'Tis but a scratch: a critical review of the Women's Health Initiative evidence associating menopausal hormone therapy with the risk of breast cancer.

ABSTRACT: Use of menopausal hormone therapy (HT) fell precipitously after 2002, largely as a result of the Women's Health Initiative's report claiming that the combination of conjugated equine estrogen (CEE) and medroxyprogesterone acetate increased breast cancer risk and did not improve quality of life. More recently, Women's Health Initiative (WHI) publications acknowledge HT as the most effective treatment for managing menopausal vasomotor symptoms and report that CEE alone reduces the risk of breast cancer by 23% while reducing breast cancer death by 40%. Their sole remaining concern is a small increase in breast cancer incidence with CEE and medroxyprogesterone acetate (1 per 1,000 women per year) but with no increased risk of breast cancer mortality. This article closely examines evidence that calls even this claim of breast cancer risk into serious question, including the WHI's reporting of nonsignificant results as if they were meaningful, a misinterpretation of its own data, and the misleading assertion that the WHI's findings have reduced the incidence of breast cancer in the United States. A generation of women has been deprived of HT largely as a result of this widely publicized misinterpretation of the data. This article attempts to rectify this misunderstanding, with the goal of helping patients and physicians make informed joint decisions about the use of HT.

Progesterone from ovulatory menstrual cycles is an important cause of breast cancer.

Many factors, including reproductive hormones, have been linked to a woman's risk of developing breast cancer (BC). We reviewed the literature regarding the relationship between ovulatory menstrual cycles (MCs) and BC risk. Physiological variations in the frequency of MCs and interference with MCs through genetic variations, pathological conditions and or pharmaceutical interventions revealed a strong link between BC risk and the lifetime number of MCs. A substantial reduction in BC risk is observed in situations without MCs. In genetic or transgender situations with normal female breasts and estrogens, but no progesterone (P4), the incidence of BC is very low, suggesting an essential role of P4. During the MC, P4 has a strong proliferative effect on normal breast epithelium, whereas estradiol (E2) has only a minimal effect. The origin of BC has been strongly linked to proliferation associated DNA replication errors, and the repeated stimulation of the breast epithelium by P4 with each MC is likely to impact the epithelial mutational burden. Long-lived cells, such as stem cells, present in the breast epithelium, can carry mutations forward for an extended period of time, and studies show that breast tumors tend to take decades to develop before detection. We therefore postulate that P4 is an important factor in a woman's lifetime risk of developing BC, and that breast tumors arising during hormonal contraception or after menopause, with or without menopausal hormone therapy, are the consequence of the outgrowth of pre-existing neoplastic lesions, eventually stimulated by estrogens and some progestins.

Low concentrations of serum testosterone predict acute myocardial infarction in men with type 2 diabetes mellitus.

BACKGROUND: The aim of the present study was to investigate the associations between endogenous testosterone concentrations and the incidence of acute myocardial infarction (AMI) in men and women with and without type 2 diabetes. METHODS: The study comprised 1109 subjects ≥40 years of age (mean age 62 ± 12 years) participating in a baseline survey in Sweden in 1993-94. Information about smoking habits and physical activity was obtained using validated questionnaires. Serum concentrations of testosterone and sex hormone-binding globulin (SHBG) were obtained using radioimmunoassay. Diagnosis of type 2 diabetes was based on WHO's 1985 criteria. Individual patient information on incident AMI was ascertained by record linkage with national inpatient and mortality registers from baseline through 2011. RESULTS: The prevalence of type 2 diabetes at baseline was 10.0% in men and 7.5% in women. During a mean follow-up of 14.1 years (±5.3), there were 74 events of AMI in men and 58 in women. In age-adjusted Cox models, a significant inverse association between concentrations of testosterone and AMI-morbidity was found in men with type 2 diabetes (HR = 0.86 CI (0.75-0.98)). In a final model also including waist-to-hip ratio, systolic blood pressure, total cholesterol and active smoking, the association still remained statistically significant (HR = 0.754 CI (0.61-0.92)). CONCLUSION: Low concentrations of testosterone predicted AMI in men with type 2 diabetes independent of other risk factors. Trials with testosterone investigating the effect regarding cardiovascular outcome are still lacking. Future trials in this field should take into account a modification effect of diabetes.

Hypnotics' association with mortality or cancer: a matched cohort study.

OBJECTIVES: An estimated 6%-10% of US adults took a hypnotic drug for poor sleep in 2010. This study extends previous reports associating hypnotics with excess mortality. SETTING: A large integrated health system in the USA. DESIGN: Longitudinal electronic medical records were extracted for a one-to-two matched cohort survival analysis. SUBJECTS: Subjects (mean age 54 years) were 10 529 patients who received hypnotic prescriptions and 23 676 matched controls with no hypnotic prescriptions, followed for an average of 2.5 years between January 2002 and January 2007. MAIN OUTCOME MEASURES: Data were adjusted for age, gender, smoking, body mass index, ethnicity, marital status, alcohol use and prior cancer. Hazard ratios (HRs) for death were computed from Cox proportional hazards models controlled for risk factors and using up to 116 strata, which exactly matched cases and controls by 12 classes of comorbidity. RESULTS: As predicted, patients prescribed any hypnotic had substantially elevated hazards of dying compared to those prescribed no hypnotics. For groups prescribed 0.4-18, 18-132 and >132 doses/year, HRs (95% CIs) were 3.60 (2.92 to 4.44), 4.43 (3.67 to 5.36) and 5.32 (4.50 to 6.30), respectively, demonstrating a dose-response association. HRs were elevated in separate analyses for several common hypnotics, including zolpidem, temazepam, eszopiclone, zaleplon, other benzodiazepines, barbiturates and sedative antihistamines. Hypnotic use in the upper third was associated with a significant elevation of incident cancer; HR=1.35 (95% CI 1.18 to 1.55). Results were robust within groups suffering each comorbidity, indicating that the death and cancer hazards associated with hypnotic drugs were not attributable to pre-existing disease. CONCLUSIONS: Receiving hypnotic prescriptions was associated with greater than threefold increased hazards of death even when prescribed <18 pills/year. This association held in separate analyses for several commonly used hypnotics and for newer shorter-acting drugs. Control of selective prescription of hypnotics for patients in poor health did not explain the observed excess mortality.

Serum selenium, genetic variation in selenoenzymes, and risk of colorectal cancer: primary analysis from the Women's Health Initiative Observational Study and meta-analysis.

BACKGROUND: Selenium may prevent colorectal cancer. However, several previous studies are small and few investigated the association between selenium and colorectal cancer among women whose selenium metabolism may differ from men. Furthermore, genetic variants in selenoenzymes may be associated with colorectal cancer risk. METHODS: This nested case-control study investigated whether serum selenium concentration and genetic variants in five selenoenzymes (glutathione peroxidase 1-4 and selenoprotein P) were associated with colorectal cancer risk in 804 colorectal cancer cases and 805 matched controls from the Women's Health Initiative (WHI) Observational Study. A meta-analysis was conducted to compare the WHI result with previous studies including 12 observational studies and two clinical trials on selenium. RESULTS: Within the WHI, selenium concentrations were relatively high (mean = 135.6 µg/L) and were not associated with colorectal cancer risk (P(trend) = 0.10); the adjusted OR comparing the fifth with first quintile was 1.26 (95% CI, 0.91-1.73). Moreover, genetic variants in selenoenzymes were not significantly associated with colorectal cancer risk. Consistent with the finding in WHI, our meta-analysis showed no association between selenium and colorectal tumor risk in women (OR = 0.97; 95% CI, 0.79-1.18) comparing the highest quantile with the lowest); however, in men, there was a significant inverse association (OR = 0.68; 95% CI, 0.57-0.82) (P = 0.01). CONCLUSION: Consistent with previous studies, we observed no protective effect of selenium on colorectal cancer among women. IMPACT: Our analyses suggest that a population with relatively high selenium concentrations, especially women, would not benefit from increasing selenium intake.

Mortality related to actigraphic long and short sleep.

BACKGROUND: The folk belief that we should sleep 8 h seems to be incorrect. Numerous studies have shown that self-reported sleep longer than 7.5 h or shorter than 6.5 h predicts increased mortality risk. This study examined if prospectively-determined objective sleep duration, as estimated by wrist actigraphy, was associated with mortality risks. METHODS: From 1995-1999, women averaging 67.6 years of age provided one-week actigraphic recordings. Survival could be estimated from follow-up continuing until 2009 for 444 of the women, with an average of 10.5 years before censoring. Multivariate age-stratified Cox regression models were controlled for history of hypertension, diabetes, myocardial infarction, cancer, and major depression. RESULTS: Adjusted survival functions estimated 61% survival (54-69%, 95% C.I.) for those with sleep less than 300 min and 78% survival (73-85%, 95% C.I.) for those with actigraphic sleep longer than 390 min, as compared with survival of 90% (85-94%, 95% C.I.) for those with sleep of 300-390 min. Time-in-bed, sleep efficiency and the timing of melatonin metabolite excretion were also significant mortality risk factors. CONCLUSION: This study confirms a U-shaped relationship between survival and actigraphically measured sleep durations, with the optimal objective sleep duration being shorter than the self-report optimums. People who sleep five or six hours may be reassured. Further studies are needed to identify any modifiable factors for this mortality and possible approaches to prevention.

Calcium/vitamin D supplementation and coronary artery calcification in the Women's Health Initiative.

OBJECTIVE: Coronary artery calcified plaque is a marker for atheromatous plaque burden and predicts future risk of cardiovascular events. The relationship between calcium plus vitamin D (calcium/D) supplementation and coronary artery calcium (CAC) has not been previously assessed in a randomized trial setting. We compared CAC scores after trial completion between women randomized to calcium/vitamin D supplementation and women randomized to placebo. METHODS: In an ancillary substudy of women randomized to calcium carbonate (1,000 mg of elemental calcium daily) plus vitamin D3 (400 IU daily) or placebo, nested within the Women's Health Initiative trial of estrogen among women who underwent hysterectomy, we measured CAC with cardiac CT in 754 women aged 50 to 59 years at randomization. Imaging for CAC was performed at 28 of 40 centers after a mean of 7 years of treatment, and scans were read centrally. CAC scores were measured by a central reading center with masking to randomization assignments. RESULTS: Posttrial CAC measurements were similar in women randomized to calcium/D supplementation and those receiving placebo. The mean CAC score was 91.6 for women receiving calcium/D and 100.5 for women receiving placebo (rank test P value = 0.74). After adjustment for coronary risk factors, multivariate odds ratios for increasing CAC score cutpoints (CAC >0, > or =10, and > or =100) for calcium/D versus placebo were 0.92 (95% CI, 0.64-1.34), 1.29 (0.88-1.87), and 0.90 (0.56-1.44), respectively. Corresponding odds ratios among women with a 50% or higher adherence to study pills and for higher levels of CAC (>300) were similar. CONCLUSIONS: Treatment with moderate doses of calcium plus vitamin D3 did not seem to alter coronary artery calcified plaque burden among postmenopausal women. Whether higher or lower doses would affect this outcome remains uncertain.

Estrogen alone in postmenopausal women and breast cancer detection by means of mammography and breast biopsy.

PURPOSE: As the influence of estrogen alone on breast cancer detection is not established, we examined this issue in the Women's Health Initiative trial, which randomly assigned 10,739 postmenopausal women with prior hysterectomy to conjugated equine estrogen (CEE; 0.625 mg/d) or placebo. METHODS: Screening mammography and breast exams were performed at baseline and annually. Breast biopsies were based on clinical findings. Effects of CEE alone on breast cancer detection were determined by using receiver operating characteristic (ROC) analyses of mammogram performance. RESULTS: After a 7.1-year mean follow-up, fewer invasive breast cancers were diagnosed in the CEE than in the placebo group, but the difference was not statistically significant. Use of CEE alone increased mammograms with short-interval follow-up recommendations (cumulative, 39.2% v 29.6.3%; P < .001) but not abnormal mammograms (ie, those suggestive of or highly suggestive of malignancy; cumulative, 7.3% v 7.0%; P = .41). Breast biopsies were more frequent in the CEE group (cumulative, 12.5% v 10.7%; P = .004) and less commonly diagnosed as cancer (8.9% v 15.8%, respectively, with positive biopsies; P = .04). Mammographic breast cancer detection in the CEE group was significantly compromised only in the early years of use. CONCLUSION: CEE alone use for 5 years results in approximately one in 11 and one in 50 women having otherwise avoidable mammograms with short-interval follow-up recommendations or breast biopsies, respectively. Although the breast biopsies on CEE were less commonly diagnosed as cancer, breast cancer detection was not substantially compromised. These findings differ from estrogen-plus-progestin use, for which significantly increased abnormal mammograms and a compromise in breast cancer detection are seen.

Relationships among dietary nutrients and subjective sleep, objective sleep, and napping in women.

OBJECTIVE: To describe which dietary nutrient variables are related to subjective and objective habitual sleep and subjective and objective napping. METHODS: Participants were 459 post-menopausal women enrolled in the Women's Health Initiative. Objective sleep was estimated using one week of actigraphy. Subjective sleep was prospectively estimated with a daily sleep diary. Dietary nutrients were calculated from food frequency questionnaires. RESULTS: The most significant correlations were with subjective napping, including (from strongest to weakest): total fat, calories, saturated fat, monounsaturated fat, trans fat, water, proline, serine, tyrosine, phenylalanine, valine, cholesterol, leucine, glutamic acid, ash, isoleucine, histidine, sodium, tryptophan, protein, threonine, cystine, methionine, phosphorous, polyunsaturated fat, animal protein, aspartic acid, arginine, lysine, alanine, caffeine, riboflavin, gamma-tocopherol, glycine, retinol, delta-tocopherol, Vitamin D, and selenium. Actigraphic nocturnal sleep duration was negatively associated with total fat, monounsaturated fat, trans fat, saturated fat, polyunsaturated fat, calories, gamma-tocopherol, cholesterol, and alpha-tocopherol-eq. CONCLUSIONS: Actigraphic total sleep time was negatively associated with intake of fats. Subjective napping, which may be a proxy for subjective sleepiness, was significantly related to fat intake as well as intake of meat.

Efficacy, safety, and tolerability of low-dose hormone therapy in managing menopausal symptoms.

Use of the lowest clinically effective dose of postmenopausal hormone therapy conforms to current recommendations and good clinical practice. Although accumulating evidence demonstrates the efficacy and tolerability of low hormone therapy doses, data about their use are limited by a lack of long-term, randomized studies. This review evaluates current evidence on the efficacy, safety, and tolerability of these preparations and their role in menopausal management.

Benefits and risks of postmenopausal hormone therapy when it is initiated soon after menopause.

The authors further analyzed results from the Women's Health Initiative randomized trials (1993-2004) of conjugated equine estrogens, with or without medroxyprogesterone acetate, focusing on health benefits versus risks among women who initiated hormone therapy soon after menopause. Data from the Women's Health Initiative observational study (1993-2004) were included in some analyses for additional precision. Results are presented here for incident coronary heart disease, stroke, venous thromboembolism, breast cancer, colorectal cancer, endometrial cancer, or hip fracture; death from other causes; a summary global index; total cancer; and total mortality. Hazard ratios for breast cancer and total cancer were comparatively higher (P < 0.05) among women who initiated hormone therapy soon after menopause, for both regimens. Among these women, use of conjugated equine estrogens appeared to produce elevations in venous thromboembolism and stroke and a reduction in hip fracture. Estrogen plus progestin results among women who initiated use soon after menopause were similar for venous thromboembolism, stroke, and hip fracture but also included evidence of longer-term elevations in breast cancer, total cancer, and the global index. These analyses provide little support for the hypothesis of favorable effects among women who initiate postmenopausal estrogen use soon after menopause, either for coronary heart disease or for health benefits versus risk indices considered.

Incident invasive breast cancer, geographic location of residence, and reported average time spent outside.

There have been reports of greater breast cancer incidence and mortality at northern compared with southern latitudes postulated to be related to vitamin D exposure. Among 71,662 participants in the Women's Health Initiative Observational Study (WHIOS) free of cancer at baseline (1993-1998), associations were explored between incident invasive postmenopausal breast cancer (n = 2,535), over approximately 8.6 years follow-up, and the following: (a) region of residence at birth, age 15 years, age 35 years; (b) region of residence at WHIOS baseline; and (c) clinic center solar irradiance. Hazard ratios and 95% confidence intervals (CI) for breast cancer were estimated after adjustment for individual level confounders. There was no difference in breast cancer risk by region of earlier life, baseline residence, or solar irradiance measured in Langelys (gm-cal) per cm(2). There was an observed 15% decreased risk among women residing in areas of low versus high solar irradiance measured in Watts per m(2) (95% CI, 2-26%). However, the associated P(trend) of 0.20 was not significant. Conversely, women who reported spending on average <30 minutes versus >2 hours outside in daylight year round at WHIOS year 4 follow-up (n = 46,926), had a 20% (95% CI, 2-41%; P(trend) = 0.001) increased risk of breast cancer. In conclusion, region of residence and geographic solar irradiance are not consistently related to risk of breast cancer and may not be sufficient proxy measures for sunlight/vitamin D exposure. The observed association between time spent outside and breast cancer risk support the hypothesis that vitamin D may protect against breast cancer.

Usefulness of baseline lipids and C-reactive protein in women receiving menopausal hormone therapy as predictors of treatment-related coronary events.

Blood lipids and high-sensitivity C-reactive protein (hs-CRP) are altered by hormone therapy. The goal of the present study was to determine whether lipids and hs-CRP have predictive value for hormone therapy benefit or risk for coronary heart disease events in postmenopausal women without previous cardiovascular disease. A nested case-control study was performed in the Women's Health Initiative hormone trials. Baseline lipids and hs-CRP were obtained from 271 incident patients with coronary heart disease (cases) and 707 controls. In a combined trial analysis, favorable lipid status at baseline tended to predict better coronary heart disease outcomes when using conjugated equine estrogen (CEE) with or without medroxyprogesterone acetate (MPA). Women with a low-density lipoprotein (LDL)/high-density lipoprotein (HDL) cholesterol ratio <2.5 had no increase in risk of coronary heart disease when using CEE with or without MPA (odds ratio 0.60, 95% confidence interval 0.34 to 1.06), whereas women with an LDL/HDL cholesterol ratio > or =2.5 had increased risk of coronary heart disease (odds ratio 1.73, 95% confidence interval 1.18 to 2.53, p for interaction = 0.02). Low hs-CRP added marginally to the value of LDL/HDL ratio <2.5 when predicting coronary heart disease benefit on hormone therapy. In conclusion, postmenopausal women with undesirable lipid levels had excess coronary heart disease risk when using CEE with or without MPA. However, women with favorable lipid levels, especially LDL/HDL cholesterol ratio <2.5, did not have increased risk of coronary heart disease with CEE with or without MPA irrespective of hs-CRP.

Conjugated equine estrogens and breast cancer risk in the Women's Health Initiative clinical trial and observational study.

The Women's Health Initiative randomized controlled trial found a trend (p = 0.09) toward a lower breast cancer risk among women assigned to daily 0.625-mg conjugated equine estrogens (CEEs) compared with placebo, in contrast to an observational literature that mostly reports a moderate increase in risk with estrogen-alone preparations. In 1993-2004 at 40 US clinical centers, breast cancer hazard ratio estimates for this CEE regimen were compared between the Women's Health Initiative clinical trial and observational study toward understanding this apparent discrepancy and refining hazard ratio estimates. After control for prior use of postmenopausal hormone therapy and for confounding factors, CEE hazard ratio estimates were higher from the observational study compared with the clinical trial by 43% (p = 0.12). However, after additional control for time from menopause to first use of postmenopausal hormone therapy, the hazard ratios agreed closely between the two cohorts (p = 0.82). For women who begin use soon after menopause, combined analyses of clinical trial and observational study data do not provide clear evidence of either an overall reduction or an increase in breast cancer risk with CEEs, although hazard ratios appeared to be relatively higher among women having certain breast cancer risk factors or a low body mass index.

Oophorectomy, hormone therapy, and subclinical coronary artery disease in women with hysterectomy: the Women's Health Initiative coronary artery calcium study.

OBJECTIVE: Surgical menopause has been associated with an increased risk of coronary heart disease events. In this study, we aimed to determine the associations between coronary artery calcium (CAC) and hysterectomy, oophorectomy, and hormone therapy use with a focus on the duration of menopause for which there was no hormone therapy use. DESIGN: In a substudy of the Women's Health Initiative placebo-controlled trial of conjugated equine estrogens (0.625 mg/d), we measured CAC by computed tomography 1.3 years after the trial was stopped. Participants included 1,064 women with previous hysterectomy, aged 50 to 59 years at baseline. The mean trial period was 7.4 years. Imaging was performed at a mean of 1.3 years after the trial was stopped. RESULTS: Mean age was 55.1 years at randomization and 64.8 years at CAC measurement. In the overall cohort, there were no significant associations between bilateral oophorectomy, years since hysterectomy, years since hysterectomy without taking hormone therapy (HT), years since bilateral oophorectomy, and years of HT use before Women's Health Initiative enrollment and the presence of CAC. However, there was a significant interaction between bilateral oophorectomy and prerandomization HT use for the presence of any CAC (P = 0.05). When multivariable analyses were restricted to women who reported no previous HT use, those with bilateral oophorectomy had an odds ratio of 2.0 (95% CI: 1.2-3.4) for any CAC compared with women with no history of oophorectomy, whereas among women with unilateral or partial oophorectomy, the odds of any CAC was 1.7 (95% CI: 1.0-2.8). Among women with bilateral oophorectomy, HT use within 5 years of oophorectomy was associated with a lower prevalence of CAC. CONCLUSIONS: Among women with previous hysterectomy, subclinical coronary artery disease was more prevalent among those with oophorectomy and no prerandomization HT use, independent of traditional cardiovascular disease risk factors. The results suggest that factors related to oophorectomy and the absence of estrogen treatment in oophorectomized women may be related to coronary heart disease.

Estrogen plus progestin and breast cancer detection by means of mammography and breast biopsy.

BACKGROUND: The effect of combined hormone therapy on breast cancer detection is not established. METHODS: We examined the effect of combined hormone therapy on breast cancer detection in the Women's Health Initiative trial, which randomized 16,608 postmenopausal women to receive conjugated equine estrogens (0.625 mg/d) plus medroxyprogesterone acetate (2.5 mg/d) or placebo. Mammography and breast examinations were performed at baseline and annually per protocol, with breast biopsies based on clinical findings. The effects of conjugated equine estrogens plus medroxyprogesterone acetate on breast cancer detection was determined throughout 5.6 years of intervention using receiver operating characteristic analyses to evaluate mammography results. RESULTS: Conjugated equine estrogens plus medroxyprogesterone acetate increased the cumulative frequency of mammograms with abnormalities vs placebo (35.0% vs 23.0%; P < .001), which had less sensitivity for cancer detection and increased cumulative breast biopsy frequency (10.0% vs 6.1%; P < .001). Although breast cancers were significantly increased and were diagnosed at higher stages in the combined hormone group, biopsies in that group less frequently diagnosed cancer (14.8% vs 19.6%; P = .006). After discontinuation of combined hormone therapy, its adverse effect on mammograms modulated but remained significantly different from that of placebo for at least 12 months (P < .001). CONCLUSIONS: Use of conjugated equine estrogens plus medroxyprogesterone acetate for approximately 5 years resulted in more than 1 in 10 and 1 in 25 women having otherwise avoidable mammogram abnormalities and breast biopsies, respectively, and compromised the diagnostic performance of both. This adverse effect on breast cancer detection should be incorporated into risk-benefit discussions with women considering even short-term combined hormone therapy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00000611.

Risk factors for chronic venous disease: the San Diego Population Study.

BACKGROUND: The etiology of chronic venous disease in the lower limbs is unclear, and very limited data are available on potential risk factors from representative population studies. METHODS: Participants in the San Diego Population Study, a free-living adult population randomly selected from age, sex, and ethnic strata, were systematically assessed for risk factors for venous disease. Categorization of normal, moderate, and severe disease was determined hierarchically through clinical examination and ultrasonography imaging by trained vascular technologists, who also performed anthropometric measures. An interviewer administered a questionnaire and an examination assessed potential risk factors for venous disease suggested by previous reports. RESULTS: In multivariable models, moderate venous disease was independently related to age, a family history of venous disease, previous hernia surgery, and normotension in both sexes. In men, current walking, the absence of cardiovascular disease, and not moving after sitting were also predictive. Additional predictors in women were weight, number of births, oophorectomy, flat feet, and not sitting. For severe disease, age, family history of venous disease, waist circumference, and flat feet were predictive in both sexes. In men, occupation as a laborer, cigarette smoking, and normotension were also independently associated with severe venous disease. Additional significant and independent predictors in women were hours standing, history of leg injury, number of births, and cardiovascular disease, but African American ethnicity was protective. Multiple other postulated risk factors for venous disease were not significant in multivariable analysis in this population. CONCLUSIONS: Although some risk factors for venous disease such as age, family history of venous disease, and findings suggestive of ligamentous laxity (hernia surgery, flat feet) are immutable, others can be modified, such as weight, physical activity, and cigarette smoking. Overall, these data provide modest support for the potential of behavioral risk-factor modification to prevent chronic venous disease.

Estrogen therapy and coronary-artery calcification.

BACKGROUND: Calcified plaque in the coronary arteries is a marker for atheromatous-plaque burden and is predictive of future risk of cardiovascular events. We examined the relationship between estrogen therapy and coronary-artery calcium in the context of a randomized clinical trial. METHODS: In our ancillary substudy of the Women's Health Initiative trial of conjugated equine estrogens (0.625 mg per day) as compared with placebo in women who had undergone hysterectomy, we performed computed tomography of the heart in 1064 women aged 50 to 59 years at randomization. Imaging was conducted at 28 of 40 centers after a mean of 7.4 years of treatment and 1.3 years after the trial was completed (8.7 years after randomization). Coronary-artery calcium (or Agatston) scores were measured at a central reading center without knowledge of randomization status. RESULTS: The mean coronary-artery calcium score after trial completion was lower among women receiving estrogen (83.1) than among those receiving placebo (123.1) (P=0.02 by rank test). After adjustment for coronary risk factors, the multivariate odds ratios for coronary-artery calcium scores of more than 0, 10 or more, and 100 or more in the group receiving estrogen as compared with placebo were 0.78 (95% confidence interval, 0.58 to 1.04), 0.74 (0.55 to 0.99), and 0.69 (0.48 to 0.98), respectively. The corresponding odds ratios among women with at least 80% adherence to the study estrogen or placebo were 0.64 (P=0.01), 0.55 (P<0.001), and 0.46 (P=0.001). For coronary-artery calcium scores of more than 300 (vs. <10), the multivariate odds ratio was 0.58 (P=0.03) in an intention-to-treat analysis and 0.39 (P=0.004) among women with at least 80% adherence. CONCLUSIONS: Among women 50 to 59 years old at enrollment, the calcified-plaque burden in the coronary arteries after trial completion was lower in women assigned to estrogen than in those assigned to placebo. However, estrogen has complex biologic effects and may influence the risk of cardiovascular events and other outcomes through multiple pathways. (ClinicalTrials.gov number, NCT00000611.)