While observational studies have suggested that vitamin D deficiency increases risk of depression, few clinical trials have tested whether vitamin D supplementation affects the occurrence of depression symptoms. The authors evaluated the impact of daily supplementation with 400 IU of vitamin D3 combined with 1,000 mg of elemental calcium on measures of depression in a randomized, double-blinded US trial comprising 36,282 postmenopausal women. The Burnam scale and current use of antidepressant medication were used to assess depressive symptoms at randomization (1995–2000). Two years later, women again reported on their antidepressant use, and 2,263 completed a second Burnam scale. After 2 years, women randomized to receive vitamin D and calcium had an odds ratio for experiencing depressive symptoms (Burnam score ≥0.06) of 1.16 (95% confidence interval: 0.86, 1.56) compared with women in the placebo group. Supplementation was not associated with antidepressant use (odds ratio = 1.01, 95% confidence interval: 0.92, 1.12) or continuous depressive symptom score. Results stratified by baseline vitamin D and calcium intake, solar irradiance, and other factors were similar. The findings do not support a relation between supplementation with 400 IU/day of vitamin D3 along with calcium and depression in older women. Additional trials testing higher doses of vitamin D are needed to determine whether this nutrient may help prevent or treat depression.
antidepressive agents; calcium; clinical trial; depression; dietary supplements; postmenopause; vitamin D; women
To examine elevated depressive symptoms and antidepressant use in relation to diabetes incidence in the Women’s Health Initiative.
RESEARCH DESIGN AND METHODS
A total of 161,808 postmenopausal women were followed for over an average of 7.6 years. Hazard ratios (HRs) estimating the effects of elevated depressive symptoms and antidepressant use on newly diagnosed incident diabetes were obtained using Cox proportional hazards models adjusted for known diabetes risk factors.
Multivariable-adjusted HRs indicated an increased risk of incident diabetes with elevated baseline depressive symptoms (HR 1.13 [95% CI 1.07–1.20]) and antidepressant use (1.18 [1.10–1.28]). These associations persisted through year 3 data, in which respective adjusted HRs were 1.23 (1.09–1.39) and 1.31 (1.14–1.50).
Postmenopausal women with elevated depressive symptoms who also use antidepressants have a greater risk of developing incident diabetes. In addition, longstanding elevated depressive symptoms and recent antidepressant medication use increase the risk of incident diabetes.
Obesity is a well-established risk factor for postmenopausal breast cancer. Recent studies suggest that smoking increases the risk of breast cancer. However, the effect of co-occurrence of smoking and obesity on breast cancer risk remains unclear. A total of 76,628 women aged 50–79 years enrolled in the Women's Health Initiative Observational Study were followed through August 14, 2009. Cox proportional hazards regression models were used to estimate hazard ratios and 95% confidence intervals. Over an average 10.3 years of follow-up, 3,378 incident cases of invasive breast cancer were identified. The effect of smoking on the risk of developing invasive breast cancer was modified significantly by obesity status among postmenopausal women, regardless of whether the obesity status was defined by body mass index (Pinteraction = 0.01) or waist circumference (Pinteraction = 0.02). A significant association between smoking and breast cancer risk was noted in nonobese women (hazard ratio = 1.25, 95% confidence interval: 1.05, 1.47) but not in obese women (hazard ratio = 0.96, 95% confidence interval: 0.69, 1.34). In conclusion, this study suggests that the effect of smoking exposure on breast cancer risk was modified by obesity among postmenopausal women. The modification effect did not differ by general versus abdominal obesity.
breast neoplasms; obesity; risk factors; smoking
SBM; SRNT; Quitlines; 1-800-Quit-Now; Tobacco; FDA
Smoking research and intervention efforts have neglected older women. Depressive symptoms, which are common in middle-aged and older women, are related to the maintenance of adult smoking.
This study investigated the relation of a composite measure of current depressive symptoms, derived from a short form of the Center for Epidemiological Studies Depression Scale, and history of depressive symptoms, derived from two items from the Diagnostic Interview Schedule, to smoking outcomes in the Women's Health Initiative Observational Study (N = 90,627). Participants were postmenopausal with an average age of 63.6 years at baseline. Participants were recruited from urban, suburban, and rural areas surrounding 40 clinical centers in the United States. Analyses controlled for age, educational level, and ethnicity.
In multinomial logistic regression analyses, depressive symptoms were related cross-sectionally to current light (odds ratio [OR] = 1.19, 95% CI = 1.14–1.23) and heavier (OR = 1.28, 95% CI = 1.23–1.32) smoking at baseline compared with nonsmokers. In prospective multiple logistic regression analyses, baseline depressive symptoms were negatively predictive of smoking cessation at a 1-year follow-up (OR = .85, 95% CI = 0.77–0.93) and at participants’ final assessments in the study (OR = .92, 95% CI = 0.85–0.98). Light smokers had more than 2 times higher odds of smoking cessation than did heavier smokers.
The present findings demonstrate a consistent link between depressive symptoms and negative smoking-related behaviors among middle-aged and older women at both light and heavier smoking levels.
Although studies exploring relationships between obesity and cognitive impairment in the elderly are conflicting, literature suggests that overweight and obesity may be protective against cognitive impairment and dementia in older women. We examine the associations between changes in weight and waist circumference with global and domain-specific cognitive function in a large, well-defined cohort of 2283 older, post-menopausal women (age 65-79) prospectively followed through the Women's Health Initiative (WHI) Study of Cognitive Aging (WHISCA). We assessed the associations between changes in weight and waist circumference collected up to 5 years prior to WHISCA enrollment and mean levels of global and domain-specific cognitive performance across an average of 5.4 years of subsequent follow-up. There was a lack of associations between weight and cognition in women who remained stable or gained weight. The only significant relationships observed were in association with weight loss (p≤0.05), most likely signaling incipient disease. Moreover, cognition was not related to changes in waist circumference. Relationships were largely independent of initial BMI, self-reported caloric intake or dieting. The lack of associations between weight gain and cognition in women is consistent with the existent literature.
Peripheral arterial disease patients are less likely than other high-risk patients to achieve ideal low density lipoprotein cholesterol (LDL-cholesterol) levels. This randomized controlled trial assessed whether a telephone counseling intervention, designed to help peripheral arterial disease patients request more intensive cholesterol lowering therapy from their physician, achieves lower LDL-cholesterol levels than two control conditions.
355 peripheral arterial disease participants with baseline LDL-cholesterol ≥ 70 mg/dl were enrolled. The primary outcome was change in LDL-cholesterol level at twelve-month follow-up. There were three parallel arms: telephone counseling intervention, attention control condition, and usual care. The intervention consisted of patient-centered counseling, delivered every six weeks, encouraging participants to request increases in cholesterol-lowering therapy from their physician. The attention control condition consisted of telephone calls every six weeks providing information only. The usual care condition participated in baseline and follow-up testing.
At 12-month follow-up, participants in the intervention improved their LDL-cholesterol level, compared to those in attention control (−18.4 mg/dl vs. −6.8 mg/dl, p= 0.010) but not compared to those in usual care (−18.4 mg/dl vs. −11.1 mg/dl, p= 0.208). Intervention participants were more likely to start a cholesterol-lowering medication or increase their cholesterol-lowering medication dose than those in the attention control (54% vs. 18%, p=0.001) and usual care (54% vs. 31%, P<0.001) conditions.
Telephone counseling that helped peripheral arterial disease patients request more intensive cholesterol-lowering therapy from their physician achieved greater LDL-cholesterol declines than an attention control arm that provided health information alone.
Intermittent claudication; secondary prevention; peripheral arterial disease
Behavior has a broad and central role in health. Behavioral interventions can be effectively used to prevent disease, improve management of existing disease, increase quality of life, and reduce healthcare costs. A summary is presented of evidence for these conclusions in cardiovascular disease/diabetes, cancer, and HIV/AIDS as well as with key risk factors: tobacco use, poor diet, physical inactivity, and excessive alcohol consumption. For each, documentation is made of (1) moderation of genetic and other fundamental biological influences by behaviors and social–environmental factors, (2) impacts of behaviors on health, (3) success of behavioral interventions in prevention, (4) disease management, (5) and quality of life, and (6) improvements in the health of populations through behavioral health promotion programs. Evidence indicates the cost effectiveness and value of behavioral interventions, especially relative to other common health services, as well as the value they add in terms of quality of life. Pertinent to clinicians and their patients as well as to health policy and population health, the benefits of behavioral interventions extend beyond impacts on a particular disease or risk factor. Rather, they include broad effects and benefits on prevention, disease management, and well-being across the life span. Among priorities for dissemination research, the application of behavioral approaches is challenged by diverse barriers, including socioeconomic barriers linked to health disparities. However, behavioral approaches including those emphasizing community and social influences appear to be useful in addressing such challenges. In sum, behavioral approaches should have a central place in prevention and health care of the 21st century.
Examine the independent and joint effects of geriatric syndromes (GS) and
cardiometabolic diseases (CMDs) on functional impairment.
Cross-sectional analysis of baseline data from the Women's Health
Initiative, including 62,829 women aged 65 years or older. GS (urinary
incontinence, falls, and depression measured by the shortened Center for
Epidemiological Studies-Depression scale/Diagnostic Interview Schedule
screening instrument) and CMD (coronary artery disease, coronary heart
failure, and diabetes) were self-reported. Physical and social functioning
and general health subscales of the Short Form-36 dichotomized at the median
for the study sample were used to assess functional impairment. Additive
interaction between burden of GS and CMD was assessed using logistic
Forty-three percent of women had at least one GS; 14.1% had at least one CMD;
and 6.9% had at least one of each. Compared with women with no GS or CMD,
women with one or more GS but no CMD were as likely to have physical
functioning impairments (odds ratio [OR] = 1.79; 95% confidence
interval [CI] = 1.73, 1.86) as those with CMD alone (OR
= 1.97; CI = 1.84, 2.10). The association with social
functioning was stronger for GS alone (OR = 2.10; CI =
2.02, 2.18) compared with CMD (OR = 1.60; CI = 1.50,
1.71). The association with general health was stronger for CMD alone (OR
= 2.15; CI = 2.01, 2.29) compared with GS (OR
= 1.68; CI = 1.62, 1.74). Significant interactions
between GS and CMD were observed for all functional measures with
20%–30% of observed ORs attributable to additive interaction.
GSs alone are associated with functional impairment in older women; the
association is stronger in the presence of even one CMD.
Geriatric syndromes; Cardiometabolic disease; Physical functioning
In the Women's Health Initiative (WHI) randomized controlled trial, use of estrogen plus progestin increased lung cancer mortality. We conducted post hoc analyses in the WHI trial evaluating estrogen alone to determine whether use of conjugated equine estrogen without progestin had a similar adverse influence on lung cancer.
The WHI study is a randomized, double-blind, placebo-controlled trial conducted in 40 centers in the United States. A total of 10 739 postmenopausal women aged 50–79 years who had a previous hysterectomy were randomly assigned to receive a once-daily 0.625-mg tablet of conjugated equine estrogen (n = 5310) or matching placebo (n = 5429). Incidence and mortality rates for all lung cancers, small cell lung cancers, and non–small cell lung cancers in the two randomization groups were compared by use of hazard ratios (HRs) and 95% confidence intervals (CIs) that were estimated from Cox proportional hazards regression analyses. Analyses were by intention to treat, and all statistical tests were two-sided.
After a mean of 7.9 years (standard deviation = 1.8 years) of follow-up, 61 women in the hormone therapy group were diagnosed with lung cancer compared with 54 in the placebo group (incidence of lung cancer per year = 0.15% vs 0.13%, respectively; HR of incidence = 1.17, 95% CI = 0.81 to 1.69, P = .39). Non–small cell lung cancers were of comparable number, stage, and grade in both groups. Deaths from lung cancer did not differ between the two groups (34 vs 33 deaths in estrogen and placebo groups, respectively; HR of death = 1.07, 95% CI = 0.66 to 1.72, P = .79).
Unlike use of estrogen plus progestin, which increased deaths from lung cancer, use of conjugated equine estrogen alone did not increase incidence or death from lung cancer.
Cognitive function and physical performance are associated, but the common sequence of cognitive and physical decline remains unclear.
In the Women’s Health Initiative Memory Study (WHIMS) clinical trial, we examined associations at baseline and over a 6-year follow-up period between the Modified Mini-Mental State (3MS) Examination and three physical performance measures (PPMs): gait speed (meters/second), chair stands (number of stands in 15 seconds), and grip strength (kilograms). Using mixed models, we examined the baseline 3MS as predictor of change in PPM, change in the 3MS as predictor of change in PPM, and baseline PPM as predictors of 3MS change.
Among 1,793 women (mean age = 70.3 years, 89% white, and mean 3MS score = 95.1), PPM were weakly correlated with 3MS—gait speed: r = .06, p = .02; chair stands: r = .09, p < .001; and grip strength: r = .10, p < .001. Baseline 3MS score was associated with subsequent PPM decline after adjustment for demographics, comorbid conditions, medications, and lifestyle factors. For every SD (4.2 points) higher 3MS score, 0.04 SD (0.04 m/s) less gait speed and 0.05 SD (0.29 kg) less grip strength decline is expected over 6 years (p ≤ .01 both). Changes in 3MS and PPM were associated, particularly with chair stands and grip strength (p < .003 both). Baseline PPMs were not associated with subsequent 3MS change.
Baseline global cognitive function and change in global cognitive function were associated with physical performance change, but baseline physical performance was not associated with cognitive change in this cohort. These analyses support the hypothesis that cognitive decline on average precedes or co-occurs with physical performance decline.
Cognitive function; Physical performance; Cognition; Physical function
A randomized trial of a pharmacist-delivered intervention (PI) versus usual care (UC) was conducted; 689 subjects with known coronary heart disease were recruited from cardiac catheterization laboratories. Participants in the PI condition received 5 pharmacist-delivered telephone counseling calls post-hospital discharge. At one year, 65% in the PI condition and 60% in the UC condition achieved an LDL-C level <100 mg/dL (P = .29); mean statin adherence was 0.88 in the PI, and 0.90 in the UC (P = .51). The highest percentage of those who reached the LDL-C goal were participants who used statins as opposed to those who did not use statins (67% versus 58%, P = .05). However, only 53% and 56% of the patients in the UC and PI conditions, respectively, were using statins. We conclude that a pharmacist-delivered intervention aimed only at improving patient adherence is unlikely to positively affect outcomes. Efforts must be oriented towards influencing physicians to increase statin prescription rates.
To examine associations among life events stress, social support, and breast cancer incidence in a cohort of postmenopausal women.
Design and main outcome measure
Women’s Health Initiative observational study participants, breast cancer free at entry, who provided assessment of stressful life events, social support, and breast cancer risk factors, were prospectively followed for breast cancer incidence (n=84,334).
During an average of 7.6 years of follow-up, 2,481 invasive breast cancers were diagnosed. In age-adjusted proportional hazards models, one stressful life event was associated with increased risk, but risk decreased with each additional stressful life event. After adjustment for confounders the decreasing risk was not significant. Stressful life events and social support appeared to interact in relation to breast cancer risk such that women who had greater number of stressful life events and low social support had a decreased risk of breast cancer.
This study found no independent association between stressful life events and breast cancer risk. The results are compatible with a more complex model of psychosocial factors interacting in relation to breast cancer risk.
Systemic inflammation may play an important role in the development of atherosclerosis, type 2 diabetes, and some cancers. Few studies have comprehensively assessed the direct relationships between dietary fiber and inflammatory cytokines, especially in minority populations. Using baseline data from 1,958 postmenopausal women enrolled in the Women’s Heath Initiative Observational Study, we examined cross-sectional associations between dietary fiber intake and markers of systemic inflammation (including serum C-reactive protein (hs-CRP), interleukin 6 (IL-6), and tumor necrosis factor α receptor 2 (TNF-α-R2)), as well as differences in these associations by ethnicity.
Multiple linear regression models were used to assess the relationship between fiber intake and makers of systemic inflammation.
After adjustment for covariates, intake of dietary fiber were inversely associated with both IL-6 (P values for trend were 0.01 for total fiber, 0.004 for soluble fiber, and 0.001 for insoluble fiber) and TNF-α-R2 (P values for trend were 0.002 for total, 0.02 for soluble, and <0.001 for insoluble fiber). Although the sample sizes were small in minority Americans, results were generally consistent with that found among European-Americans. We did not observe any significant association between intake of dietary fiber and hs-CRP.
These findings lend support to the hypothesis that a high-fiber diet is associated with lower plasma levels of IL-6 and TNF-α-R2. Contrary to previous reports, however, there was no association between fiber and hs-CRP among postmenopausal women. Future studies on the influence of diet on inflammation should include IL-6 and TNF-α-R2 and enroll participants from ethnic minorities.
dietary fiber; C-reactive protein; interleukin-6; tumor necrosis factor-alpha receptor 2; inflammation; cytokines; epidemiology; cardiovascular disease; nutrition
Objective To evaluate resting heart rate as an independent predictor of cardiovascular risk in women.
Design Prospective cohort study.
Setting The Women’s Health Initiative was undertaken at 40 research clinics in the United States.
Participants 129 135 postmenopausal women.
Main outcome measure Clinical cardiovascular events.
Results During a mean of 7.8 (SD 1.6) years of follow up, 2281 women were identified with myocardial infarction or coronary death and 1877 with stroke. We evaluated associations between resting heart rate and cardiovascular events in Cox regression models adjusted for multiple covariates. Higher resting heart rate was independently associated with coronary events (hazard ratio 1.26, 95% confidence interval 1.11 to 1.42 for highest [>76 beats per minute] v lowest quintile [≤62 beats per minute]; P=0.001), but not with stroke. The relation between heart rate and coronary events did not differ between white women and women from other ethnic groups (P for interaction=0.45) or between women with and without diabetes (P for interaction=0.31), but it was stronger in women aged 50-64 at baseline than in those aged 65-79 (P for interaction=0.009).
Conclusion Resting heart rate, a low tech and inexpensive measure of autonomic tone, independently predicts myocardial infarction or coronary death, but not stroke, in women.
Trial registration ClinicalTrials.gov NCT00000611.
Rationale and Objectives
The rates of enrollment of volunteers for brain magnetic resonance imaging (MRI) studies vary by demographic and clinical characteristics. We use data from a large MRI study to identify factors associated with differential enrollment and to examine potential biases this may produce in study results.
Materials and Methods
Results from recruitment of 1,431 women into the MRI substudy of the Women's Health Initiative Memory Study (WHIMS-MRI) are described. A sensitivity analysis was conducted to estimate the degree of bias associated with missing data on estimates of risk factor relationships.
Of 2,345 women contacted from an established cohort of women older than 70 years of age, 72% consented to undergo screening for WHIMS-MRI. Scanning was ultimately completed on 61%. Completion rates varied according to a range of sociodemographic, lifestyle, and clinical characteristics that may be related to study outcomes. Plausible levels of selective enrollment in magnetic resonance imaging studies may produce moderate biases (< ±20%) in characterizations of risk factor relationships. Adverse events, such as claustrophobia, occurred during 1.7% of the attempted scans and, in 0.8% of instances, led to lost data.
Enrollment of older women into brain imaging studies is feasible, although selection biases may limit how well study cohorts reflect more general populations.
Informed consent; magnetic resonance imaging; clinical trial
Professional societies and government organizations have promoted guidelines and best practices that encourage clinicians to routinely integrate cessation counseling into patient encounters. While research in health maintenance organizations has demonstrated that the development and maintenance of office systems do enable clinicians’ smoking-cessation services, little is known about the adoption of system strategies in diverse organizations serving disadvantaged populations.
Data were collected via face-to-face interviews from November 2001 to October 2002 using a standardized systems assessment checklist at service delivery sites of 83 funded community health service agencies, which included hospitals, community health centers, and other organizations (e.g., substance abuse, mental health, and multiservice). The content of the structured assessment reflected system elements with proven effectiveness that have been included in guidelines and best practices recommendations. Detailed information was collected on the implementation strategies.
This study found considerable attention to systems that support cessation services in diverse healthcare organizations, but much remains to be done. There is a wide diversity of implementation strategies employed, with varied degrees of sophistication.
A major challenge is to develop systems capable of providing population-based feedback to, and between, providers, which will enable further quality improvement efforts.
The objective of this study was to determine the effects of a brief primary care provider–delivered counseling intervention on the reduction of alcohol consumption by high-risk drinkers. The intervention was implemented as part of routine primary care medical practice.
We performed a controlled clinical trial with 6- and 12-month follow-up. Three primary care practices affiliated with an academic medical center were randomly assigned to special intervention (SI) or usual care (UC). A total of 9,772 primary care patients were screened for high-risk drinking. A fourth site was added later. From the group that was screened, 530 high-risk drinkers entered into the study, with 447 providing follow-up at 12 months. The intervention consisted of brief (5–10 minute) patient-centered counseling plus an office system that cued providers to intervene and provided patient educational materials.
At 12-month follow-up, after controlling for baseline differences in alcohol consumption, SI participants had significantly larger changes (P =.03) in weekly alcohol intake compared to UC (SI=−5.7 drinks per week; UC=−3.1 drinks per week), and of those who changed to safe drinking at 6 months more SI participants maintained that change at 12 months than UC.
Project Health provides evidence that screening and very brief (5–10 minute) advice and counseling delivered by a patient's personal physician or nurse practitioner as a routine part of a primary care visit can reduce alcohol consumption by high-risk drinkers.
high-risk drinking; primary care; provider-delivered intervention
Individuals with peripheral arterial disease (PAD) have a 3- to 6-fold increased risk of coronary heart disease and stroke compared to those without PAD. We documented physician-reported practice behavior, knowledge, and attitudes regarding atherosclerotic risk factor reduction in patients with PAD.
National physician survey.
General internists (N = 406), family practitioners (N = 435), cardiologists (N = 473), and vascular surgeons (N = 264) randomly identified using the American Medical Association's physician database.
MEASUREMENTS AND MAIN RESULTS
Physicians were randomized to 1 of 3 questionnaires describing a) a 55- to 65-year-old patient with PAD; b) a 55- to 65-year-old patient with coronary artery disease (CAD), or c) a 55- to 65-year-old patient without clinically evident atherosclerosis (no disease). A mailed questionnaire was used to compare physician behavior, knowledge, and attitude regarding risk factor reduction for each patient. Rates of prescribed antiplatelet therapy were significantly lower for the patient with PAD than for the patient with CAD. Average low-density lipoprotein levels at which physicians “almost always” initiated lipid-lowering drugs were 121.6 ± 23.5 mg/dL, 136.3 ± 28.9 mg/dL, and 149.7 ± 24.4 mg/dL for the CAD, PAD, and no-disease patients, respectively (P < .001). Physicians stated that antiplatelet therapy (P < .001) and cholesterol-lowering therapy (P < .001) were extremely important significantly more often for the CAD than for the PAD patient. Perceived importance of risk factor interventions was highly correlated with practice behavior. Compared to other specialties, cardiologists had lowest thresholds, whereas vascular surgeons had the highest thresholds for initiating cholesterol-lowering interventions for the patient with PAD. Cardiologists were significantly more likely to report “almost always” prescribing antiplatelet therapy for the patient with PAD than were all other physicians.
Deficiencies in physician knowledge and attitudes contribute to lower rates of atherosclerotic risk factor reduction for patients with PAD. Reversing these deficiencies may reduce the high rates of cardiovascular morbidity and mortality associated with PAD.
peripheral vascular disease; quality of care; cardiovascular disease
To assess the use of a brief provider-delivered alcohol counseling intervention of 5 to 10 minutes with high-risk drinking patients by primary care providers trained in the counseling intervention and provided with an office support system.
A group randomized study design was used. Office sites were randomized to either a usual care or special intervention condition, within which physicians and patients were nested. The unit of analysis was the patient.
Primary care internal medicine practices affiliated with an academic medical center.
Twenty-nine providers were randomized by practice site to receive training and an office support system to provide an alcohol counseling special intervention or to continue to provide usual care.
Special intervention providers received 2 1/2 hours of training in a brief alcohol-counseling intervention and were then supported by an office system that screened patients, cued providers to intervene, and made patient education materials available as tip sheets.
MEASUREMENTS AND MAIN RESULTS
Implementation of the counseling steps was measured by patient exit interviews (PEI) immediately following the patient visit. The interval between the date of training and the date of the PEI ranged from 6 to 32 months. Special intervention providers were twice as likely as usual care providers to discuss alcohol use with their patients. They carried out every step of the counseling sequence significantly more often than did usual care providers (p < .001). This intervention effect persisted over the 32 months of follow-up.
Physicians and other health-care providers trained in a brief provider-delivered alcohol intervention will counsel their high-risk drinking patients when cued to do so and supported by a primary care office system.
alcoholism; problem drinking; counseling
Emerging evidence suggests that women with menopausal vasomotor symptoms (VMS) have increased cardiovascular disease (CVD) risk as measured by surrogate markers. We investigated the relationships between VMS and clinical CVD events and all-cause mortality in the Women's Health Initiative Observational Study (WHI-OS).
We compared the risk of incident CVD events and all-cause mortality between four groups of women (total N=60,027): (1) No VMS at menopause onset and no VMS at WHI-OS enrollment (no VMS [referent group]); (2) VMS at menopause onset, but not at WHI-OS enrollment (early VMS); (3) VMS at both menopause onset and WHI-OS enrollment (persistent VMS [early and late]); and (4) VMS at WHI-OS enrollment, but not at menopause onset (late VMS).
For women with early VMS (N=24,753), compared to no VMS (N=18,799), hazard ratios (HRs) and 95% confidence intervals (CIs) in fully-adjusted models were: major CHD, 0.94 (0.84, 1.06); stroke, 0.83 (0.72, 0.96); total CVD, 0.89 (0.81, 0.97); and all-cause mortality, 0.92 (0.85, 0.99). For women with persistent VMS (N=15,084), there was no significant association with clinical events. For women with late VMS (N=1,391) compared to no VMS, HRs and 95% CIs were: major CHD, 1.32 (1.01, 1.71); stroke, 1.14 (0.82, 1.59); total CVD, 1.23 (1.00, 1.52); and all-cause mortality, 1.29 (1.08, 1.54).
Early VMS were not associated with increased CVD risk. Rather, early VMS were associated with decreased risk of stroke, total CVD events, and all-cause mortality. Late VMS were associated with increased CHD risk and all-cause mortality. The predictive value of VMS for clinical CVD events may vary with onset of VMS at different stages of menopause. Further research examining the mechanisms underlying these associations is needed. Future studies will also be necessary to investigate whether VMS that develop for the first time in the later postmenopausal years represent a pathophysiologic process distinct from classical perimenopausal VMS.
Vasomotor symptoms; Hot flashes; Cardiovascular disease; Women's health
In the post intervention period of the Women’s Health Initiative (WHI) clinical trial, estrogen plus progestin increased total cancer incidence and an adverse influence on lung cancer mortality was suggested.
We conducted post hoc analyses over the full follow-up period of the WHI randomized, placebo-controlled clinical trial evaluating daily conjugated equine estrogen (CEE, 0.625 mg) plus medroxyprogesterone acetate (MPA, 2.5 mg) influence on lung cancer incidence and mortality in 16,608 postmenopausal women.
After 5.6 years intervention and 2.4 years additional follow-up (mean), there were 109 lung cancers in the hormone group and 85 in the placebo group (hazard ratio (HR) 1.23, 95% confidence interval (CI), 0.92, 1.63, P=0.16). While the difference was not statistically significant, for non-small cell lung cancer a possible divergence emerged over time, with more diagnoses in the CEE plus MPA group (96 vs 72 cases, respectively, HR 1.28, 95% CI 0.94, 1.73, P=0.12) and these cancers were more commonly poorly differentiated and more commonly had distant metastasis. Deaths from lung cancer were significantly increased in the CEE plus MPA group (73 vs 40 deaths, respectively, HR 1.71, 95% CI 1.16, 2.52, P=0.01) as were deaths from non-small cell lung cancer (62 vs 31 deaths, respectively, HR 1.87, 95% CI 1.22, 2.88, P=0.004). Small cell lung cancer incidence and mortality was comparable between randomization groups.
Use of estrogen plus progestin did not increase lung cancer incidence but significantly increased deaths from lung cancer. The effect may primarily be through influence on non-small cell lung cancer outcome.