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.
endometrial carcinoma; survivorship; body mass index; physical activity
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.
insomnia; sleep disorder; sleep disturbance; risk factors; thyroid cancer
Low 25 hydroxyvitamin D (25(OH) D) concentrations have been associated with radiologic worsening of osteoarthritis in some reports. However, the results are mixed and few studies have evaluated associations between 25(OH) D concentrations and both total vitamin D intake and clinical joint symptoms.
Cross-sectional analyses of information from a subset of 1993 postmenopausal women obtained at baseline entry in the Women's Health Initiative Calcium plus Vitamin D clinical trial.
Main Outcome Measures
25(OH) D concentration, total vitamin D intake (diet plus supplements), presence and severity of joint pain and joint swelling.
The 25(OH) D levels were commonly low with 53% having deficient (< 50 nmol/L) and only 17% having sufficient (> 72 nmol/L) levels. Joint pain (reported by 74%) and joint swelling (reported by 34%) were also commonly reported. 25(OH) D concentrations were modestly correlated with total vitamin D intake (R =0.29, P<0.0001); however, considerable variability in 25(OH) D concentrations for a given vitamin D intake was seen. In adjusted linear regression models, lower serum 25(OH) D concentrations were associated with higher average joint pain score (P=0.01 for trend) with differences most apparent in the lowest 25(OH) D levels sextile.
Relatively low 25(OH) D levels and a high frequency of joint symptoms were common in this population of postmenopausal women. Total vitamin D intake was only modestly associated with 25(OH) D. Low serum 25(OH) D concentrations were associated with higher joint pain scores. These findings can inform the design of future intervention trials.
Endometrial cancer is primarily a hormonally-mediated disease. As such, factors that mediate or reflect exposure to estrogens, or that mediate response to such exposure, may plausibly be associated with endometrial cancer risk. History of migraines, another hormonally-mediated condition, has recently been associated with a reduced risk of hormone receptor-positive breast cancer; however, the relationship between migraines and endometrial cancer has not previously been explored. We evaluated the relationship between migraine history and endometrial cancer risk in postmenopausal women, considering also the potential impact of nonsteroidal anti-inflammatory drug (NSAID) use, given the relationship of NSAIDs to hormones and to migraine history. We identified 93,384 women participating in the Women's Health Initiative prospective cohort who had an intact uterus at the time of study entry. Using Cox proportional hazards regression, we assessed risk of endometrial cancer during study follow-up according to history of migraines and according to current NSAID use at the time of study entry, adjusting for age, study arm, race, and hormone therapy use. We also evaluated interaction in these associations by body mass index. Having a history of migraines was not associated with endometrial cancer risk [hazard ratio (HR)=0.91, 95% confidence interval (CI): 0.75–1.11], regardless of body mass index (BMI) or NSAID use status. Similarly, current NSAID use was not associated with endometrial cancer risk (HR=1.03, 95% CI: 0.89–1.18), regardless of BMI. Migraine history and NSAID use do not appear to be associated with risk of endometrial cancer.
endometrial cancer; migraine; nonsteroidal anti-inflammatory drugs
Background and purpose
Previous studies have shown that physical inactivity and obesity are risk factors for the development of colorectal cancer. However, controversy exists regarding the influence of these factors on survival in colorectal cancer patients. We evaluated the impact of recreational physical activity and body mass index (BMI) before and after colorectal cancer diagnosis on disease-specific mortality and all-cause mortality.
Patients and Methods
This prospective cohort study included 1339 women enrolled in the Women’s Health Initiative study who were diagnosed with colorectal cancer subsequent to study enrolment. BMI and recreational physical activity were measured before cancer diagnosis at study entry (pre-diagnostic) and after diagnosis at study follow-up interviews (post-diagnostic). We used Cox regression to estimate the association between pre- and post-diagnostic exposures and survival after colorectal cancer diagnosis.
Among women diagnosed with colorectal cancer, 265 (13%) deaths occurred during a median study follow-up of 11.9 years, of which 171 (65%) were attributed to colorectal cancer. Compared with women reporting no pre-diagnostic recreational physical activity, those reporting activity levels of ≥18 MET-hours/week had significantly lower colorectal cancer-specific mortality (hazard ratio (HR)=0.68; 95% confidence interval (CI): 0.41–1.13) and all-cause mortality (HR=0.63; 95% CI: 0.42–0.96). Similar inverse associations were seen for post-diagnostic recreational physical activity. Neither pre- nor post-diagnostic BMI were associated with mortality after colorectal cancer diagnosis.
Recreational physical activity before and after CR colorectal cancer C diagnosis, but not BMI, is associated with more favourable survival.
Physical activity; body mass index; colorectal cancer; survival; postmenopausal
Data on cardiovascular diseases (CVD) and cognitive decline are conflicting. Our objective was to investigate if CVD is associated with an increased risk for cognitive decline and to examine whether hypertension, diabetes, or adiposity modify the effect of CVD on cognitive functioning.
Methods and Results
Prospective follow‐up of 6455 cognitively intact, postmenopausal women aged 65 to 79 years old enrolled in the Women's Health Initiative Memory Study (WHIMS). CVD was determined by self‐report. For cognitive decline, we assessed the incidence of mild cognitive impairment (MCI) or probable dementia (PD) via modified mini‐mental state examination (3 MS) score, neurocognitive, and neuropsychiatric examinations. The median follow‐up was 8.4 years. Women with CVD tended to be at increased risk for cognitive decline compared with those free of CVD (hazard ratio [HR], 1.29; 95% CI: 1.00, 1.67). Women with myocardial infarction or other vascular disease were at highest risk (HR, 2.10; 95% CI: 1.40, 3.15 or HR, 1.97; 95% CI: 1.34, 2.87). Angina pectoris was moderately associated with cognitive decline (HR 1.45; 95% CI: 1.05, 2.01) whereas no significant relationships were found for atrial fibrillation or heart failure. Hypertension and diabetes increased the risk for cognitive decline in women without CVD. Diabetes tended to elevate the risk for MCI/PD in women with CVD. No significant trend was seen for adiposity.
CVD is associated with cognitive decline in elderly postmenopausal women. Hypertension and diabetes, but not adiposity, are associated with a higher risk for cognitive decline. More research is warranted on the potential of CVD prevention for preserving cognitive functioning.
cardiovascular diseases; cognitive decline; postmenopausal women
Smoking is associated with tooth loss. However, smoking's relationship to the specific reason for tooth loss in postmenopausal women is unknown.
Postmenopausal women (n = 1,106) who joined a Women's Health Initiative ancillary study (The Buffalo OsteoPerio Study) underwent oral examinations for assessment of the number of missing teeth, as well as the self-reported reasons for tooth loss. The authors obtained information about smoking status via a self-administered questionnaire. The authors calculated odds ratios (ORs) and 95 percent confidence intervals (CIs) by means of logistic regression to assess smoking's association with overall tooth loss, as well as with tooth loss due to periodontal disease (PD) and with tooth loss due to caries.
After adjusting for age, education, income, body mass index (BMI), history of diabetes diagnosis, calcium supplement use and dental visit frequency, the authors found that heavy smokers (≥ 26 pack-years) were significantly more likely to report having experienced tooth loss compared with never smokers (OR = 1.82; 95 percent CI, 1.10-3.00). Smoking status, packs smoked per day, years of smoking, pack-years and years since quitting smoking were significantly associated with tooth loss due to PD. For pack-years, the association for heavy smokers compared with that for never smokers was OR = 6.83 (95 percent CI, 3.40-13.72). The study results showed no significant associations between smoking and tooth loss due to caries.
Conclusions and Practical Implications
Smoking may be a major factor in tooth loss due to PD. However, smoking appears to be a less important factor in tooth loss due to caries. Further study is needed to explore the etiologies by which smoking is associated with different types of tooth loss. Dentists should counsel their patients about the impact of smoking on oral health, including the risk of tooth loss due to PD.
Tooth loss; periodontal diseases; caries; smoking; menopause; women's health
For Hispanic women, the Breast Cancer Risk Assessment Tool (BCRAT; “Gail Model”) combines 1990–1996 breast cancer incidence for Hispanic women with relative risks for breast cancer risk factors from non-Hispanic white (NHW) women. BCRAT risk projections have never been comprehensively evaluated for Hispanic women. We compared the relative risks and calibration of BCRAT risk projections for 6,353 Hispanic to 128,976 NHW postmenopausal participants aged 50 and older in the Women’s Health Initiative (WHI). Calibration was assessed by the ratio of the number of breast cancers observed with that expected by the BCRAT (O/E). We re-evaluated calibration for an updated BCRAT that combined BCRAT relative risks with 1993–2007 breast cancer incidence that is contemporaneous with the WHI. Cox regression was used to estimate relative risks. Discriminatory accuracy was assessed using the concordance statistic (AUC). In the WHI Main Study, the BCRAT underestimated the number of breast cancers by 18% in both Hispanics (O/E = 1.18, P = 0.06) and NHWs (O/E = 1.18, P < 0.001). Updating the BCRAT improved calibration for Hispanic women (O/E = 1.08, P = 0.4) and NHW women (O/E = 0.98, P = 0.2). For Hispanic women, relative risks for number of breast biopsies (1.71 vs. 1.27, P = 0.03) and age at first birth (0.97 vs. 1.24, P = 0.02) differed between the WHI and BCRAT. The AUC was higher for Hispanic women than NHW women (0.63 vs. 0.58, P = 0.03). Updating the BCRAT with contemporaneous breast cancer incidence rates improved calibration in the WHI. The modest discriminatory accuracy of the BCRAT for Hispanic women might improve by using risk factor relative risks specific to Hispanic women.
Hispanic; Breast cancer; Risk prediction; Risk assessment; BCRAT
During the intervention phase in the Women's Health Initiative (WHI) clinical trial, use of estrogen plus progestin reduced the colorectal cancer diagnosis rate, but the cancers were found at a substantially higher stage. To assess the clinical relevance of the findings, analyses of the influence of combined hormone therapy on colorectal cancer incidence and colorectal cancer mortality were conducted after extended follow-up.
Patients and Methods
The WHI study was a randomized, double-blind, placebo-controlled clinical trial involving 16,608 postmenopausal women with an intact uterus who were randomly assigned to daily 0.625 mg conjugated equine estrogen plus 2.5 mg medroxyprogesterone acetate (n = 8,506) or matching placebo (n = 8,102). Colorectal cancer diagnosis rates and colorectal cancer mortality were assessed.
After a mean of 5.6 years (standard deviation [SD], 1.03 years) of intervention and 11.6 years (SD, 3.1 years) of total follow-up, fewer colorectal cancers were diagnosed in the combined hormone therapy group compared with the placebo group (diagnoses/year, 0.12% v 0.16%; hazard ratio [HR], 0.72; 95% CI, 0.56 to 0.94; P = .014). Bowel screening examinations were comparable between groups throughout. Cancers in the combined hormone therapy group more commonly had positive lymph nodes (50.5% v 28.6%; P < .001) and were at higher stage (regional or distant, 68.8% v 51.4%; P = .003). Although not statistically significant, there was a higher number of colorectal cancer deaths in the combined hormone therapy group (37 v 27 deaths; 0.04% v 0.03%; HR, 1.29; 95% CI, 0.78 to 2.11; P = .320).
The findings, suggestive of diagnostic delay, do not support a clinically meaningful benefit for combined hormone therapy on colorectal cancer.
To examine determinants of racial/ethnic differences in diabetes incidence among postmenopausal women participating in the Women’s Health Initiative.
RESEARCH DESIGN AND METHODS
Data on race/ethnicity, baseline diabetes prevalence, and incident diabetes were obtained from 158,833 women recruited from 1993–1998 and followed through August 2009. The relationship between race/ethnicity, other potential risk factors, and the risk of incident diabetes was estimated using Cox proportional hazards models from which hazard ratios (HRs) and 95% CIs were computed.
Participants were aged 63 years on average at baseline. The racial/ethnic distribution was 84.1% non-Hispanic white, 9.2% non-Hispanic black, 4.1% Hispanic, and 2.6% Asian. After an average of 10.4 years of follow-up, compared with whites and adjusting for potential confounders, the HRs for incident diabetes were 1.55 for blacks (95% CI 1.47–1.63), 1.67 for Hispanics (1.54–1.81), and 1.86 for Asians (1.68–2.06). Whites, blacks, and Hispanics with all factors (i.e., weight, physical activity, dietary quality, and smoking) in the low-risk category had 60, 69, and 63% lower risk for incident diabetes. Although contributions of different risk factors varied slightly by race/ethnicity, most findings were similar across groups, and women who had both a healthy weight and were in the highest tertile of physical activity had less than one-third the risk of diabetes compared with obese and inactive women.
Despite large racial/ethnic differences in diabetes incidence, most variability could be attributed to lifestyle factors. Our findings show that the majority of diabetes cases are preventable, and risk reduction strategies can be effectively applied to all racial/ethnic groups.
Randomized trial evidence demonstrates that non-steroidal anti-inflammatory drug (NSAID) use, particularly long-term use, reduces the incidence of colorectal neoplasia. Recent data also suggests an inverse association between NSAID use and death due to colorectal cancer (CRC).
We examined the association between NSAID use and CRC mortality among 160,143 post-menopausal women enrolled in the Women's Health Initiative. Women provided details on medication use at baseline and three years after enrollment. Reported CRC cases were locally confirmed and centrally adjudicated; cause of death was determined according to centralized medical record and death certificate review. Cox regression was used to investigate the association between NSAID use and CRC mortality.
Overall, NSAID use at baseline was not associated with CRC mortality (HR: 0.93; 95% CI 0.76, 1.14). However, women who reported NSAID use at both baseline and year-three experienced reductions in CRC mortality (HR: 0.72; 95% CI 0.54, 0.95) compared to non-users.
Results suggest that NSAID use is associated with lower CRC mortality among post-menopausal women who use these medications more consistently over time.
Our results support prolonged NSAID use in post-menopausal women for the prevention of poor CRC outcomes.
colorectal cancer mortality; NSAIDs; WHI
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.
Past studies of relationships between alcohol and hip fracture have generally focused on total alcohol consumed and not type of alcohol. Different types of alcohol consist of varying components which may affect risk of hip fracture differentially. This study seeks to examine the relationship between alcohol consumption, with a focus on type of alcohol consumed (e.g. beer, wine, or hard liquor) and hip fracture risk in post-menopausal women.
The longitudinal cohort consisted of U.S. post-menopausal women aged 50–79 years enrolled between 1993–1998 in the Women’s Health Initiative Clinical Trials and Observational Study (N=115,655).
Women were categorized as non-drinkers, past drinkers, infrequent drinkers and drinkers by preference of alcohol type (i.e. those who preferred wine, beer, hard liquor, or who had no strong preference). Mean alcohol consumption among current drinkers was 3.3 servings per week; this was similar among those who preferred wine, beer and liquor. After adjustment for potential confounders, alcohol preference was strongly correlated with hip fracture risk (p = 0.0167); in particular, women who preferred wine were at lower risk than non-drinkers (OR=0.78; 95% CI 0.64-0.95), past drinkers (OR=0.85; 95% CI 0.72-1.00), infrequent drinkers (OR=0.73; 95% CI 0.61-0.88), hard liquor drinkers (OR=0.87; 95% CI 0.71-1.06), beer drinkers (OR=0.72; 95% CI 0.55-0.95) and those with no strong preference (OR=0.89; 95% CI 0.89; 95% CI 0.73-1.10).
Preference of alcohol type was associated with hip fracture; women who preferentially consumed wine had a lower risk of hip fracture compared to non-drinkers, past drinkers, and those with other alcohol preferences.
Alcohol; Wine; Hip fracture; Osteoporosis; Women’s Health Initiative
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
Emerging evidence suggests that metformin may reduce breast cancer incidence, but reports are mixed and few provide information on tumor characteristics. Therefore, we assessed associations among diabetes, metformin use, and breast cancer in postmenopausal women participating in Women's Health Initiative clinical trials.
Patients and Methods
In all, 68,019 postmenopausal women, including 3,401 with diabetes at study entry, were observed over a mean of 11.8 years with 3,273 invasive breast cancers diagnosed. Diabetes incidence status was collected throughout follow-up, with medication information collected at baseline and years 1, 3, 6, and 9. Breast cancers were confirmed by review of central medical records and pathology reports. Cox proportional hazards regression, adjusted for breast cancer risk factors, compared breast cancer incidence in women with diabetes who were metformin users or nonusers with breast cancer incidence in women without diabetes.
Compared with that in women without diabetes, breast cancer incidence in women with diabetes differed by diabetes medication type (P = .04). Women with diabetes receiving medications other than metformin had a slightly higher incidence of breast cancer (hazard ratio [HR], 1.16; 95% CI, 0.93 to 1.45), and women with diabetes who were given metformin had lower breast cancer incidence (HR, 0.75; 95% CI, 0.57 to 0.99). The association was observed for cancers positive for both estrogen receptor and progesterone receptor and those that were negative for human epidermal growth factor receptor 2.
Metformin use in postmenopausal women with diabetes was associated with lower incidence of invasive breast cancer. These results can inform future studies evaluating metformin use in breast cancer management and prevention.
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.