of baseline tenderness and presence of tenderness at year 1 follow-up) and change from baseline in percent mammographic density.
Active therapy increased the odds of new-onset breast tenderness (CEE + MPA vs. placebo risk ratio [RR] 3.01, 95% confidence interval [95% CI] 1.96-4.62; CEE vs. placebo RR 1.70, 95% CI 1.14-2.53). Among women assigned to CEE + MPA, mean increase in mammographic density was greater among participants reporting new-onset of breast tenderness than among participants without new-onset breast tenderness (11.3% vs. 3.9% at year 1, 9.4% vs. 3.2% at year 2, P < 0.001). Among women assigned to CEE alone, increase in mammographic density at year 1 follow-up was not significantly different in women with new-onset breast tenderness compared to women without new-onset breast tenderness (2.4% vs. 0.6% at year 1, 2.2% vs. 1.0% at year 2, P = 0.30).
The new-onset of breast tenderness after initiation of CEE + MPA, but not CEE alone, is associated with greater increases in mammographic density.
Mammographic density; breast density; breast tenderness; mastalgia; mastodynia; conjugated equine estrogen; medroxyprogesterone acetate
Current literature examining associations between vitamin D and chronic disease generally use a single assessment of 25-hydroxyvitamin D (25(OH)D), assuming an individual’s 25(OH)D concentration is consistent over time.
We investigated the intraindividual variability between two measures of plasma 25(OH)D concentrations collected ~5 years apart (1997-2000 to 2002-2005) in 672 postmenopausal women participating in the Women’s Health Initiative. Plasma 25(OH)D was assessed using the DiaSorin LIAISON® chemiluminescence immunoassay. The within-pair coefficient of variation (CV) was 4.9% using blinded quality control samples. Mean and standard deviations (SD) of 25(OH)D at the two time points were compared using a paired t-test. An intraindividual CV and intra-class correlation coefficient (ICC) were used to assess intraindividual variability. A Spearman correlation coefficient (r) assessed the strength of the association between the two measures and concordance in vitamin D status at two time points
Mean 25(OH)D concentrations (nmol/L) significantly increased over time from 60.0 (SD=22.2) to 67.8 (SD=22.2) (p<0.05). The CV was 24.6%, the ICC (95% Confidence Interval (CI)) was 0.59 (0.54-0.64), and the Spearman r was 0.61 (95% CI=0.56-0.66). Greater concordance over 5 years was observed in participants with sufficient compared to deficient or inadequate baseline 25(OH)D concentrations (weighted kappa=0.39). Reliability measures were moderately influenced by season of blood draw and vitamin D supplement use.
There is moderate intraindividual variation in 25(OH)D concentrations over approximately 5 years.
These data support the use of a one-time measure of blood 25(OH)D in prospective studies with ≤ 5 years of follow-up.
25-hydroxyvitamin D; intraindividual variation; vitamin D; biomarkers; postmenopausal women
The Women’s Health Initiative Estrogen-alone Trial was stopped early after 7.1 years (mean) follow-up. Postintervention health outcomes have not been reported.
To examine health outcomes associated with randomization to conjugated equine estrogen (CEE) treatment in women with prior hysterectomy after 10.7 (mean) years follow-up through August 2009.
Design, Setting, and Participants
The intervention phase was a double-blind, placebo-controlled, randomized trial of CEE, 0.625 mg/day or placebo in 10,739 US postmenopausal women aged 50–79 years with prior hysterectomy. Follow-up continued after the planned trial completion date among 7645 (78%) surviving participants who provided written consent.
Main Outcome Measures
The primary outcomes were CHD and invasive breast cancer. A global index of risks and benefits included these 2 endpoints plus stroke, pulmonary embolism, colorectal cancer, hip fracture, and death.
Postintervention risks for women assigned to CEE vs. placebo were similar to the intervention period for CHD (annualized rates 0.64% in CEE vs. 0.67% in placebo; hazard ratio (HR)=0.97, 95% CI 0.75–1.25), breast cancer (0.26% vs. 0.34%; HR=0.75, 0.51–1.09), and total mortality (1.47% vs. 1.48%; HR=1.00, CI 0.84–1.18). Postintervention risks changed for stroke (0.36% vs. 0.41%; HR=0.89, 0.64–1.24), deep vein thrombosis (0.17% vs. 0.27%; HR=0.63, 0.41–0.98), and hip fracture (0.36% vs. 0.28%; HR=1.27, 0.88–1.82). Over the entire follow-up, lower breast cancer incidence in the CEE group persisted (0.27% vs. 0.35%; HR=0.77, 0.62–0.95). Health outcomes were more favorable for younger compared to older women for CHD (p for age-interaction=0.049), total MI (p-interaction=0.007), colorectal cancer (p-interaction=0.04), total mortality (p-interaction =0.04), and global index (p-interaction=0.009).
Among postmenopausal women with prior hysterectomy followed for 10.7 years, CEE use for a median of 5.9 years was not associated with an increased or decreased risk of CHD, deep vein thrombosis, stroke, hip fracture, colorectal cancer, or total mortality. A decreased risk of breast cancer persisted.
estrogen; coronary heart disease; breast cancer; stroke; pulmonary embolism; hip fracture; colorectal cancer; total mortality; Women’s Health Initiative
Cytokines play a major role in bone remodeling in vitro and in animal models, with evidence supporting the involvement of inflammatory markers in the pathogenesis of osteoporosis. However, less is known about the longitudinal association of inflammatory markers with hip fracture. We tested whether high receptor levels of pro-inflammatory cytokines are associated with an increased risk of hip fracture in older women. We used a nested case-control study design from the Women's Health Initiative Observational Study (WHI-OS) and selected 400 cases with physician adjudicated incident hip fractures and 400 age, race, and date of blood draw matched controls. Participants were chosen from 39,795 postmenopausal women without previous hip fractures, not using estrogens or other bone-active therapies. Incident hip fractures (median follow-up 7.1 years) were verified by review of radiographs and confirmed by blinded central adjudicators. Hip fractures with a pathological cause were excluded. In multivariable models, the risk of hip fracture for subjects with the highest levels of inflammatory markers (quartile 4) compared with those with lower levels (quartiles 1, 2, and 3) was 1.43 (95% CI, 0.98 to 2.07) for IL-6 SR and 1.41 (95% CI, 0.97 to 2.05) for TNF SR1 and 1.57 (95% CI, 1.09 to 2.25) for TNF SR2. In subjects with all three markers in the highest quartile, the risk ratio of fracture was 2.27 (95% CI to 1.04 to 4.93) in comparison with subjects with 0 or 1 elevated marker(s) (p trend = 0.042). Elevated levels of inflammatory markers for all 3 cytokine soluble receptors were associated with an increased risk of hip fractures in older women. Future clinical trials should test whether interventions to decrease inflammatory marker levels reduces hip fractures.
Inflammation; hip fractures; cytokines; women; osteoporosis; nested case-control
In contrast to many observational studies, women in the Women’s Health Initiative (WHI) trial randomised to oestrogen-alone had lower invasive breast cancer incidence than those assigned placebo. Influence of oestrogen use on breast cancer mortality has not been reported.
Between 1993 and 1998, the WHI enrolled 10,739 postmenopausal women from 40 US centres into a randomized, double-masked, placebo-controlled trial evaluating oral conjugated equine oestrogen (0·625 mg/d). Women aged 50–79 years with prior hysterectomy, anticipated 3-year survival, and mammography clearance were randomized by a computerized, permuted block algorithm, stratified by age group and centre, to receive oestrogen or matching placebo. The trial was terminated early, in 2004, for an adverse effect on stroke. In extended follow-up through August 2009, we assessed long-term effects of oestrogen use on invasive breast cancer incidence, tumor characteristics, and mortality. Cox regression models were used to estimate intention-to-treat hazard ratios [HRs].
After a median 11.8 (interquartile range [IQR], 9·1 to 12·9) years of follow-up, conjugated equine oestrogen-alone use for a median of 5·9 (IQR, 2·5 to 7·3) years was associated with lower invasive breast cancer incidence compared to placebo (151 vs. 199 breast cancers; annualized rates, 0·27% vs. 0·35%; HR, 0·77; 95% confidence interval [CI], 0·62 to 0·95; P=0·02) with no difference (P=0·76) between intervention-phase (HR, 0·79; 95% CI, 0·61 to 1·02) and post-intervention effects (HR, 0·75; 95% CI: 0·51 to 1·09) ). Potential effect modification by benign breast disease (P=0·01) and family history of breast cancer (P=0·02) was observed. In the oestrogen-alone group fewer women died from breast cancer (6 vs.16 deaths; annualized rates 0·009% vs. 0·024%; HR, 0·37; 95% CI, 0·13 to 0·91; P=0.03) and fewer died from all causes after a breast cancer diagnosis (30 vs. 50 deaths; annualized rates, 0·046% vs. 0·076%; HR, 0·62; 95% CI, 0·39 to 0·9;, P=0·04).
Women with hysterectomy seeking relief of climacteric symptoms may be given reassurance regarding breast cancer influence of oestrogen use consistent with durations observed in this trial. However, these findings do not support oestrogen use for breast cancer risk reduction since this benefit may not apply to populations at higher risk.
US National Heart, Lung and Blood Institute. Wyeth provided study medications.
menopausal hormone therapy; breast neoplasms; breast cancer mortality; prevention trial
Multiplexing arrays increase the throughput and decrease sample requirements for studies employing multiple biomarkers. The goal of this project was to examine the performance of Multiplex arrays for measuring multiple protein biomarkers in saliva and serum. Specimens from the OsteoPerio ancillary study of the Women’s Health Initiative Observational Study were used. Participants required the presence of at least 6 teeth and were excluded based on active cancer and certain bone issues but were not selected on any specific condition. Quality control (QC) samples were created from pooled serum and saliva. Twenty protein markers were measured on five multiplexing array panels. Sample pretreatment conditions were optimized for each panel. Recovery, lower limit of quantification (LLOQ) and imprecision were determined for each analyte. Statistical adjustment at the plate level was used to reduce imprecision estimates and increase the number of usable observations. Sample pre-treatment improved recovery estimates for many analytes. The LLOQ for each analyte agreed with manufacturer specifications except for MMP-1 and MMP-2 which were significantly higher than reported. Following batch adjustment, 17 of 20 biomarkers in serum and 9 of 20 biomarkers in saliva demonstrated acceptable precision, defined as <20% coefficient of variation (<25% at LLOQ). The percentage of cohort samples having levels within the reportable range for each analyte varied from 10% to 100%. The ratio of levels in saliva to serum varied from 1∶100 to 28∶1. Correlations between saliva and serum were of moderate positive magnitude and significant for CRP, MMP-2, insulin, adiponectin, GM-CSF and IL-5. Multiplex arrays exhibit high levels of analytical imprecision, particularly at the batch level. Careful sample pre-treatment can enhance recovery and reduce imprecision. Following statistical adjustments to reduce batch effects, we identified biomarkers that are of acceptable quality in serum and to a lesser degree in saliva using Multiplex arrays.
The authors’ objective was to discern whether lifestyle or health-related factors were confounders, effect modifiers, or irrelevant with regard to understanding observational associations of serum 25-hydroxyvitamin D (25(OH)D) with colorectal and breast cancer. The authors conducted nested case-control studies of colorectal cancer (310 cases, 310 controls) and breast cancer (1,080 cases, 1,080 controls) in the Women’s Health Initiative Calcium and Vitamin D Clinical Trial (1994–2005). Case-control matching factors included age, latitude, race/ethnicity, and blood collection date. Serum 25(OH)D was assayed in baseline fasting blood. Conditional logistic regression was used to estimate odds ratios for each cancer by serum 25(OH)D concentration, comparing the relative effects of successively adding body mass index, physical activity, and other health and lifestyle characteristics particular to each cancer. In models with matching factors only, low (vs. high) serum 25(OH)D was associated with a colorectal cancer odds ratio of 2.72 (95% confidence interval (CI): 1.55, 4.77) and a breast cancer odds ratio of 1.33 (95% CI: 1.02, 1.72). In multivariate-adjusted models for colorectal cancer, the association strengthened (OR = 4.45, 95% CI: 1.96, 10.10). However, in multivariate-adjusted breast cancer models, associations were no longer significant (OR = 1.06, 95% CI: 0.78, 1.43). Adjusting for health and lifestyle characteristics has differential effects depending on the cancer site; when modeling such relations, investigators should take these factors into account.
breast neoplasms; colorectal neoplasms; 25-hydroxyvitamin D; postmenopausal women; randomized controlled trials
Exposures to cadmium, lead, and mercury are associated with adverse health effects, including cardiovascular disease, which may be promoted by lipid peroxidation. The authors examined cadmium, lead, and mercury in relation to plasma levels of F2-8α isoprostanes (isoprostane), 9-hydroperoxy-10,12-octadecadienoic acid (9-HODE), 13-hydroxy-9,11-octadecadienoic acid (13-HODE), and thiobarbituric acid reactive substances (TBARS) in 252 women from western New York State (2005–2007). Healthy premenopausal women were followed for ≤2 menstrual cycles, with biomarkers of lipid peroxidation being assessed ≤8 times per cycle. Metals were measured at baseline in whole blood. Linear mixed models were used to estimate the association between cadmium, lead, and mercury and lipid peroxidation biomarkers. Median cadmium, lead, and mercury levels were 0.30 μg/L, 0.86 μg/dL, and 1.10 μg/L, respectively. Blood cadmium, lead, and mercury were not associated with increases in isoprostane, TBARS, 9-HODE, or 13-HODE levels. Isoprostane levels decreased 6.80% (95% confidence interval: −10.40, −3.20) per 1% increase in mercury. However, after adjustment for a simulated strong confounding factor, such as precisely measured fish consumption, the observed association was attenuated, suggesting that this unexpected association could be attributable to unmeasured confounding. In this population of healthy premenopausal women with low exposure levels, cadmium, lead, and mercury were not associated with elevated lipid peroxidation biomarkers.
cadmium; hydroxyl-octadecadienoic acid; isoprostane; lead; mercury; oxidative stress; thiobarbituric acid reactive substances; women
Menstrual bleeding patterns are considered relevant indicators of reproductive health, though few studies have evaluated patterns among regularly menstruating premenopausal women. The authors evaluated self-reported bleeding patterns, incidence of spotting, and associations with reproductive hormones among 201 women in the BioCycle Study (2005–2007) with 2 consecutive cycles. Bleeding patterns were assessed by using daily questionnaires and pictograms. Marginal structural models were used to evaluate associations between endogenous hormone concentrations and subsequent total reported blood loss and bleeding length by weighted linear mixed-effects models and weighted parametric survival analysis models. Women bled for a median of 5 days (standard deviation: 1.5) during menstruation, with heavier bleeding during the first 3 days. Only 4.8% of women experienced midcycle bleeding. Increased levels of follicle-stimulating hormone (β = 0.20, 95% confidence interval: 0.13, 0.27) and progesterone (β = 0.06, 95% confidence interval: 0.03, 0.09) throughout the cycle were associated with heavier menstrual bleeding, and higher follicle-stimulating hormone levels were associated with longer menses. Bleeding duration and volume were reduced after anovulatory compared with ovulatory cycles (geometric mean blood loss: 29.6 vs. 47.2 mL; P = 0.07). Study findings suggest that detailed characterizations of bleeding patterns may provide more insight than previously thought as noninvasive markers for endocrine status in a given cycle.
anovulation; bleeding patterns; menstrual blood loss; metrorrhagia; reproductive hormones
C-reactive protein (CRP) is one of the most commonly used markers of acute phase reaction in clinical settings and predictors of cardiovascular risk in healthy women; however, data on its physiologic regulation in premenopausal women are sparse. The objective of this study was to evaluate the association between endogenous reproductive hormones and CRP in the BioCycle Study (2005–2007). Women aged 18–44 years from western New York were followed prospectively for up to 2 menstrual cycles (n = 259). Serum levels of CRP, estradiol, progesterone, luteinizing hormone, and follicle-stimulating hormone were measured up to 8 times per cycle, timed by fertility monitors. CRP levels varied significantly across the cycle (P < 0.001). More women were classified as being at elevated risk of cardiovascular disease (CRP, >3 mg/L) during menses compared with other phases (12.3% vs. 7.4%; P < 0.001). A 10-fold increase in estradiol was associated with a 24.3% decrease in CRP (95% confidence interval: 19.3, 29.0). A 10-fold increase in luteal progesterone was associated with a 19.4% increase in CRP (95% confidence interval: 8.4, 31.5). These results support the hypothesis that endogenous estradiol might have antiinflammatory effects and highlight the need for standardization of CRP measurement to menstrual cycle phase in reproductive-aged women.
estrogens; inflammation; menstrual cycle
Calcium and vitamin D may be inversely related to breast cancer risk, in part by affecting mammographic density. However, results from previous, mostly cross-sectional studies have been mixed, and there have been few randomized clinical trials of the effect of calcium and vitamin D supplementation on change in mammographic density.
We assessed the effect of one year of supplementation on mammographic density in 330 postmenopausal women enrolled in the Women’s Health Initiative Hormone Therapy (HT) and Calcium and Vitamin D (CaD) trials. Women were randomized to receive 1000 mg/day of elemental calcium carbonate plus 400 IU/day of vitamin D3 or placebo.
After approximately one year, mammographic density decreased 2% in the CaD supplementation group and increased 1% in the placebo group (ratio of means = 0.97; 95% confidence interval (CI) = 0.81–1.17). Results suggested potential interaction by HT use (P = 0.08). Among women randomized to HT placebo, the ratio of mean density comparing CaD supplementation and placebo groups was 0.82 (95%CI = 0.61–1.11) vs. 1.16 (95%CI = 0.92–1.45) in women randomized to active HT. In sensitivity analyses limited to women taking ≥80% of study supplements, ratios were 0.67 (95%CI = 0.41–1.07) in women not assigned to HT and 1.07 (95%CI = 0.79–1.47) women assigned to HT.
We observed no overall effect of vitamin D and calcium supplementation on mammographic density after one year.
Potential interaction between these nutrients and estrogen as related to mammographic density warrants further study.
breast; calcium; clinical trial; mammography; vitamin D
Laboratory studies suggest vitamin D may inhibit pancreatic cancer cell growth. However, epidemiologic studies of vitamin D and pancreatic cancer risk have been conflicting.
To determine whether prediagnostic levels of plasma 25-hydroxyvitamin D (25[OH]D) (IDS Inc. enzymeimuunoassay) were associated with risk of pancreatic cancer, we performed a pooled analysis of nested case-control studies with 451 cases and 1167 controls from five cohorts through 2008. Median follow-up among controls was 14.1 years in HPFS, 18.3 years in NHS, 25.3 years in PHS, 12.2 years in WHI, and 14.4 years in WHS. Logistic regression was used to compare the odds of pancreatic cancer by plasma level of 25(OH)D.
Mean plasma 25(OH)D was lower in cases versus controls (61.3 vs. 64.5 nmol/L, P=0.005). In logistic regression models, plasma 25(OH)D was inversely associated with odds of pancreatic cancer. Participants in quintiles two through five had multivariable-adjusted odds ratios (OR [95% confidence intervals]) of 0.79 (0.56–1.10), 0.75 (0.53–1.06), 0.68 (0.48–0.97), and 0.67 (0.46–0.97); P-trend=0.03), respectively, compared to the bottom quintile. Compared to those with insufficient levels (25[OH]D<50 nmol/L), ORs were 0.75 (0.58–0.98) for subjects with relative insufficiency (25[OH]D 50–<75 nmol/L) and 0.71 (0.52–0.97) for those with sufficient levels (25[OH]D≥75 nmol/L). No increased risk was noted in subjects with 25(OH)D≥100 nmol/L, as suggested in a prior study. In subgroup analyses, ORs for the top versus bottom quartile of 25(OH)D were 0.72 (0.48–1.08) for women, 0.73 (0.40–1.31) for men, and 0.73 (0.51–1.03) for Whites.
Among participants in five large prospective cohorts, higher plasma levels of 25(OH)D were associated with a lower risk for pancreatic cancer.
Low circulating 25(OH)D may predispose individuals to the development of pancreatic cancer.
Pancreatic cancer; Vitamin D; Prospective cohort; Epidemiology
Case–control studies have reported that exogenous estrogen use is associated with increased risk of skin cancer. The effects of menopausal hormone therapy on incidence of nonmelanoma skin cancer and melanoma were evaluated in post hoc analyses of the Women’s Health Initiative randomized placebo-controlled hormone therapy trials of combined estrogen plus progestin (E + P) and estrogen only (E-alone).
Postmenopausal women aged 50–79 years were randomly assigned to conjugated equine estrogen (0.625 mg/d) plus medroxyprogesterone acetate (2.5 mg/d) or placebo in the E + P trial if they had an intact uterus (N = 16 608) or to conjugated equine estrogen alone or placebo in the E-alone trial if they had a hysterectomy (N =10 739); the mean follow-up was 5.6 and 7.1 years, respectively. Incident nonmelanoma skin cancers (n = 980 [E + P trial]; n = 820 [E-alone trial]) and melanomas (n = 57 [E + P trial]; n =38 [E-alone trial]) were ascertained by self-report. Incident cases of cutaneous malignant melanoma were confirmed by physician review of medical records. Incidences of nonmelanoma skin cancer and melanoma were compared between the two randomization groups within each trial using hazard ratios (HRs), with corresponding 95% confidence intervals (CIs) and Wald statistic P values from Cox proportional hazards models. All statistical tests were two-sided.
Rates of incident nonmelanoma skin cancer and melanoma were similar between the active hormone (combined analysis of E + P and E-alone) and placebo groups (nonmelanoma skin cancer: HR = 0.98, 95% CI = 0.89 to 1.07; melanoma: HR = 0.92, 95% CI = 0.61 to 1.37). Results were similar for the E + P and E-alone trials when analyzed individually.
Menopausal hormone therapy did not affect overall incidence of nonmelanoma skin cancer or melanoma. These findings do not support a role of menopausal estrogen, with or without progestin, in the development of skin cancer in postmenopausal women.
Low 25 hydroxyvitamin D (25(OH)D) levels have been linked to hip fracture in White women. To study the association of 25(OH)D to risk of fracture in multiethnic women, we performed a nested case control study within the prospective Women’s Health Initiative Observational Study. Incident fractures were identified in 381 Black, 192 Hispanic, 113 Asian and 46 American Indian women over an average of 8.6 years. A random sample of 400 White women who fractured was chosen. One control was selected per case and matched on age, race/ethnicity and blood draw date. 25(OH)D, parathyroid hormone and vitamin D binding protein (DBP) were measured in fasting baseline serum. Conditional logistic regression models were used to calculate the odds ratio (OR) and 95% Confidence Intervals (95% CI). In multivariable models, higher 25(OH)D levels as compared with levels <20ng/mL were associated with a lower risk of fracture in White women: (20-<30 ng/mL), OR=0.82; (0.59, 1.16) and (≥30.0 ng/mL), OR=0.55; (0.34, 0.89), p trend=0.02. In contrast, higher 25(OH)D (≥20 ng/mL) as compared with levels <20ng/mL were associated with a higher risk of fracture in Black women, OR=1.45; (1.06, 1.98), p trend=0.043. Higher 25(OH)D (≥30.0 ng/mL) was associated with higher fracture risk in Asian women after adjusting for DBP, OR=2.78; (0.99, 7.88), (p trend=0.04). There was no association between 25(OH)D and fracture in Hispanic or American Indian women. Our results suggest divergent associations between 25(OH)D and fracture by race/ethnicity. The optimal level of 25(OH)D for skeletal health may differ in White and Black women.
Fractures; serum vitamin D; race/ethnicity; osteoporosis; 25 hydroxyvitamin D
Folic acid is recommended to reproductive-aged women to prevent birth defects, though little is known about the effects of dietary intake on other reproductive outcomes. Improved pregnancy rates have been documented after folic acid supplement use, suggesting a possible link with ovulation, however research is limited. Our objective was to evaluate the association between dietary folate intake, hormone levels, and sporadic anovulation in healthy, regularly menstruating women.
The BioCycle study (2005–2007) prospectively followed 259 healthy women aged 18–44 years from the western New York region for up to 2 menstrual cycles. Total folate and specific sources of folate were assessed up to 4 times per cycle by 24-hour recall. Estradiol, progesterone, luteinizing hormone, and follicle-stimulating hormone were measured in serum up to 8 times per cycle, timed using fertility monitors. Anovulation was defined as a cycle with peak progesterone concentration ≤5 ng/mL and no LH peak in the mid/late luteal phase. Higher intake of dietary folate (in dietary equivalents) across tertiles had a marginally significant association with greater luteal progesterone levels (P trend 0.08). Higher intake of synthetic folate was significantly associated with higher luteal progesterone levels (P trend 0.05). Specifically, women in the 3rd tertile of synthetic folate intake had, on average, 16.0% (95% CI, 0.5–33.8%) higher luteal progesterone levels compared to women in the 1st tertile. Moreover, consumption of synthetic folate was significantly and inversely associated with anovulation such that women in the 3rd tertile had a 64% (95% CI, 8–86%) decreased odds of anovulation compared to the women in the 1st tertile (P trend 0.03).
These findings suggest that a diet high in synthetic folate may be associated with increased progesterone levels and lower risk of sporadic anovulation. Further study of the effect of dietary folate and folic acid supplement use on reproductive health is warranted.
In the Women’s Health Initiative (WHI) trial of calcium plus vitamin D (CaD), we examined the treatment effect on incidence and mortality for all invasive cancers. Postmenopausal women (N = 36,282) were randomized to 1,000 mg of elemental calcium with 400 IU vitamin D3 or placebo. Cox models estimated risk of cancer incidence and mortality. After 7.0 yr, 1,306 invasive cancers were diagnosed in the supplement and 1,333 in the placebo group [hazard ratio (HR) = 0.98; CI = 0.90, 1.05, unweighted P = 0.54]. Mortality did not differ between supplement (315, annualized% = .26) and placebo [(347, 0.28%; P = 0.17; HR = 0.90 (0.77, 1.05)]. Significant treatment interactions on incident cancer were found for family history of cancer, personal total intake of vitamin D, smoking, and WHI dietary trial randomized group. Calcium/vitamin D supplementation did not reduce invasive cancer incidence or mortality. Supplementation lowered cancer risk in the WHI healthy diet trial arm and in women without a first-degree relative with cancer. The interactions are only suggestive given multiple testing considerations. The low vitamin D dose provided, limited adherence, and lack of serum 25(OH)D values should be considered when interpreting these findings.
To investigate whether the association between physical activity and serum 25-hydroxyvitamin D (25(OH)D) concentrations is independent of sun exposure, body size, and other potential explanatory variables.
Using data from a sample of 1,343 postmenopausal women, from the Women’s Health Initiative, linear regression was used to examine the associations of duration (minutes/week) of recreational activity and of yard work with 25(OH)D concentrations (nmol/L).
In age-adjusted analyses, positive associations were observed between 25(OH)D concentrations and both duration of recreational physical activity (β=0.71, SE(0.09), P<0.001) and yard work (β=0.36, SE(0.10), P=0.004). After further adjustment for vitamin D intake, self-reported sunlight exposure, waist circumference, and season of blood draw, 25(OH)D was significantly associated with recreational activity (β=0.21, SE(0.09), P=0.014) but not with yard work (β=0.18, SE(0.09), P=0.061). Interactions were observed between season and both recreational activity (Pinteraction=0.082) and yard work (Pinteraction=0.038) such that these activity-25(OH)D associations were greater during summer/fall compared to winter/spring. Self-reported sunlight exposure and measures of body size did not modify the associations.
The observed age-adjusted activity-25(OH)D associations were attenuated after adjusting for explanatory variables and were modified by season of blood draw. Adopting a lifestyle that incorporates outdoor physical activity during summer/fall, consuming recommended amounts of vitamin D, and maintaining a healthy weight may improve or maintain vitamin D status in postmenopausal women.
25-hydroxyvitamin D; vitamin D; serum; sunlight exposure; physical activity; epidemiology; women
It is hypothesized that inflammation may mediate the relationship between obesity and endometrial cancer risk. We examined the associations of three inflammation markers, C-reactive protein (CRP), interleukin (IL)-6, and tumor necrosis factor (TNF)-α, with risk of endometrial cancer.
A case-cohort study was nested within the Women’s Health Initiative, a cohort of postmenopausal women. Baseline plasma samples of 151 incident endometrial cancer cases and 301 subcohort subjects not using hormones were assayed.
CRP, but not IL-6 or TNF-α, was positively associated with endometrial cancer risk after adjusting for age and BMI [hazard ratio comparing extreme quartiles (HRq4-q1) = 2.29; 95% confidence interval (CI) = 1.13–4.65; ptrend = 0.012). After additional adjustment for estradiol and insulin, this association was attenuated (HRq4-q1 = 1.70;95% CI= 0.78–3.68; ptrend = 0.127). Obesity (BMI ≥ 30 kg/m2) was associated with endometrial cancer risk in an age-adjusted model. The obesity effect was reduced by 48%, 67%, and 77% when either estradiol, CRP, or insulin, respectively, was included in the model, and it became null when all three factors were adjusted for simultaneously.
The association between inflammation, as indicated by a relatively high level of CRP, and endometrial cancer risk may partially be explained by hyperinsulinemia and elevated estradiol. Nevertheless, all three factors contribute to and mediate the link between obesity and endometrial cancer in postmenopausal women not using hormones.
The association between obesity and endometrial cancer risk in postmenopausal women may be attributed to inflammation, insulin resistance, and elevated estrogen.
Little is known about risk factors for triple negative breast cancer (TNBC), which has a worse prognosis compared to hormone receptor-positive breast cancer. We examined the association of smoking and alcohol intake with TNBC and estrogen receptor-positive (ER+) breast cancer.
Among 146,985 women enrolled in the Women’s Health Initiative, 300 TNBC cases and 2,479 ER+ cases were identified over a median of 8.0 years of follow-up. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI).
Cigarette smoking was not associated with TNBC, whereas drinkers had reduced risk compared to never drinkers. In contrast, both exposures showed slight positive associations with ER+ breast cancer: for women with ≥40 pack-years of smoking, the HR was 1.24, 95% CI 1.06–1.44; for women consuming ≥7 servings of alcohol per week the HR was 1.26, 95% CI 1.06–1.50. Intakes of wine and hard liquor were also significantly positively associated with ER+ breast cancer.
These findings from a large cohort of postmenopausal women suggest that smoking and alcohol consumption are not associated with increased risk of TNBC, but may be modestly associated with increased risk of ER+ breast cancer.
breast neoplasms; triple-negative; estrogen receptor-positive; cigarette smoking; alcohol consumption; postmenopausal women