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1.  Effects of Hormone Therapy on Cognition and Mood in Recently Postmenopausal Women: Findings from the Randomized, Controlled KEEPS–Cognitive and Affective Study 
PLoS Medicine  2015;12(6):e1001833.
Menopausal hormone therapy (MHT) reportedly increases the risk of cognitive decline in women over age 65 y. It is unknown whether similar risks exist for recently postmenopausal women, and whether MHT affects mood in younger women. The ancillary Cognitive and Affective Study (KEEPS-Cog) of the Kronos Early Estrogen Prevention Study (KEEPS) examined the effects of up to 4 y of MHT on cognition and mood in recently postmenopausal women.
Methods and Findings
KEEPS, a randomized, double-blinded, placebo-controlled clinical trial, was conducted at nine US academic centers. Of the 727 women enrolled in KEEPS, 693 (95.3%) participated in the ancillary KEEPS-Cog, with 220 women randomized to receive 4 y of 0.45 mg/d oral conjugated equine estrogens (o-CEE) plus 200 mg/d micronized progesterone (m-P) for the first 12 d of each month, 211 women randomized to receive 50 μg/d transdermal estradiol (t-E2) plus 200 mg/d m-P for the first 12 d of each month, and 262 women randomized to receive placebo pills and patches. Primary outcomes included the Modified Mini-Mental State examination; four cognitive factors: verbal learning/memory, auditory attention/working memory, visual attention/executive function, and speeded language/mental flexibility; and a mood measure, the Profile of Mood States (POMS). MHT effects were analyzed using linear mixed-effects (LME) models, which make full use of all available data from each participant, including those with missing data. Data from those with and without full data were compared to assess for potential biases resulting from missing observations. For statistically significant results, we calculated effect sizes (ESs) to evaluate the magnitude of changes.
On average, participants were 52.6 y old, and 1.4 y past their last menstrual period. By month 48, 169 (24.4%) and 158 (22.8%) of the 693 women who consented for ancillary KEEPS-Cog were lost to follow-up for cognitive assessment (3MS and cognitive factors) and mood evaluations (POMS), respectively. However, because LME models make full use all available data, including data from women with missing data, 95.5% of participants were included in the final analysis (n = 662 in cognitive analyses, and n = 661 in mood analyses). To be included in analyses, women must have provided baseline data, and data from at least one post-baseline visit. The mean length of follow-up was 2.85 y (standard deviation [SD] = 0.49) for cognitive outcomes and 2.76 (SD = 0.57) for mood outcomes. No treatment-related benefits were found on cognitive outcomes. For mood, model estimates indicated that women treated with o-CEE showed improvements in depression and anxiety symptoms over the 48 mo of treatment, compared to women on placebo. The model estimate for the depression subscale was −5.36 × 10−2 (95% CI, −8.27 × 10−2 to −2.44 × 10−2; ES = 0.49, p < 0.001) and for the anxiety subscale was −3.01 × 10−2 (95% CI, −5.09 × 10−2 to −9.34 × 10−3; ES = 0.26, p < 0.001). Mood outcomes for women randomized to t-E2 were similar to those for women on placebo. Importantly, the KEEPS-Cog results cannot be extrapolated to treatment longer than 4 y.
The KEEPS-Cog findings suggest that for recently postmenopausal women, MHT did not alter cognition as hypothesized. However, beneficial mood effects with small to medium ESs were noted with 4 y of o-CEE, but not with 4 y of t-E2. The generalizability of these findings is limited to recently postmenopausal women with low cardiovascular risk profiles.
Trial Registration NCT00154180 and NCT00623311
In a randomized, controlled trial, Carey Gleason and colleagues examine the effects of hormone therapies on cognitive and mood outcomes in recently postmenopausal women.
Editors' Summary
Menopause (“change of life”)—the time in a woman’s life when her menstrual periods stop—is a normal part of aging and usually occurs around the age of 50. In the years before menopause (the menopausal transition or perimenopause), the levels of estrogen and progesterone—sex hormones produced by the ovaries that prepare the woman’s body every month for a possible pregnancy—go up and down irregularly. This variation in hormone levels changes the frequency and characteristics of a woman’s periods but can also cause hot flashes (feeling hot on and off during the day), night sweats, vaginal dryness, bone thinning, and mood swings. Some women sail through menopause without experiencing any of these symptoms, but for other women menopausal symptoms, which can continue for several years after menopause, can be debilitating. For these women, menopausal hormone therapy (MHT, previously known as hormone replacement therapy, or HRT)—treatment with various combinations and types of estrogen and progesterone—can be prescribed during or after the menopausal transition to manage their troublesome symptoms.
Why Was This Study Done?
Although MHT has helped many women deal with their menopausal symptoms, it can increase a woman’s risk of heart disease, stroke, blood clots, and breast cancer. There is also some evidence that MHT increases the risk of cognitive decline (decline in thinking, language, memory, understanding, and judgment) and dementia in women who start taking MHT after the age of 65. However, other evidence suggests that MHT might enhance cognition and mood if it is given at menopause rather than later. In this randomized, double-blinded, placebo-controlled clinical trial (the KEEPS-Cog trial, an ancillary study of the Kronos Early Estrogen Prevention Study, which examined the effect of MHT on cardiovascular health), the researchers investigate the effects of up to four years of MHT on cognition and mood in recently postmenopausal women living in the US. A randomized, placebo-controlled clinical trial compares the outcomes of participants assigned an active intervention or a placebo (dummy) intervention through the play of chance; in a double-blinded trial, neither the researchers nor the participants know who is receiving which treatment until the trial ends.
What Did the Researchers Do and Find?
In the KEEPS-Cog trial, 220 healthy recently postmenopausal women took an estrogen pill every day and a progesterone pill for the first 12 days of each month, 211 women wore an estradiol patch (transdermal estradiol) and took a progesterone pill for the first 12 days of each month, and 262 women received placebo patches and pills for up to four years (the average follow-up was a little less than three years). The researchers assessed the trial participants for their overall cognitive health using an instrument called the Modified Mini-Mental State Examination, for four specific cognitive functions using several established instruments, for depression symptoms using the Beck Depression Inventory, and for mood using the Profile of Mood States instrument at baseline and at 18, 36, and 48 months. Statistical analysis of the data collected indicates that, during the trial, there were no treatment-related effects on cognition or depression symptoms. However, women treated with estrogen pills and progesterone (but not those treated with estradiol patches and progesterone) showed improvements in some mood symptoms compared to women in the placebo group.
What Do These Findings Mean?
Before starting their trial, the researchers hypothesized that, because the body handles different formulations and types of estrogen in different ways, transdermal estradiol but not oral estrogen would improve cognition and mood in recently postmenopausal women when compared to placebo. Notably, the findings suggest that MHT does not alter cognition as hypothesized and that oral rather than transdermal estrogen has a small to moderate beneficial effect on mood. Importantly, these findings provide no information about the effects of MHT beyond four years and, because most of the women in the study were white, well-educated, and at low risk of cardiovascular disease, may not be applicable to the general postmenopausal population of the US and of other countries. Moreover, because MHT improved menopausal symptoms in the women receiving hormones, the trial was not truly double-blinded. However, despite these and other study limitations, the researchers suggest that their findings could now be used to help women make more informed decisions about whether to use MHT to manage their menopausal symptoms.
Additional Information
Please access these websites via the online version of this summary at
The US National Institute on Aging provides detailed information for women about menopause (in English and Spanish) and about hormones and menopause
The UK National Health Service Choices website also provides detailed information about menopause and about menopausal hormone therapy, including some personal stories
The US Food and Drug Administration provides answers to common questions about menopause and hormones (in English and Spanish)
MedlinePlus provides links to further resources and advice about menopause and about menopausal hormone therapy (in English and Spanish)
More information about the KEEPS-Cog trial is available
PMCID: PMC4452757  PMID: 26035291
2.  Traditional Nonsteroidal Anti-Inflammatory Drugs and Postmenopausal Hormone Therapy: A Drug–Drug Interaction? 
PLoS Medicine  2007;4(5):e157.
Suppression of prostacyclin (PGI2) is implicated in the cardiovascular hazard from inhibitors of cyclooxygenase (COX)-2. Furthermore, estrogen confers atheroprotection via COX-2–dependent PGI2 in mice, raising the possibility that COX inhibitors may undermine the cardioprotection, suggested by observational studies, of endogenous or exogenous estrogens.
Methods and Findings
To identify an interaction between hormone therapy (HT) and COX inhibition, we measured a priori the association between concomitant nonsteroidal anti-inflammatory drugs (NSAIDs), excluding aspirin, in peri- and postmenopausal women on HT and the incidence of myocardial infarction (MI) in a population-based epidemiological study. The odds ratio (OR) of MI in 1,673 individuals and 7,005 controls was increased from 0.66 (95% confidence interval [CI] 0.50–0.88) when taking HT in the absence of traditional (t)NSAIDs to 1.50 (95% CI 0.85–2.64) when taking the combination of HT and tNSAIDs, resulting in a significant (p < 0.002) interaction. The OR when taking aspirin at doses of 150 mg/d or more was 1.41 (95% CI 0.47–4.22). However, a similar interaction was not observed with other commonly used drugs, including lower doses of aspirin, which target preferentially COX-1.
Whether estrogens confer cardioprotection remains controversial. Such a benefit was observed only in perimenopausal women in the only large randomized trial designed to address this issue. Should such a benefit exist, these results raise the possibility that COX inhibitors may undermine the cardioprotective effects of HT.
It is controversial whether estrogens confer cardioprotection. This study suggests that even should such a benefit exist, COX inhibitors may undermine cardioprotective effects of hormone therapy.
Editors' Summary
There is currently a great deal of uncertainty regarding the effect of postmenopausal hormone therapy on heart disease in women. Premenopausal women are much less likely to experience heart attacks and strokes than men, a difference that does not exist between postmenopausal women and men. One mechanism that might explain these observations relates to the effect of estrogen, which is thought to have a protective effect on the heart. Hormone replacement therapy (HT) consisting of replacement estrogen, and sometimes progesterone as well, is often taken by women experiencing symptoms of menopause. Evidence from observational studies and the Womens' Health Initiative (WHI) trial has suggested that HT protects against heart disease in perimenopausal women. However, researchers have suggested that any beneficial effect of hormone replacement therapy on the heart might be counteracted by the effects of certain types of painkillers also being taken by women involved in the studies. These painkillers, nonsteroidal anti inflammatory drugs ( NSAIDs), prevent production of a molecule called prostacyclin. Prostacyclin plays a role in preventing blood clotting and is therefore thought to be important in protecting the heart. Estrogen, however, acts to increase production of prostacyclin, and it is therefore theoretically possible that hormone replacement therapy does have a beneficial effect on heart health, but which is counteracted by the negative effects of NSAIDs.
Why Was This Study Done?
In this study, the researchers wanted to find out whether there was any evidence for an interaction between NSAID use, hormone replacement therapy, and heart disease. Such understanding in turn might help to identify more clearly whether hormone replacement therapy protects against heart disease in specific subgroups of postmenopausal women.
What Did the Researchers Do and Find?
This study was carried out using information from the UK's General Practice Research Database, which is the largest computer database of anonymous medical records from primary care anywhere in the world. It contains information entered by UK general practitioners on their patients' drug prescriptions, diagnoses, referrals to hospital, and other data. The researchers here searched for all individuals from the database who were aged between 50 and 84 years on 1 January 1997, and then followed them up through the database for four years, or until the individual died, reached 85 years of age, or was diagnosed with a heart attack or cancer. From this search, the researchers found 1,673 women who had heart attacks or who died from coronary heart disease; these were considered “cases.” Then, these 1,673 women were matched against 20,000 “control” women of similar age. Information was pulled out for each case or control on their use of hormone replacement therapy, NSAIDs (covering 21 different drugs, but most commonly diclofenac, ibuprofen, and naproxen), and various risk factors for heart disease. The researchers then compared use of hormone replacement therapy and NSAIDs between the cases and controls, while making statistical adjustments for other risk factors (such as diabetes and smoking, for example).
  The researchers found that current use of hormone replacement therapy was associated with a lower risk of heart attack than non-use. The odds ratio (chance of a heart attack among HT users compared to the chance among non-users of HT) was 0.78. However, when looking at women who used NSAIDs at the same time as hormone replacement therapy, the researchers found no suggestion of a reduction in risk of heart attack: the odds ratio for the chance of heart attack among this group of women, as compared to nonusers of both NSAIDs and hormone replacement therapy, was 1.50.
What Do These Findings Mean?
These findings suggest that hormone replacement therapy and NSAIDs might interact, with NSAIDs acting against a role for hormone replacement therapy in preventing heart attacks. At face value, these results are in conflict with the findings of one large trial, the WHI trial, which failed to find a benefit of HT in preventing heart attacks. However, a recent analysis of WHI suggests cardioprotective effects of HT in women close to the time of the menopause and this coincides with the younger age of women in the observational studies such as the present one rather than in the WHI overall. Observational research studies, such as the present one, are often difficult to interpret because the groups being compared are not necessarily equivalent. It's possible that women who take hormone replacement therapy, or NSAIDs, are in some way different from women who do not, which will bias the findings. Determination of the clinical implications of these findings would most appropriately be resolved in future trials, designed to address the question of interest.
Additional Information.
Please access these Web sites via the online version of this summary at
Resources from the US National Institutes of Health on menopausal hormone therapy, including links to information about the Women's Health Initiative trials, information about managing menopausal symptoms, and more
Resources from the US National Institutes of Health (MedlinePlus) about heart disease in women
Information from NHS Direct, the UK National Health Service, about hormone replacement therapy
The UK General Practice Research Database is the database utilized in this article
Wikipedia entry on nonsteroidal anti-inflammatory drugs (NSAIDs) (note: Wikipedia is an internet encyclopedia anyone can edit)
PMCID: PMC1872041  PMID: 17518513
3.  Hip Fracture Incidence in Relation to Age, Menopausal Status, and Age at Menopause: Prospective Analysis 
PLoS Medicine  2009;6(11):e1000181.
Using data from the UK Million Women Study, Emily Banks and colleagues investigate the relationships between the incidence of hip fracture and a woman's age, menopausal status, and age at menopause.
Bone mineral density is known to decrease rapidly after the menopause. There is limited evidence about the separate contributions of a woman's age, menopausal status and age at menopause to the incidence of hip fracture.
Methods and Findings
Over one million middle-aged women joined the UK Million Women Study in 1996–2001 providing information on their menopausal status, age at menopause, and other factors, which was updated, where possible, 3 y later. All women were registered with the UK National Health Service (NHS) and were routinely linked to information on cause-specific admissions to NHS hospitals. 561,609 women who had never used hormone replacement therapy and who provided complete information on menopausal variables (at baseline 25% were pre/perimenopausal and 75% postmenopausal) were followed up for a total of 3.4 million woman-years (an average 6.2 y per woman). During follow-up 1,676 (0.3%) were admitted to hospital with a first incident hip fracture. Among women aged 50–54 y the relative risk (RR) of hip fracture risk was significantly higher in postmenopausal than premenopausal women (adjusted RR 2.22, 95% confidence interval [CI] 1.22–4.04; p = 0.009); there were too few premenopausal women aged 55 y and over for valid comparisons. Among postmenopausal women, hip fracture incidence increased steeply with age (p<0.001), with rates being about seven times higher at age 70–74 y than at 50–54 y (incidence rates of 0.82 versus 0.11 per 100 women over 5 y). Among postmenopausal women of a given age there was no significant difference in hip fracture incidence between women whose menopause was due to bilateral oophorectomy compared to a natural menopause (adjusted RR 1.20, 95% CI 0.94–1.55; p = 0.15), and age at menopause had little, if any, effect on hip fracture incidence.
At around the time of the menopause, hip fracture incidence is about twice as high in postmenopausal than in premenopausal women, but this effect is short lived. Among postmenopausal women, age is by far the main determinant of hip fracture incidence and, for women of a given age, their age at menopause has, at most, a weak additional effect.
Please see later in the article for the Editors' Summary
Editors' Summary
Anyone can break a hip but most hip fractures occur in elderly people. As people age, their bones gradually lose minerals and become less dense, which weakens the bones and makes them more susceptible to fracture. Because women lose bone density faster than men as they age and because women constitute the majority of the elderly, three-quarters of hip fractures occur in women. Hip fractures can cause long-term health problems and premature death. Thus, although surgical repair of a broken hip usually only requires a hospital stay of about a week, a quarter of elderly people who were living independently before their fracture have to stay in a nursing home for at least a year after their injury and a fifth of elderly people who break a hip die within the year. Most hip fractures are caused by falls. Regular exercise to improve strength and balance combined with review of medicines (to reduce side effects and interactions), regular eye examinations, and the removal of fall hazards from the home can help to prevent hip fractures in elderly people.
Why Was This Study Done?
Bone density decreases very rapidly in women immediately after menopause—the time when menstruation permanently stops—and then continues to decrease more slowly with age. Most women have their menopause in their early 50s but menopause can occur in younger women. Early menopause is thought to be a risk factor for osteoporosis (thinning of the bones) and fractures later in life but little is known about how menopause influences hip fracture risk as women age. In this prospective study (a type of study in which a group of people is followed for several years to see whether they develop a particular condition), the researchers investigate the incidence of hip fractures in relation to age, menopausal status, and age at menopause among the participants of the Million Women Study. This study, which recruited 1.3 million women aged 50–64 years who attended UK breast cancer screening clinics between 1996 and 2001, has been investigating how reproductive and lifestyle factors affect women's health.
What Did the Researchers Do and Find?
At enrollment and three years later, the study participants provided information about their menopausal status and other health and lifestyle factors likely to affect their fracture risk. From these data, the researchers identified more than half a million women who had never used hormone replacement therapy (which reduces fracture risk) and who had given complete information about their menopausal status. They then looked for statistical associations between the occurrence of a first hip fracture in these women over the next few years and their age, menopausal status, and age at menopause. Among women aged 50–54 years, postmenopausal women were twice as likely to have a hip fracture as premenopausal women. Among postmenopausal women, the incidence of hip fractures increased steeply with age and was seven times higher in 70–74-year olds than in 50–54-year olds. Women who had their menopause before age 45 had a slightly increased risk of hip fracture but any effect of age at menopause on the risk of hip fracture was small compared to the effect of age itself, and the slightly increased risk may have been due to other factors that could not be fully accounted for in the analysis.
What Do These Findings Mean?
These findings indicate that around the time of menopause, although hip fractures are rare, the risk of a fracture in postmenopausal women is twice that in premenopausal women. The findings also show that among postmenopausal women, age is the major determinant of hip fracture risk and that for women of a given age, their age at menopause has little effect on hip fracture risk. Women attending breast cancer screening clinics and completing questionnaires about their health may not be representative of the general population. Furthermore, these findings rely on women self-reporting their menopausal status accurately. Nevertheless, the results of this study suggest that clinicians advising women about hip fracture prevention should probably base their advice on the woman's age and on age-related factors such as frailty rather than on factors related to menopause. Clinicians can also now reassure elderly women who had an early menopause that their risk of hip fracture is unlikely to be higher than that of similar women who had a later menopause.
Additional Information
Please access these Web sites via the online version of this summary at
The American Academy of Orthopaedic Surgeons has detailed information about hip fractures
The US National Institute of Arthritis and Muscoloskeletal and Skin Diseases has an interactive feature called “Check up on your bones and provides detailed information about osteoporosis, including advice on fall prevention
The US Centers for Disease Control and Prevention has a fact sheet about hip fractures among older adults
MedlinePlus has links to resources about hip fracture, osteoporosis, and menopause (in English and Spanish)
More information on the Million Women Study is available
PMCID: PMC2766835  PMID: 19901981
4.  Bilateral oophorectomy is not associated with increased mortality: the California Teachers Study 
Fertility and sterility  2011;97(1):111-117.
To investigate the effect of surgical menopause due to bilateral oophorectomy on mortality, in light of evidence that bilateral oophorectomy among premenopausal women rapidly reduces endogenous hormone levels thereby modifying risks of cardiovascular disease and breast cancer.
The California Teachers Study (CTS) is a prospective cohort study of 133,479 women initiated in 1995–1996 through a mailed, self-administered questionnaire. Relative risks (RR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards regression.
CTS participants who, at baseline, reported having surgical menopause due to bilateral oophorectomy (n=9,785), were compared to participants with natural menopause (n=32,219).
Main outcome measures
We investigated whether bilateral oophorectomy was associated with all-cause, cardiovascular, or cancer mortality, overall and by menopausal hormone therapy (HT) use status.
Among participants younger than 45 years of age at menopause, multivariable relative risks were 0.86 (95% CI, 0.74–1.00), 0.85 (95% CI, 0.66–1.11) and 0.91 (95% CI, 0.67–1.23) for all-cause mortality, cardiovascular mortality and cancer mortality, respectively. Among participants with an age at menopause of 45 years or later, multivariable relative risks were 0.87 (95% CI, 0.80–0.94), 0.83 (95% CI, 0.71–0.96) and 0.84 (95% CI, 0.72–0.98) for all-cause, cardiovascular and cancer mortality, respectively. The association between bilateral oophorectomy and mortality did not differ by baseline status of HT use.
Surgical menopause due to bilateral oophorectomy vs. natural menopause does not increase all-cause, cardiovascular, or cancer mortality.
PMCID: PMC3245786  PMID: 22088205
surgical menopause and mortality; bilateral oophorectomy; mortality; California Teachers Study
5.  The Women’s Health Initiative Hormone Therapy Trials: Update and Overview of Health Outcomes During the Intervention and Post-Stopping Phases 
Menopausal hormone therapy continues in clinical use but questions remain regarding its risks and benefits for chronic disease prevention.
To provide a comprehensive, integrated overview of findings from the two Women’s Health Initiative (WHI) hormone therapy (HT) trials with extended post-intervention follow up.
27,347 postmenopausal women, age 50–79 years, were enrolled at 40 US centers. Interventions were conjugated equine estrogens (CEE, 0.625 mg/day) with medroxyprogesterone acetate (MPA, 2.5 mg/day) for women with an intact uterus (N = 16,608) and CEE alone for women with hysterectomy (N= 10,739), or their placebos. Intervention continued for 5.6 and 7.2 years (median), respectively, with cumulative follow-up of 13 years through September 30, 2010.
The primary efficacy and safety outcomes were coronary heart disease (CHD) and invasive breast cancer, respectively. A global index also included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and deaths. Secondary and quality-of-life outcomes were also assessed.
During the intervention phase for CEE+MPA, the hazard ratio (HR) for CHD was 1.18 (95% confidence interval [CI] 0.95–1.45) and overall risks outweighed benefits, with increases in invasive breast cancer, stroke, pulmonary embolism, and the global index. Other risks included increased dementia (in women >65 years), gallbladder disease, and urinary incontinence, while benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Post-intervention, most risks and benefits dissipated, although some elevation in breast cancer risk persisted (cumulative hazard ratio [HR] =1.28; 95% confidence interval, 1.11–1.48). During intervention for CEE alone, risks and benefits were more balanced, with a HR for CHD of 0.94 (0.78–1.14), increased stroke and venous thrombosis, decreased hip fractures and diabetes, and over cumulative follow-up, decreased breast cancer (HR=0.79 [0.65–0.97]). Neither regimen affected all-cause mortality. With CEE, younger women (50–59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index (nominal P values for trend by age <0.05), but not for stroke and venous thrombosis. Absolute risks of adverse events (measured by the global index) per 10,000 women per year on CEE+MPA ranged from 12 excess cases for age 50–59 to 38 for age 70–79 and, for CEE, from 19 fewer cases for age 50–59 to 51 excess cases for age 70–79. Results for quality of life outcomes in both trials were mixed.
Menopausal hormone therapy has a complex pattern of risks and benefits. While appropriate for symptom management in some women, its use for chronic disease prevention is not supported by the WHI randomized trials.
clinical Identifier: NCT00000611
PMCID: PMC3963523  PMID: 24084921
6.  Cancer Screening with Digital Mammography for Women at Average Risk for Breast Cancer, Magnetic Resonance Imaging (MRI) for Women at High Risk 
Executive Summary
The purpose of this review is to determine the effectiveness of 2 separate modalities, digital mammography (DM) and magnetic resonance imaging (MRI), relative to film mammography (FM), in the screening of women asymptomatic for breast cancer. A third analysis assesses the effectiveness and safety of the combination of MRI plus mammography (MRI plus FM) in screening of women at high risk. An economic analysis was also conducted.
Research Questions
How does the sensitivity and specificity of DM compare to FM?
How does the sensitivity and specificity of MRI compare to FM?
How do the recall rates compare among these screening modalities, and what effect might this have on radiation exposure? What are the risks associated with radiation exposure?
How does the sensitivity and specificity of the combination of MRI plus FM compare to either MRI or FM alone?
What are the economic considerations?
Clinical Need
The effectiveness of FM with respect to breast cancer mortality in the screening of asymptomatic average- risk women over the age of 50 has been established. However, based on a Medical Advisory Secretariat review completed in March 2006, screening is not recommended for women between the ages of 40 and 49 years. Guidelines published by the Canadian Task Force on Preventive Care recommend mammography screening every 1 to 2 years for women aged 50 years and over, hence, the inclusion of such women in organized breast cancer screening programs. In addition to the uncertainty of the effectiveness of mammography screening from the age of 40 years, there is concern over the risks associated with mammographic screening for the 10 years between the ages of 40 and 49 years.
The lack of effectiveness of mammography screening starting at the age of 40 years (with respect to breast cancer mortality) is based on the assumption that the ability to detect cancer decreases with increased breast tissue density. As breast density is highest in the premenopausal years (approximately 23% of postmenopausal and 53% of premenopausal women having at least 50% of the breast occupied by high density), mammography screening is not promoted in Canada nor in many other countries for women under the age of 50 at average risk for breast cancer. It is important to note, however, that screening of premenopausal women (i.e., younger than 50 years of age) at high risk for breast cancer by virtue of a family history of cancer or a known genetic predisposition (e.g., having tested positive for the breast cancer genes BRCA1 and/or BRCA2) is appropriate. Thus, this review will assess the effectiveness of breast cancer screening with modalities other than film mammography, specifically DM and MRI, for both pre/perimenopausal and postmenopausal age groups.
International estimates of the epidemiology of breast cancer show that the incidence of breast cancer is increasing for all ages combined whereas mortality is decreasing, though at a slower rate. The observed decreases in mortality rates may be attributable to screening, in addition to advances in breast cancer therapy over time. Decreases in mortality attributable to screening may be a result of the earlier detection and treatment of invasive cancers, in addition to the increased detection of ductal carcinoma in situ (DCIS), of which certain subpathologies are less lethal. Evidence from the Surveillance, Epidemiology and End Results (better known as SEER) cancer registry in the United States, indicates that the age-adjusted incidence of DCIS has increased almost 10-fold over a 20 year period, from 2.7 to 25 per 100,000.
There is a 4-fold lower incidence of breast cancer in the 40 to 49 year age group than in the 50 to 69 year age group (approximately 140 per 100,000 versus 500 per 100,000 women, respectively). The sensitivity of FM is also lower among younger women (approximately 75%) than for women aged over 50 years (approximately 85%). Specificity is approximately 80% for younger women versus 90% for women over 50 years. The increased density of breast tissue in younger women is likely responsible for the decreased accuracy of FM.
Treatment options for breast cancer vary with the stage of disease (based on tumor size, involvement of surrounding tissue, and number of affected axillary lymph nodes) and its pathology, and may include a combination of surgery, chemotherapy and/or radiotherapy. Surgery is the first-line intervention for biopsy-confirmed tumors. The subsequent use of radiation, chemotherapy or hormonal treatments is dependent on the histopathologic characteristics of the tumor and the type of surgery. There is controversy regarding the optimal treatment of DCIS, which is considered a noninvasive tumour.
Women at high risk for breast cancer are defined as genetic carriers of the more commonly known breast cancer genes (BRCA1, BRCA2 TP53), first degree relatives of carriers, women with varying degrees of high risk family histories, and/or women with greater than 20% lifetime risk for breast cancer based on existing risk models. Genetic carriers for this disease, primarily women with BRCA1 or BRCA2 mutations, have a lifetime probability of approximately 85% of developing breast cancer. Preventive options for these women include surgical interventions such as prophylactic mastectomy and/or oophorectomy, i.e., removal of the breasts and/or ovaries. Therefore, it is important to evaluate the benefits and risks of different screening modalities, to identify additional options for these women.
This Medical Advisory Secretariat review is the second of 2 parts on breast cancer screening, and concentrates on the evaluation of both DM and MRI relative to FM, the standard of care. Part I of this review (March 2006) addressed the effectiveness of screening mammography in 40 to 49 year old average-risk women. The overall objective of the present review is to determine the optimal screening modality based on the evidence.
Evidence Review Strategy
The Medical Advisory Secretariat followed its standard procedures and searched the following electronic databases: Ovid MEDLINE, EMBASE, Ovid MEDLINE In-Process & Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and The International Network of Agencies for Health Technology Assessment database. The subject headings and keywords searched included breast cancer, breast neoplasms, mass screening, digital mammography, magnetic resonance imaging. The detailed search strategies can be viewed in Appendix 1.
Included in this review are articles specific to screening and do not include evidence on diagnostic mammography. The search was further restricted to English-language articles published between January 1996 and April 2006. Excluded were case reports, comments, editorials, nonsystematic reviews, and letters.
Digital Mammography: In total, 224 articles specific to DM screening were identified. These were examined against the inclusion/exclusion criteria described below, resulting in the selection and review of 5 health technology assessments (HTAs) (plus 1 update) and 4 articles specific to screening with DM.
Magnetic Resonance Imaging: In total, 193 articles specific to MRI were identified. These were examined against the inclusion/exclusion criteria described below, resulting in the selection and review of 2 HTAs and 7 articles specific to screening with MRI.
The evaluation of the addition of FM to MRI in the screening of women at high risk for breast cancer was also conducted within the context of standard search procedures of the Medical Advisory Secretariat. as outlined above. The subject headings and keywords searched included the concepts of breast cancer, magnetic resonance imaging, mass screening, and high risk/predisposition to breast cancer. The search was further restricted to English-language articles published between September 2007 and January 15, 2010. Case reports, comments, editorials, nonsystematic reviews, and letters were not excluded.
MRI plus mammography: In total, 243 articles specific to MRI plus FM screening were identified. These were examined against the inclusion/exclusion criteria described below, resulting in the selection and review of 2 previous HTAs, and 1 systematic review of 11 paired design studies.
Inclusion Criteria
English-language articles, and English or French-language HTAs published from January 1996 to April 2006, inclusive.
Articles specific to screening of women with no personal history of breast cancer.
Studies in which DM or MRI were compared with FM, and where the specific outcomes of interest were reported.
Randomized controlled trials (RCTs) or paired studies only for assessment of DM.
Prospective, paired studies only for assessment of MRI.
Exclusion Criteria
Studies in which outcomes were not specific to those of interest in this report.
Studies in which women had been previously diagnosed with breast cancer.
Studies in which the intervention (DM or MRI) was not compared with FM.
Studies assessing DM with a sample size of less than 500.
Digital mammography.
Magnetic resonance imaging.
Screening with film mammography.
Outcomes of Interest
Breast cancer mortality (although no studies were found with such long follow-up).
Recall rates.
Summary of Findings
Digital Mammography
There is moderate quality evidence that DM is significantly more sensitive than FM in the screening of asymptomatic women aged less than 50 years, those who are premenopausal or perimenopausal, and those with heterogeneously or extremely dense breast tissue (regardless of age).
It is not known what effect these differences in sensitivity will have on the more important effectiveness outcome measure of breast cancer mortality, as there was no evidence of such an assessment.
Other factors have been set out to promote DM, for example, issues of recall rates and reading and examination times. Our analysis did not show that recall rates were necessarily improved in DM, though examination times were lower than for FM. Other factors including storage and retrieval of screens were not the subject of this analysis.
Magnetic Resonance Imaging
There is moderate quality evidence that the sensitivity of MRI is significantly higher than that of FM in the screening of women at high risk for breast cancer based on genetic or familial factors, regardless of age.
Radiation Risk Review
Cancer Care Ontario conducted a review of the evidence on radiation risk in screening with mammography women at high risk for breast cancer. From this review of recent literature and risk assessment that considered the potential impact of screening mammography in cohorts of women who start screening at an earlier age or who are at increased risk of developing breast cancer due to genetic susceptibility, the following conclusions can be drawn:
For women over 50 years of age, the benefits of mammography greatly outweigh the risk of radiation-induced breast cancer irrespective of the level of a woman’s inherent breast cancer risk.
Annual mammography for women aged 30 – 39 years who carry a breast cancer susceptibility gene or who have a strong family breast cancer history (defined as a first degree relative diagnosed in their thirties) has a favourable benefit:risk ratio. Mammography is estimated to detect 16 to 18 breast cancer cases for every one induced by radiation (Table 1). Initiation of screening at age 35 for this same group would increase the benefit:risk ratio to an even more favourable level of 34-50 cases detected for each one potentially induced.
Mammography for women under 30 years of age has an unfavourable benefit:risk ratio due to the challenges of detecting cancer in younger breasts, the aggressiveness of cancers at this age, the potential for radiation susceptibility at younger ages and a greater cumulative radiation exposure.
Mammography when used in combination with MRI for women who carry a strong breast cancer susceptibility (e.g., BRCA1/2 carriers), which if begun at age 35 and continued for 35 years, may confer greatly improved benefit:risk ratios which were estimated to be about 220 to one.
While there is considerable uncertainty in the risk of radiation-induced breast cancer, the risk expressed in published studies is almost certainly conservative as the radiation dose absorbed by women receiving mammography recently has been substantially reduced by newer technology.
A CCO update of the mammography radiation risk literature for 2008 and 2009 gave rise to one article by Barrington de Gonzales et al. published in 2009 (Barrington de Gonzales et al., 2009, JNCI, vol. 101: 205-209). This article focuses on estimating the risk of radiation-induced breast cancer for mammographic screening of young women at high risk for breast cancer (with BRCA gene mutations). Based on an assumption of a 15% to 25% or less reduction in mortality from mammography in these high risk women, the authors conclude that such a reduction is not substantially greater than the risk of radiation-induced breast cancer mortality when screening before the age of 34 years. That is, there would be no net benefit from annual mammographic screening of BRCA mutation carriers at ages 25-29 years; the net benefit would be zero or small if screening occurs in 30-34 year olds, and there would be some net benefit at age 35 years or older.
The Addition of Mammography to Magnetic Resonance Imaging
The effects of the addition of FM to MRI screening of high risk women was also assessed, with inclusion and exclusion criteria as follows:
Inclusion Criteria
English-language articles and English or French-language HTAs published from September 2007 to January 15, 2010.
Articles specific to screening of women at high risk for breast cancer, regardless of the definition of high risk.
Studies in which accuracy data for the combination of MRI plus FM are available to be compared to that of MRI and FM alone.
RCTs or prospective, paired studies only.
Studies in which women were previously diagnosed with breast cancer were also included.
Exclusion Criteria
Studies in which outcomes were not specific to those of interest in this report.
Studies in which there was insufficient data on the accuracy of MRI plus FM.
Both MRI and FM.
Screening with MRI alone and FM alone.
Outcomes of Interest
Summary of Findings
Magnetic Resonance Imaging Plus Mammography
Moderate GRADE Level Evidence that the sensitivity of MRI plus mammography is significantly higher than that of MRI or FM alone, although the specificity remains either unchanged or decreases in the screening of women at high risk for breast cancer based on genetic/familial factors, regardless of age.
These studies include women at high risk defined as BRCA1/2 or TP53 carriers, first degree relatives of carriers, women with varying degrees of high risk family histories, and/or >20% lifetime risk based on existing risk models. This definition of high risk accounts for approximately 2% of the female adult population in Ontario.
PMCID: PMC3377503  PMID: 23074406
7.  Menopausal Hormone Therapy and Lung Cancer-Specific Mortality Following Diagnosis: The California Teachers Study 
PLoS ONE  2014;9(7):e103735.
Previous results from research on menopausal hormone therapy (MHT) and lung cancer survival have been mixed and most have not studied women who used estrogen therapy (ET) exclusively. We examined the associations between MHT use reported at baseline and lung cancer-specific mortality in the prospective California Teachers Study cohort. Among 727 postmenopausal women diagnosed with lung cancer from 1995 through 2007, 441 women died before January 1, 2008. Hazard Ratios (HR) and 95% Confidence Intervals (CI) for lung-cancer-specific mortality were obtained by fitting multivariable Cox proportional hazards regression models using age in days as the timescale. Among women who used ET exclusively, decreases in lung cancer mortality were observed (HR, 0.69; 95% CI, 0.52–0.93). No association was observed for estrogen plus progestin therapy use. Among former users, shorter duration (<5 years) of exclusive ET use was associated with a decreased risk of lung cancer mortality (HR, 0.56; 95% CI, 0.35–0.89), whereas among recent users, longer duration (>15 years) was associated with a decreased risk (HR, 0.60; 95% CI, 0.38–0.95). Smoking status modified the associations with deceases in lung cancer mortality observed only among current smokers. Exclusive ET use was associated with decreased lung cancer mortality.
PMCID: PMC4117568  PMID: 25079077
8.  The Effect of Elevated Body Mass Index on Ischemic Heart Disease Risk: Causal Estimates from a Mendelian Randomisation Approach 
PLoS Medicine  2012;9(5):e1001212.
A Mendelian randomization analysis conducted by Børge G. Nordestgaard and colleagues using data from observational studies supports a causal relationship between body mass index and risk for ischemic heart disease.
Adiposity, assessed as elevated body mass index (BMI), is associated with increased risk of ischemic heart disease (IHD); however, whether this is causal is unknown. We tested the hypothesis that positive observational associations between BMI and IHD are causal.
Methods and Findings
In 75,627 individuals taken from two population-based and one case-control study in Copenhagen, we measured BMI, ascertained 11,056 IHD events, and genotyped FTO(rs9939609), MC4R(rs17782313), and TMEM18(rs6548238). Using genotypes as a combined allele score in instrumental variable analyses, the causal odds ratio (OR) between BMI and IHD was estimated and compared with observational estimates. The allele score-BMI and the allele score-IHD associations used to estimate the causal OR were also calculated individually. In observational analyses the OR for IHD was 1.26 (95% CI 1.19–1.34) for every 4 kg/m2 increase in BMI. A one-unit allele score increase associated with a 0.28 kg/m2 (95 CI% 0.20–0.36) increase in BMI and an OR for IHD of 1.03 (95% CI 1.01–1.05) (corresponding to an average 1.68 kg/m2 BMI increase and 18% increase in the odds of IHD for those carrying all six BMI increasing alleles). In instrumental variable analysis using the same allele score the causal IHD OR for a 4 kg/m2 increase in BMI was 1.52 (95% CI 1.12–2.05).
For every 4 kg/m2 increase in BMI, observational estimates suggested a 26% increase in odds for IHD while causal estimates suggested a 52% increase. These data add evidence to support a causal link between increased BMI and IHD risk, though the mechanism may ultimately be through intermediate factors like hypertension, dyslipidemia, and type 2 diabetes. This work has important policy implications for public health, given the continuous nature of the BMI-IHD association and the modifiable nature of BMI. This analysis demonstrates the value of observational studies and their ability to provide unbiased results through inclusion of genetic data avoiding confounding, reverse causation, and bias.
Please see later in the article for the Editors' Summary
Editors' Summary
Ischemic heart disease (IHD; also known as coronary heart disease) is the leading cause of death among adults in developed countries. In the US alone, IHD kills nearly half a million people every year. With age, fatty deposits (atherosclerotic plaques) build up in the walls of the coronary arteries, the blood vessels that supply the heart with oxygen and nutrients. The resultant reduction in the heart's blood supply causes shortness of breath, angina (chest pains that are usually relieved by rest), and potentially fatal heart attacks (myocardial infarctions). Risk factors for IHD include smoking, high blood pressure (hypertension), abnormal amounts of cholesterol and other fat in the blood (dyslipidemia), type 2 diabetes, and being overweight or obese (having excess body fat). Treatments for IHD include lifestyle changes (for example, losing weight) and medications that lower blood pressure and blood cholesterol levels. The narrowed arteries can also be widened using a device called a stent or surgically bypassed.
Why Was This Study Done?
Prospective observational studies have shown an association between a high body mass index (BMI, a measure of body fat that is calculated by dividing a person's weight in kilograms by their height in meters squared; a BMI greater than 30 kg/m2 indicates obesity) and an increased risk of IHD. Observational studies, which ask whether people who are exposed to a suspected risk factor develop a specific disease more often than people who are not exposed to the risk factor, cannot prove, however, that changes in BMI/adiposity cause IHD. Obese individuals may share other characteristics that cause both IHD and obesity (confounding) or, rather than obesity causing IHD, IHD may cause obesity (reverse causation). Here, the researchers use “Mendelian randomization” to examine whether elevations in BMI across the lifecourse have a causal impact on IHD risk. Three common genetic variants—FTO(rs9939609), MC4R(rs17782313), and TMEM18(rs6548238)—which have the largest single genetic variant associations with BMI were used in this study. Given that gene variants are inherited essentially randomly with respect to conventional confounding factors and are not subject reverse causation, use of these as instruments (or proxy measures) for variation in BMI as a risk factor (as opposed to measuring BMI directly) allows researchers to comment on whether obesity is causally involved in IHD.
What Did the Researchers Do and Find?
The researchers analyzed data from two population-based studies in which adults were physically examined and answered a lifestyle questionnaire before being followed to see how many developed IDH. They also analyzed data from a case-control study on IDH (in a case-control study, people with a disease are matched with similar people without the disease and the occurrence of risk factors in the patients and controls is compared). Overall, the researchers measured the BMI of 75,627 white individuals, among whom 11,056 already had IDH or developed it, and determined which of the BMI-increasing genetic variants each participant carried. On the basis of the observational data, every 4 kg/m2 increase in BMI increased the odds of IDH by 26% (an odds ratio of 1.26). Using a score derived from the combination of the three genetic variants, the researchers confirmed an association between each BMI increasing allele and both BMI (as expected) and IHD (0.28 kg/m2 and an odds ratio for IHD of 1.03, respectively). On average, compared to people carrying no BMI-increasing gene variants, people carrying six BMI-increasing gene variants had a 1.68 kg/m2 increase in BMI and an 18% increase in IHD risk. To extend this and to essentially reassess the original, observational, relationship between BMI and IHD risk, an “instrumental variable analysis” was used to examine the causal effect of a lifetime change in BMI on the risk of IDH. In this, it was found that for every 4 kg/m2 increase in BMI increased the odds of IDH by 52%.
What Do These Findings Mean?
These findings support a causal link between increased BMI and IDH risk, although it may be that BMI affects IDH through intermediate factors such as hypertension, dyslipidemia, and diabetes. The findings also show that observational studies into the impact of elevated BMI on IHD risk were consistent with this, but also that the inclusion of genetic data increases the value of observational studies by making it possible to avoid issues such as confounding and reverse causation. Finally, these findings and those of recent, observational studies have important implications for public-health policy because they show that the association between BMI (which is modifiable by lifestyle changes) and IHD is continuous. That is, any increase in BMI increases the risk of IHD; there is no threshold below which a BMI increase has no effect on IDH risk. Thus, public-health policies that aim to reduce BMI by even moderate levels could substantially reduce the occurrence of IDH in populations.
Additional Information
Please access these Web sites via the online version of this summary at
The American Heart Association provides information about IHD and tips on keeping the heart healthy, including weight management; it also provides personal stories about IHD
The UK National Health Service Choices website provides information about IHD, including information on prevention and personal stories about IHD
Information is available from the British Heart Foundation on heart disease and keeping the heart healthy
The US National Heart Lung and Blood Institute also provides information on IHD (in English and Spanish)
MedlinePlus provides links to many other sources of information on IHD (in English and Spanish)
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
PMCID: PMC3341326  PMID: 22563304
9.  Oral Contraceptives and Menopausal Hormone Therapy: Relative and Attributable Risks of Cardiovascular Disease, Cancer, and Other Health Outcomes 
Annals of epidemiology  2014;25(3):193-200.
To summarize the relative risks (RR) and attributable risks (AR) of major health outcomes associated with use of combined oral contraceptives (OCs) and menopausal hormone therapy (HT).
For OCs, measures of association are from meta-analyses of observational studies. For HT, these measures are from the Women’s Health Initiative (WHI), a large randomized trial of HT for chronic disease prevention in postmenopausal women aged 50-79.
Current OC use increases risks of venous thromboembolism and ischemic stroke. However, women of reproductive age are at low baseline risk, so the AR are small. OC use also increases risk of breast and liver cancer and reduces risk of ovarian, endometrial, and colorectal cancer; the net effect is a modest reduction in total cancer. The WHI results show that HT does not prevent coronary events or overall chronic disease in postmenopausal women as a whole. Subgroup analyses suggest that timing of HT initiation influences the relation between such therapy and coronary risk, as well as its overall risk-benefit balance, with more favorable effects (on a relative scale) in younger or recently menopausal women than in older women or those further past the menopausal transition. However, even if the RR do not vary by these characteristics, the low absolute baseline risks of younger or recently menopausal women translate into low ARs in this group.
OC and HT can safely be used for contraception and treatment of vasomotor symptoms, respectively, by healthy women at low baseline risk for CVD and breast cancer.
PMCID: PMC4389282  PMID: 25534509
attributable risk; attributable risk percent; coronary heart disease; cancer; epidemiology; estrogen; hazard ratio; menopausal hormone therapy; mortality; observational studies; oral contraceptives; progestin; randomized clinical trials; relative risk; stroke; venous thromboembolism; women
10.  Promotional Tone in Reviews of Menopausal Hormone Therapy After the Women's Health Initiative: An Analysis of Published Articles 
PLoS Medicine  2011;8(3):e1000425.
Adriane Fugh-Berman and colleagues analyzed a selection of published opinion pieces on hormone therapy and show that there may be a connection between receiving industry funding for speaking, consulting, or research and the tone of such opinion pieces.
Even after the Women's Health Initiative (WHI) found that the risks of menopausal hormone therapy (hormone therapy) outweighed benefit for asymptomatic women, about half of gynecologists in the United States continued to believe that hormones benefited women's health. The pharmaceutical industry has supported publication of articles in medical journals for marketing purposes. It is unknown whether author relationships with industry affect promotional tone in articles on hormone therapy. The goal of this study was to determine whether promotional tone could be identified in narrative review articles regarding menopausal hormone therapy and whether articles identified as promotional were more likely to have been authored by those with conflicts of interest with manufacturers of menopausal hormone therapy.
Methods and Findings
We analyzed tone in opinion pieces on hormone therapy published in the four years after the estrogen-progestin arm of the WHI was stopped. First, we identified the ten authors with four or more MEDLINE-indexed reviews, editorials, comments, or letters on hormone replacement therapy or menopausal hormone therapy published between July 2002 and June 2006. Next, we conducted an additional search using the names of these authors to identify other relevant articles. Finally, after author names and affiliations were removed, 50 articles were evaluated by three readers for scientific accuracy and for tone. Scientific accuracy was assessed based on whether or not the findings of the WHI were accurately reported using two criteria: (1) Acknowledgment or lack of denial of the risk of breast cancer diagnosis associated with hormone therapy, and (2) acknowledgment that hormone therapy did not benefit cardiovascular disease endpoints. Determination of promotional tone was based on the assessment by each reader of whether the article appeared to promote hormone therapy. Analysis of inter-rater consistency found moderate agreement for scientific accuracy (κ = 0.57) and substantial agreement for promotional tone (κ = 0.65). After discussion, readers found 86% of the articles to be scientifically accurate and 64% to be promotional in tone. Themes that were common in articles considered promotional included attacks on the methodology of the WHI, arguments that clinical trial results should not guide treatment for individuals, and arguments that observational studies are as good as or better than randomized clinical trials for guiding clinical decisions. The promotional articles we identified also implied that the risks associated with hormone therapy have been exaggerated and that the benefits of hormone therapy have been or will be proven. Of the ten authors studied, eight were found to have declared payment for speaking or consulting on behalf of menopausal hormone manufacturers or for research support (seven of these eight were speakers or consultants). Thirty of 32 articles (90%) evaluated as promoting hormone therapy were authored by those with potential financial conflicts of interest, compared to 11 of 18 articles (61%) by those without such conflicts (p = 0.0025). Articles promoting the use of menopausal hormone therapy were 2.41 times (95% confidence interval 1.49–4.93) as likely to have been authored by authors with conflicts of interest as by authors without conflicts of interest. In articles from three authors with conflicts of interest some of the same text was repeated word-for-word in different articles.
There may be a connection between receiving industry funding for speaking, consulting, or research and the publication of promotional opinion pieces on menopausal hormone therapy.
Please see later in the article for the Editors' Summary
Editors' Summary
Over the past three decades, menopausal hormones have been heavily promoted for preventing disease in women. However, the Women's Health Initiative (WHI) study—which enrolled more than 26,000 women in the US and which was published in 2004—found that estrogen-progestin and estrogen-only formulations (often prescribed to women around the age of menopause) increased the risk of stroke, deep vein thrombosis, dementia, and incontinence. Furthermore, this study found that the estrogen-progestin therapy increased rates of breast cancer. In fact, the estrogen-progestin arm of the WHI study was stopped in 2002 due to harmful findings, and the estrogen-only arm was stopped in 2004, also because of harmful findings. In addition, the study also found that neither therapy reduced cardiovascular risk or markedly benefited health-related quality of life measures.
Despite these results, two years after the results of WHI study were published, a survey of over 700 practicing gynecologists—the specialists who prescribe the majority of menopausal hormone therapies—in the US found that almost half did not find the findings of the WHI study convincing and that 48% disagreed with the decision to stop the trial early. Furthermore, follow-up surveys found similar results.
Why Was This Study Done?
It is unclear why gynecologists and other physicians continue to prescribe menopausal hormone therapies despite the results of the WHI. Some academics argue that published industry-funded reviews and commentaries may be designed to convey specific, but subtle, marketing messages and several academic analyses have used internal industry documents disclosed in litigation cases. So this study was conducted to investigate whether hormone therapy–promoting tone could be identified in narrative review articles and if so, whether these articles were more likely to have been authored by people who had accepted funding from hormone manufacturers.
What Did the Researchers Do and Find?
The researchers conducted a comprehensive literature search that identified 340 relevant articles published between July 2002 and June 2006—the four years following the cessation of the estrogen-progestin arm of the women's health initiative study. Ten authors had published four to six articles, 47 authored two or three articles, and 371 authored one article each. The researchers focused on authors who had published four or more articles in the four-year period under study and, after author names and affiliations were removed, 50 articles were evaluated by three readers for scientific accuracy and for tone. After individually analyzing a batch of articles, the readers met to provide their initial assessments, to discuss them, and to reach consensus on tone and scientific accuracy. Then after the papers were evaluated, each author was identified and the researchers searched for authors' potential financial conflicts of interest, defined as publicly disclosed information that the authors had received payment for research, speaking, or consulting on behalf of a manufacturer of menopausal hormone therapy.
Common themes in the 50 articles included arguments that clinical trial results should not guide treatment for individuals and suggestions that the risks associated with hormone therapy have been exaggerated and that the benefits of hormone therapy have been or will be proven. Furthermore, of the ten authors studied, eight were found to have received payment for research, speaking or consulting on behalf of menopause hormone manufacturers, and 30 of 32 articles evaluated as promoting hormone therapy were authored by those with potential financial conflicts of interest. Articles promoting the use of menopausal hormone therapy were more than twice as likely to have been written by authors with conflicts of interest as by authors without conflicts of interest. Furthermore, Three authors who were identified as having financial conflicts of interest were authors on articles where sections of their previously published articles were repeated word-for-word without citation.
What Do These Findings Mean?
The findings of this study suggest that there may be a link between receiving industry funding for speaking, consulting, or research and the publication of apparently promotional opinion pieces on menopausal hormone therapy. Furthermore, such publications may encourage physicians to continue prescribing these therapies to women of menopausal age. Therefore, physicians and other health care providers should interpret the content of review articles with caution. In addition, medical journals should follow the International Committee of Medical Journal Editors Uniform Requirements for Manuscripts, which require that all authors submit signed statements of their participation in authorship and full disclosure of any conflicts of interest.
Additional Information
Please access these Web sites via the online version of this summary at
The US National Heart, Lung, and Blood Institute has more information on the Womens Health Initiative
The US National Institutes of Health provide more information about the effects of menopausal hormone replacement therapy
The Office of Women's Health, U.S. Department of Health and Human Services provides information on menopausal hormone therapy
The International Committee of Medical Journal Editors Uniform Requirements for Manuscripts presents Uniform Requirements for Manuscripts published in biomedical journals
The National Womens Health Network, a consumer advocacy group that takes no industry money, has factsheets and articles about menopausal hormone therapy
PharmedOut, a Georgetown University Medical Center project, has many resources on pharmaceutical marketing practices
PMCID: PMC3058057  PMID: 21423581
11.  Long-Term Exposure to Air Pollution and Cardiorespiratory Disease in the California Teachers Study Cohort 
Rationale: Several studies have linked long-term exposure to particulate air pollution with increased cardiopulmonary mortality; only two have also examined incident circulatory disease.
Objectives: To examine associations of individualized long-term exposures to particulate and gaseous air pollution with incident myocardial infarction and stroke, as well as all-cause and cause-specific mortality.
Methods: We estimated long-term residential air pollution exposure for more than 100,000 participants in the California Teachers Study, a prospective cohort of female public school professionals. We linked geocoded residential addresses with inverse distance-weighted monthly pollutant surfaces for two measures of particulate matter and for several gaseous pollutants. We examined associations between exposure to these pollutants and risks of incident myocardial infarction and stroke, and of all-cause and cause-specific mortality, using Cox proportional hazards models.
Measurements and Main Results: We found elevated hazard ratios linking long-term exposure to particulate matter less than 2.5 μm in aerodynamic diameter (PM2.5), scaled to an increment of 10 μg/m3 with mortality from ischemic heart disease (IHD) (1.20; 95% confidence interval [CI], 1.02–1.41) and, particularly among postmenopausal women, incident stroke (1.19; 95% CI, 1.02–1.38). Long-term exposure to particulate matter less than 10 μm in aerodynamic diameter (PM10) was associated with elevated risks for IHD mortality (1.06; 95% CI, 0.99–1.14) and incident stroke (1.06; 95% CI, 1.00–1.13), while exposure to nitrogen oxides was associated with elevated risks for IHD and all cardiovascular mortality.
Conclusions: This study provides evidence linking long-term exposure to PM2.5 and PM10 with increased risks of incident stroke as well as IHD mortality; exposure to nitrogen oxides was also related to death from cardiovascular diseases.
PMCID: PMC3208653  PMID: 21700913
particulate matter; cardiovascular diseases; air pollutants; epidemiology
12.  Prevalence of cardiovascular risk factors in postmenopausal women: A rural study 
Journal of Mid-Life Health  2010;1(1):26-29.
The present observational, cross-sectional prospective study was conducted during the period of 1 year in one of the rural health centers to study prevalence of conventional cardiovascular disease risk factors (CVRFs) in postmenopausal women.
Materials and Methods:
Five hundred consecutive postmenopausal women were screened for detailed information regarding common menopausal symptoms, the presence or absence of conventional CVRFs. Physical activity was measured, and dietary lifestyle was also assessed. Use of hormone replacement therapy (HRT) and other drugs were also noted. Knowledge regarding their menopause was also evaluated.
Mean age at menopause was 49.35 years, Mean number of menopausal symptoms was 6.70 ± 5.76, and mean duration since menopause was (MDSM = 4.70 years)). Fatigue, lack of energy (70%), cold hand and feet, rheumatology-related symptoms (60%) cold sweats, weight gain, irritability, and nervousness (50%), palpitation of heart, excitable/anxiety (30%) each were common complaints. Hypertension was diagnosed or a person was a known hypertensive (56%). Diabetes was diagnosed or a person was known diabetic in 21%, and BMI was found to be 25 kg/m2 in 78%. Truncal obesity with waist-hip ratio >0.8 in 68% females, whereas abdominal obesity with waist size >88 cm was in 60% women. Dyslipidemia was seen in 39%. It was defined by the presence of high TC (=200 mg/dL) in 30%, high LDL-c (=130 mg/dL) in 27%, low HDLc (<40 mg/dL) in 21% or high TG (=150 mg/dL) in 31%. Metabolic syndrome was present in 13% of cases. CRP was found positive in 12 out of 39 total evaluated women, and serum uric acid was found >6.5 mg/dL in 4%. Smoking (0.5%), alcohol (0%,), tobacco chewing (4%), and family history of premature heart disease (9%) were recorded. Lifestyle was active in 35%, hectic in 10%, and sedentary in 55% of postmenopausal women (PMWs). Only 5% of women were receiving HRT, 0.5% isoflavone-containing phytoestrogens, 0.4% tibolone, 24% anti-HT, 9% anti-diabetic, 8% lipid-lowering drugs, and only three patients were on anti-obesity along with dietary and lifestyle management. Out of 68 patients, who were advised for electrocardiography (ECG), 23 were found positive for ischemic changes on ECG and out of 12 women advised for treadmill test (TMT), only four were found positive for ischemic heart disease (IHD). Risk factor count of more than four was found in 11%. Over all 96% of women were affected by menopause or related problems. Only 9% were aware about their menopause, 3% for importance of lifestyle modification, weight and dietary management programs to ameliorate menopause or menopause-compounded CVRFs.
This study showed alarmingly high prevalence of most of the conventional CVRFs, especially diabetes, hypertension, dyslipidemia, obesity, and other risk factors in postmenopausal women from rural areas.
PMCID: PMC3139259  PMID: 21799635
Cardiovascular; menopause; risk factor
13.  Can Biomarkers Identify Women at Increased Stroke Risk? The Women's Health Initiative Hormone Trials 
PLoS Clinical Trials  2007;2(6):e28.
The Women's Health Initiative hormone trials identified a 44% increase in ischemic stroke risk with combination estrogen plus progestin and a 39% increase with estrogen alone. We undertook a case-control biomarker study to elucidate underlying mechanisms, and to potentially identify women who would be at lower or higher risk for stroke with postmenopausal hormone therapy (HT).
The hormone trials were randomized, double-blind, and placebo controlled.
The Women's Health Initiative trials were conducted at 40 clinical centers in the United States.
The trials enrolled 27,347 postmenopausal women, aged 50–79 y.
We randomized 16,608 women with intact uterus to conjugated estrogens 0.625 mg with medroxyprogesterone acetate 2.5 mg daily or placebo, and 10,739 women with prior hysterectomy to conjugated estrogens 0.625 mg daily or placebo.
Outcome Measures:
Stroke was ascertained during 5.6 y of follow-up in the estrogen plus progestin trial and 6.8 y of follow-up in the estrogen alone trial.
No baseline clinical characteristics, including gene polymorphisms, identified women for whom the stroke risk from HT was higher. Paradoxically, women with higher baseline levels of some stroke-associated biomarkers had a lower risk of stroke when assigned to estrogen plus progestin compared to placebo. For example, those with higher IL-6 were not at increased stroke risk when assigned to estrogen plus progestin (odds ratio 1.28) but were when assigned to placebo (odds ratio 3.47; p for difference = 0.02). Similar findings occurred for high baseline PAP, leukocyte count, and D-dimer. However, only an interaction of D-dimer during follow-up interaction with HT and stroke was marginally significant (p = 0.03).
Biomarkers did not identify women at higher stroke risk with postmenopausal HT. Some biomarkers appeared to identify women at lower stroke risk with estrogen plus progestin, but these findings may be due to chance.
Editorial Commentary
Background: The Women's Health Initiative hormone trials originally set out to evaluate whether postmenopausal hormone therapy (HT, estrogen in the case of women who had had a hysterectomy, and estrogen plus progestin for women who had not had a hysterectomy) reduced the risk of heart attacks and strokes, as compared to placebo. The trials were stopped early, and the investigators found that both estrogen alone, as well as estrogen plus progestin increased the risk of stroke amongst women participating in the trials. As part of a secondary analysis of data from these trials, the investigators aimed to explore possible associations between various biological markers (such as variants in particular genes, and levels of particular lipids, proteins, and other markers in blood), and the risk of a woman experiencing a stroke in the trials. Specifically, they wanted to evaluate whether there was any evidence for particular markers being associated with the risk of a stroke; and then whether that risk was modified by whether a woman took HT in the trials.
What the trial shows: In this study, the researchers collected early cases of ischemic stroke in the trials (combining cases among women taking estrogen with those for women taking both estrogen and progestin), and matched these to control individuals, or women participating in the trials who did not experience a stroke. Two hundred five women who experienced a stroke were compared to 878 control individuals. The markers analyzed included those for which there was already some evidence for an association with stroke. Several clinical characteristics and some biomarkers, as measured at the start of the trial, but none of the gene variants, were linked with later risk of stroke. However, none of these clinical characteristics or gene variants specifically identified women who were at greater risk of experiencing a stroke within the HT arms of the trial. High levels of two biomarkers, IL-6 and PAP, did seem to identify women who were at lower risk of experiencing a stroke within the HT arms of the trial. This finding is interesting, because high levels of these markers had previously been suggested as being associated with a higher risk of stroke. Levels of several biomarkers changed during the trial, but for only one biomarker, D-dimer, did the change (an increase in levels) seem to predict higher risk of stroke amongst women receiving HT.
Strengths and limitations: A particular strength of this study includes the nesting of a case-control study within the Women's Health Initiative trials, in which HT or placebo was randomly assigned. This design minimizes the chance that individuals taking HT differ in their stroke risk from individuals taking placebo. However, the power of this study to detect anything other than large associations is limited; together with the limitation of multiple statistical testing, the findings here must be interpreted as hypotheses for further study and not definitive conclusions.
Contribution to the evidence: This study adds data relating to possible predictive risk markers for stroke among users of HT. The hypotheses raised here remain to be tested in further studies.
PMCID: PMC1891725  PMID: 17571161
14.  Estrogen Plus Progestin and Breast Cancer Incidence and Mortality in the Women’s Health Initiative Observational Study 
In the Women’s Health Initiative (WHI) randomized trial, estrogen plus progestin increased both breast cancer incidence and mortality. In contrast, most observational studies associate estrogen plus progestin with favorable prognosis breast cancers. To address differences, a cohort of WHI observational study participants with characteristics similar to the WHI clinical trial was studied.
We identified 41 449 postmenopausal women with no prior hysterectomy and mammogram negative within 2 years who were either not hormone users (n = 25 328) or estrogen and progestin users (n = 16 121). Multivariable-adjusted Cox proportional hazard regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CI). All statistical tests were two-sided.
After a mean of 11.3 (SD = 3.1) years, with 2236 breast cancers, incidence was higher in estrogen plus progestin users than in nonusers (0.60% vs 0.42%, annualized rate, respectively; HR = 1.55, 95% CI = 1.41 to 1.70, P < .001). Women initiating hormone therapy closer to menopause had higher breast cancer risk with linear diminishing influence as time from menopause increased (P < .001). Survival after breast cancer, measured from diagnosis, was similar in combined hormone therapy users and nonusers (HR = 1.03, 95% CI = 0.79 to 1.35). On a population basis, there were somewhat more deaths from breast cancer, measured from cohort entry (HR = 1.32, 95% CI = 0.90 to 1.93, P = .15), and more all-cause deaths after breast cancer (HR = 1.65, 95% CI = 1.29 to 2.12, P < .001) in estrogen plus progestin users than in nonusers.
Consistent with WHI randomized trial findings, estrogen plus progestin use is associated with increased breast cancer incidence. Because prognosis after diagnosis on combined hormone therapy is similar to that of nonusers, increased breast cancer mortality can be expected.
PMCID: PMC3691942  PMID: 23543779
15.  Adverse Trends in Ischemic Heart Disease Mortality among Young New Yorkers, Particularly Young Black Women 
PLoS ONE  2016;11(2):e0149015.
Ischemic heart disease (IHD) mortality has been on the decline in the United States for decades. However, declines in IHD mortality have been slower in certain groups, including young women and black individuals.
Trends in IHD vary by age, sex, and race in New York City (NYC). Young female minorities are a vulnerable group that may warrant renewed efforts to reduce IHD.
IHD mortality trends were assessed in NYC 1980–2008. NYC Vital Statistics data were obtained for analysis. Age-specific IHD mortality rates and confidence bounds were estimated. Trends in IHD mortality were compared by age and race/ethnicity using linear regression of log-transformed mortality rates. Rates and trends in IHD mortality rates were compared between subgroups defined by age, sex and race/ethnicity.
The decline in IHD mortality rates slowed in 1999 among individuals aged 35–54 years but not ≥55. IHD mortality rates were higher among young men than women age 35–54, but annual declines in IHD mortality were slower for women. Black women age 35–54 had higher IHD mortality rates and slower declines in IHD mortality than women of other race/ethnicity groups. IHD mortality trends were similar in black and white men age 35–54.
The decline in IHD mortality rates has slowed in recent years among younger, but not older, individuals in NYC. There was an association between sex and race/ethnicity on IHD mortality rates and trends. Young black women may benefit from targeted medical and public health interventions to reduce IHD mortality.
PMCID: PMC4755569  PMID: 26882207
16.  Marital status and ischemic heart disease incidence and mortality in women: a large prospective study 
BMC Medicine  2014;12:42.
Being married has been associated with a lower mortality from ischemic heart disease (IHD) in men, but there is less evidence of an association for women, and it is unclear whether the associations with being married are similar for incident and for fatal IHD. We examined the relation between marital status and IHD incidence and mortality in the Million Women Study.
A total of 734,626 women (mean age 60 years) without previous heart disease, stroke or cancer, were followed prospectively for hospital admissions and deaths. Adjusted relative risks (RRs) for IHD were calculated using Cox regression in women who were married or living with a partner versus women who were not. The role of 14 socio-economic, lifestyle and other potential confounding factors was investigated.
81% of women reported being married or living with a partner and they were less likely to live in deprived areas, to smoke or be physically inactive, but had a higher alcohol intake than women who were not married or living with a partner. During 8.8 years of follow-up, 30,747 women had a first IHD event (hospital admission or death) and 2,148 died from IHD. Women who were married or living with a partner had a similar risk of a first IHD event as women who were not (RR = 0.99, 95% confidence interval (CI) 0.96 to 1.02), but a significantly lower risk of IHD mortality (RR = 0.72, 95% CI 0.66 to 0.80, P <0.0001). This lower risk of IHD death was evident both in women with and without a prior IHD hospital admission (respectively: RR = 0.72, 95% CI 0.60 to 0.85, P <0.0001, n = 683; and 0.70, 95% CI 0.62 to 0.78, P <0.0001, n = 1,465). These findings did not vary appreciably between women of different socio-economic groups or by lifestyle and other factors.
After adjustment for socioeconomic, lifestyle and other factors, women who were married or living with a partner had a similar risk of developing IHD but a substantially lower IHD mortality compared to women who were not married or living with a partner.
PMCID: PMC4103700  PMID: 24618083
Marital status; Ischemic heart disease; Incidence; Mortality; Women
17.  Sex-based differences in cardiac ischaemic injury and protection: therapeutic implications 
British Journal of Pharmacology  2014;171(3):541-554.
Ischaemic heart disease (IHD) is the most frequent cause of mortality among men and women. Many epidemiological studies have demonstrated that premenopausal women have a reduced risk for IHD compared with their male counterparts. The incidence of IHD in women increases after menopause, suggesting that IHD is related to declining oestrogen levels. Experimental observations have confirmed the results of epidemiological studies investigating sex-specific differences in cardiac tolerance to ischaemia. Female sex appears also to favourably influence cardiac remodelling after ischaemia/reperfusion injury. Furthermore, sex-related differences in ischaemic tolerance of the adult myocardium can be influenced by interventions during the early phases of ontogenetic development. Detailed mechanisms of these sex-related differences remain unknown; however, they involve the genomic and non-genomic effects of sex steroid hormones, particularly the oestrogens, which have been the most extensively studied. Although the protective effects of oestrogen have many potential therapeutic implications, clinical trials have shown that oestrogen replacement in postmenopausal women may actually increase the incidence of IHD. The results of these trials have illustrated the complexity underlying the mechanisms involved in sex-related differences in cardiac tolerance to ischaemia. Sex-related differences in cardiac sensitivity to ischaemia/reperfusion injury may also influence therapeutic strategies in women with acute coronary syndrome. Women undergo coronary intervention less frequently and a lower proportion of women receive evidence-based therapy compared with men. Although our understanding of this important topic has increased in recent years, there is an urgent need for intensive experimental and clinical research to develop female-specific therapeutic strategies. Only then we will be able to offer patients better evidence-based treatment, a better quality of life and lower mortality.
PMCID: PMC3969071  PMID: 23750471
acute coronary syndrome; cardioprotection; oestrogen; heart; ischaemia/reperfusion injury; sex differences; therapeutic implications
18.  Ischemic heart disease and stroke mortality in African-American, Hispanic, and non-Hispanic white men and women, 1985 to 1991. 
Western Journal of Medicine  1998;169(3):139-145.
We compare recent trends in ischemic heart disease (IHD) and stroke mortality in California among the 6 major sex-racial or -ethnic groups. Rates of age-specific and -adjusted mortality were calculated for persons aged 35 and older during the years 1985 to 1991. Log-linear regression modeling was performed to estimate the average annual percentage change in mortality. During 1985 through 1991, the mortality for IHD and stroke was generally highest for African Americans, intermediate for non-Hispanic whites, and lowest for Hispanics. Age-adjusted mortality for IHD declined significantly in all sex-racial or -ethnic groups except African-American women, and stroke rates declined significantly in all groups except African-American and Hispanic men. African Americans had excess IHD mortality relative to non-Hispanic whites until late in life, after which mortality of non-Hispanic whites was higher. Similarly, African Americans and Hispanics had excess stroke mortality relative to non-Hispanic whites early in life, whereas stroke mortality in non-Hispanic whites was higher at older ages. The lower IHD and stroke mortality among Hispanics was paradoxical, given the generally adverse risk profile and socioeconomic status observed among Hispanics. An alarmingly high prevalence of self-reported cardiovascular disease risk factors in 1994 to 1996, particularly hypertension, leisure-time sedentary lifestyle, and obesity, is a serious public health concern, with implications for future trends in cardiovascular disease mortality. Of particular concern was the growing disparities in stroke and IHD mortality among younger-aged African Americans relative to Hispanics and non-Hispanic whites.
PMCID: PMC1305195  PMID: 9771151
19.  Mortality in Pharmacologically Treated Older Adults with Diabetes: The Cardiovascular Health Study, 1989–2001 
PLoS Medicine  2006;3(10):e400.
Diabetes mellitus (DM) confers an increased risk of mortality in young and middle-aged individuals and in women. It is uncertain, however, whether excess DM mortality continues beyond age 75 years, is related to type of hypoglycemic therapy, and whether women continue to be disproportionately affected by DM into older age.
Methods and Findings
From the Cardiovascular Health Study, a prospective study of 5,888 adults, we examined 5,372 participants aged 65 y or above without DM (91.2%), 322 with DM treated with oral hypoglycemic agents (OHGAs) (5.5%), and 194 with DM treated with insulin (3.3%). Participants were followed (1989–2001) for total, cardiovascular disease (CVD), coronary heart disease (CHD), and non-CVD/noncancer mortality. Compared with non-DM participants, those treated with OHGAs or insulin had adjusted hazard ratios (HRs) for total mortality of 1.33 (95% confidence interval [CI], 1.10 to 1.62) and 2.04 (95% CI, 1.62 to 2.57); CVD mortality, 1.99 (95% CI, 1.54 to 2.57) and 2.16 (95% CI, 1.54 to 3.03); CHD mortality, 2.47 (95% CI, 1.89 to 3.24) and 2.75 (95% CI, 1.95 to 3.87); and infectious and renal mortality, 1.35 (95% CI, 0.70 to 2.59) and 6.55 (95% CI, 4.18 to 10.26), respectively. The interaction of age (65–74 y versus ≥75 y) with DM was not significant. Women treated with OHGAs had a similar HR for total mortality to men, but a higher HR when treated with insulin.
DM mortality risk remains high among older adults in the current era of medical care. Mortality risk and type of mortality differ between OHGA and insulin treatment. Women treated with insulin therapy have an especially high mortality risk. Given the high absolute CVD mortality in older people, those with DM warrant aggressive CVD risk factor reduction.
The negative impact on mortality of diabetes persists into old age. Elderly people with diabetes might be twice as likely to die from CVD as people without diabetes. More aggressive treatment of CVD risk factors in older patients should be considered.
Editors' Summary
Diabetes is a growing global health problem. By 2030, 300 million people worldwide may have this chronic, incurable disorder, double the current number. People with diabetes have dangerously high amounts of sugar in their blood. Blood-sugar levels are normally controlled by insulin, a hormone made by the pancreas that tells cells to absorb sugar from the blood. This control fails in people with diabetes, either because they make no insulin (type 1 diabetes) or because their cells are insensitive to insulin (type 2 diabetes). Type 1 diabetes is controlled with insulin injections; type 2 diabetes is controlled with diet, exercise, and pills that reduce blood-sugar levels. Long-term complications of diabetes include kidney failure, blindness, and nerve damage. Individuals with diabetes also have an increased risk of developing cardiovascular disease (CVD)—heart problems, strokes, and poor circulation—because of damage to their blood vessels.
Why Was This Study Done?
Epidemiological studies (investigations of disease patterns, causes, and control in populations) have indicated that diabetes increases the risk of death (mortality) from CVD in young and middle-aged people, but it is not known whether this is also true for old people. It is also not known what effect long-term treatment for diabetes has on mortality or whether the risk of death from CVD is decreasing in diabetic people as it is in the general US population. This information would help physicians provide health care and lifestyle advice to people with diabetes. In this study, the researchers have investigated mortality patterns in elderly diabetic people by looking at data collected between 1989 and 2001 by the US Cardiovascular Health Study, an observational study of nearly 6,000 people aged over 65 years (in this type of study participants are observed without imposing any specific changes to their lifestyle, behavior, medical care, or treatments).
What Did the Researchers Do and Find?
Participants were screened at the start of the Cardiovascular Health Study for CVD and diabetes (defined as drug-treated disease), for established CVD risk factors such as high blood pressure and smoking, for recently recognized CVD risk factors (for example, subclinical CVD), and for psychosocial factors associated with diabetes that might influence mortality, such as frailty and depression. At this time, about 5% of the participants were taking oral hypoglycemic agents for diabetes and about 3% were taking insulin. During the 11-year study, 40% of the participants died. After adjusting for CVD risk factors and psychosocial factors, the researchers calculated that people treated with oral hypoglycemic agents were 1.3 times as likely to die from all causes and people treated with insulin were twice as likely to die as people without diabetes. The risk of death from CVD was about twice as high in both groups of diabetic participants as in non-diabetic participants; the risk of death from coronary heart disease was increased about 2.5-fold. These adjusted relative risks are very similar to those found in previous studies. The researchers also report that participants treated with insulin were six times more likely to die from infectious diseases or renal failure than nondiabetic participants, and women treated with insulin had a particularly high mortality risk.
What Do These Findings Mean?
These findings indicate that the negative impact on mortality of diabetes persists into old age and that death from CVD is currently declining in both older diabetic people and nondiabetic people. In addition, they show that diabetic people treated with insulin are at a greater risk of dying relative to people without diabetes and those taking oral hypoglycemic agents. This might reflect the type of diabetes that these people had, but this was not investigated. How long participants had had diabetes was also not considered, nor how many people developed diabetes during the study. These and other limitations might mean that the reported excess mortality due to diabetes is an underestimate. Nevertheless, the estimate that elderly people with diabetes are twice as likely to die from CVD as people without diabetes is important. Many elderly people die anyway because of CVD, so this increased risk represents many more deaths than the similar increased risk in younger diabetic populations. Yet, elderly people often receive less-intensive management of CVD risk factors than younger people. The results of this study suggest that rectifying this situation could prolong the lives of many elderly people with diabetes.
Additional Information.
Please access these Web sites via the online version of this summary at
MedlinePlus encyclopedia has pages on diabetes, heart disease, stroke and poor circulation
The US National Institute of Diabetes and Digestive and Kidney Diseases provides patient information on diabetes
Information for patients on prevention, diagnosis, and management of diabetes is available from the America Diabetes Association
Patient information is available from the American Heart Association on all aspects of heart disease, including its association with diabetes
Wikipedia pages on diabetes and cardiovascular disease (note that Wikipedia is a free online encyclopedia that anyone can edit)
Further information is available about the Cardiovascular Health Study
PMCID: PMC1609124  PMID: 17048978
20.  The rationale, design, and baseline characteristics of the Women’s Health Initiative Memory Study of Younger Women (WHIMS-Y) 
Brain research  2013;1514:3-11.
The Women’s Health Initiative Memory Study-Younger (WHIMS-Y) was designed to assess the effect of prior random assignment to hormone therapy (HT) (conjugated equine estrogen (CEE) alone or CEE plus medroxyprogesterone acetate (MPA)) on global cognitive function in younger middle-aged women relative to placebo. WHIMS-Y was an ancillary study to the Women’s Health Initiative (WHI) HT trial and enrolled 1361 women who were aged 50-54 years and postmenopausal at WHI enrollment. WHIMS-Y will examine whether an average of 5.4 years of HT during early menopause has longer term protective effects on global cognitive function and if these effects vary by regimen, time between menopause and study initiation, and prior use of HT. We present the study rationale and design. We describe enrollment, adherence to assigned WHI therapy, and compare risk factor characteristics of the WHIMS-Y cohort at the time of WHI enrollment to similar aged women in the WHI HT who did not enroll in WHIMS-Y. Challenges of WHIMS-Y include lower than expected and differential enrollment. Strengths of WHIMS-Y include balance in baseline risk factors between treatment groups, standardized and masked data collection, and high rates of retention and on-trial adherence and exposure. In addition, the telephone-administered cognitive battery showed adequate construct validity. WHIMS-Y provided an unprecedented chance to examine the hypothesis that HT may have protective effects on cognition in younger postmenopausal women aged 50-54 years. Integrated into the WHI, WHIMS-Y optimized the experience of WHI investigators to ensure high retention and excellent quality assurance across sites.
PMCID: PMC3684042  PMID: 23578696
Postmenopausal hormone therapy; Cognitive function; Aging
21.  Diet Drink Consumption and the Risk of Cardiovascular Events: A Report from the Women’s Health Initiative 
Data are limited regarding the influence of diet drink consumption on cardiovascular disease (CVD) outcomes.
We aimed to evaluate the relationship between diet drink intake and cardiovascular events.
We conducted a retrospective cohort study, utilizing data from the national, multicenter Women’s Health Initiative Observational Study (WHI OS), recruiting subjects from 1993 to 1998.
Post-menopausal women with available diet drink intake data, without pre-existing CVD and who survived ≥ 60 days were included in the study.
A composite of incident coronary heart disease, heart failure, myocardial infarction, coronary revascularization procedure, ischemic stroke, peripheral arterial disease and CVD death was used as the primary outcome. CVD death and all-cause mortality were secondary outcomes. Adjusted Cox proportional hazards models were used to compare primary and secondary outcomes across diet drink intake strata.
In all, 59,614 women, mean age 62.8 years, were included for analysis. In unadjusted analysis over a follow-up of 8.7 ± 2.7 years, the primary outcome occurred in 8.5 % of the women consuming ≥ 2 diet drinks/day, compared to 6.9 %, 6.8 % and 7.2 % in the 5–7/week, 1–4/week and 0–3/month groups, respectively. After controlling for other CVD risk factors, women who consumed ≥ 2 drinks/day had a higher adjusted risk of CVD events (HR 1.3, 95 % CI 1.1–1.5), CVD mortality (HR 1.5, 95 % CI 1.03–2.3) and overall mortality (HR 1.3, 95 % CI 1.04–1.5) compared to the reference group (0–3 drinks/month).
This analysis demonstrates an association between high diet drink intake and CVD outcomes and mortality in post-menopausal women in the WHI OS.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-014-3098-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4371001  PMID: 25515135
diet; cardiovascular diseases; lifestyle; diet drinks; artificial sweeteners
22.  Ovarian Cancer and Body Size: Individual Participant Meta-Analysis Including 25,157 Women with Ovarian Cancer from 47 Epidemiological Studies 
PLoS Medicine  2012;9(4):e1001200.
A reanalysis of published and unpublished data from epidemiological studies examines the association between height, body mass index, and the risk of developing ovarian cancer.
Only about half the studies that have collected information on the relevance of women's height and body mass index to their risk of developing ovarian cancer have published their results, and findings are inconsistent. Here, we bring together the worldwide evidence, published and unpublished, and describe these relationships.
Methods and Findings
Individual data on 25,157 women with ovarian cancer and 81,311 women without ovarian cancer from 47 epidemiological studies were collected, checked, and analysed centrally. Adjusted relative risks of ovarian cancer were calculated, by height and by body mass index.
Ovarian cancer risk increased significantly with height and with body mass index, except in studies using hospital controls. For other study designs, the relative risk of ovarian cancer per 5 cm increase in height was 1.07 (95% confidence interval [CI], 1.05–1.09; p<0.001); this relationship did not vary significantly by women's age, year of birth, education, age at menarche, parity, menopausal status, smoking, alcohol consumption, having had a hysterectomy, having first degree relatives with ovarian or breast cancer, use of oral contraceptives, or use of menopausal hormone therapy. For body mass index, there was significant heterogeneity (p<0.001) in the findings between ever-users and never-users of menopausal hormone therapy, but not by the 11 other factors listed above. The relative risk for ovarian cancer per 5 kg/m2 increase in body mass index was 1.10 (95% CI, 1.07–1.13; p<0.001) in never-users and 0.95 (95% CI, 0.92–0.99; p = 0.02) in ever-users of hormone therapy.
Ovarian cancer is associated with height and, among never-users of hormone therapy, with body mass index. In high-income countries, both height and body mass index have been increasing in birth cohorts now developing the disease. If all other relevant factors had remained constant, then these increases in height and weight would be associated with a 3% increase in ovarian cancer incidence per decade.
Please see later in the article for the Editors' Summary
Editors' Summary
Cancer of the ovaries, usually referred to as ovarian cancer, is the fifth leading cause of cancer death in women, and, unfortunately, symptoms (such as abdominal pain and swelling) usually occur late in the disease process; fewer than one-third of ovarian cancers are detected before they have spread outside of the ovaries. There is no definitive evidence that screening reduces mortality from ovarian cancer, and given the poor prognosis of advanced ovarian cancer, there has been much research over recent years to increase understanding of this serious condition. There are recognized risk factors that increase the chance of developing ovarian cancer, such as increasing age, having fewer children, not having used oral contraceptives, and use of menopausal hormone therapy. Age and oral contraceptive use have by far the biggest impact on ovarian cancer risk.
Why Was This Study Done?
To date, there is no definitive information about the relevance of women's height, weight, and body mass index to their subsequent risk of developing ovarian cancer. There have been roughly 50 epidemiological studies of ovarian cancer, but only about half of these studies have published results on the association between body size and ovarian cancer risk, and so far, these findings have been inconsistent. Therefore, the researchers—an international collaboration of researchers studying ovarian cancer—re-analyzed the available epidemiological evidence to investigate the relationship between ovarian cancer risk and adult height, weight, and body mass index, and to examine the consistency of the findings across study designs.
What Did the Researchers Do and Find?
After an extensive literature search, the researchers identified 47 eligible studies that collected individual data on women's reproductive history, use of hormonal therapies, height, weight, and/or body mass index, and in which the principal investigators of each study accepted the invitation from the researchers to be involved in the re-analysis. The researchers combined data from the different studies. To ensure that women in one study were only directly compared with controls (similar women without ovarian cancer) in the same study, all analyses were routinely stratified by study, center within study, age, parity, use of oral contraceptives, use of hormonal therapy for menopause, and menopausal status or hysterectomy.
The 47 studies were conducted in 14 countries and comprised a total of 25,157 women with ovarian cancer (mostly from Europe and North America) and 81,311 women without ovarian cancer. The researchers found a significant increase in relative risk (1.07) of ovarian cancer per 5 cm increase in height. Furthermore, this risk did not vary depending on other studied factors—age, year of birth, education, age at menarche, parity, menopausal status, smoking, alcohol consumption, having had a hysterectomy, having first degree relatives with ovarian or breast cancer, use of oral contraceptives, or use of menopausal hormone therapy. However, the researchers found that for body mass index, the risks depended on whether women had ever taken menopausal hormone therapy: the relative risk for ovarian cancer per 5 kg/m2 increase in body mass index was 1.10 in women who had never taken menopausal hormone therapy but was only 0.95 in women who had previously taken menopausal hormone therapy.
What Do These Findings Mean?
These findings suggest that increasing height can be considered as a risk factor for ovarian cancer and that in women who have never taken menopausal hormone therapy, increased body mass index can be considered an additional risk factor. These findings have public health implications, especially in high-income countries, because the average height of women has increased by about 1 cm per decade and average body mass index has increased by about 1 kg/m2 per decade. The findings suggest an associated increase in ovarian cancer incidence of 3% per decade if all other factors relevant for ovarian cancer remain constant.
Additional Information
Please access these web sites via the online version of this summary at
The following organizations give more information on ovarian cancer which may be of use to patients: MedicineNet, the US National Cancer Institute, Ovarian Cancer National Alliance, Macmillan Cancer Support
PMCID: PMC3317899  PMID: 22606070
23.  Calcium Plus Vitamin D Supplementation and Mortality in Postmenopausal Women: The Women's Health Initiative Calcium–Vitamin D Randomized Controlled Trial 
Calcium and vitamin D (CaD) supplementation trials including the Women's Health Initiative (WHI) trial of CaD have shown nonsignificant reductions in total mortality. This report examines intervention effects on total and cause-specific mortality by age and adherence.
The WHI CaD trial was a randomized, double-blind, placebo-controlled trial that enrolled 36,282 postmenopausal women aged 51–82 years from 40 U.S. clinical centers. Women were assigned to 1,000 mg of elemental calcium carbonate and 400 IU of vitamin D3 daily or placebo with average follow-up of 7.0 years.
The hazard ratio (HR) for total mortality was 0.91 (95% confidence interval [CI], 0.83–1.01) with 744 deaths in women randomized to CaD versus 807 deaths in the placebo group. HRs were in the direction of reduced risk but nonsignificant for stroke and cancer mortality, but near unity for coronary heart disease and other causes of death. HRs for total mortality were 0.89 in the 29,942 women younger than 70 years (95% CI, 0.79–1.01) and 0.95 in the 6,340 women aged 70 and older (95% CI, 0.80–1.12; p value for age interaction = .10). No statistically significant interactions were observed for any baseline characteristics. Treatment effects did not vary significantly by season.
In the WHI CaD trial, supplementation did not have a statistically significant effect on mortality rates but the findings support the possibility that these supplements may reduce mortality rates in postmenopausal women. These data can neither support nor refute recommendations for higher dose vitamin D supplementation to reduce cancer or total mortality.
PMCID: PMC2800808  PMID: 19221190
Calcium; Vitamin D; Mortality; Cause-specific mortality; Women's Health Initiative
24.  Estimating the potential contribution of stroke treatments and preventative policies to reduce the stroke and ischemic heart disease mortality in Turkey up to 2032: a modelling study 
BMC Public Health  2016;16:46.
Stroke and Ischemic Heart Diseases (IHD) are the main cause of premature deaths globally, including Turkey. There is substantial potential to reduce stroke and IHD mortality burden; particularly by improving diet and health behaviours at the population level. Our aim is to estimate and compare the potential impact of ischemic stroke treatment vs population level policies on ischemic stroke and IHD deaths in Turkey if achieved like other developed countries up to 2022 and 2032.
We developed a Markov model for the Turkish population aged >35 years. The model follows the population over a time horizon of 10 and 20 years. We modelled seven policy scenarios: a baseline scenario, three ischemic stroke treatment improvement scenarios and three population level policy intervention scenarios (based on target reductions in dietary salt, transfat and unsaturated fat intake, smoking prevalence and increases in fruit and vegetable consumption). Parameter uncertainty was explored by including probabilistic sensitivity analysis.
In the baseline scenario, we forecast that approximately 655,180 ischemic stroke and IHD deaths (306,500 in men; 348,600 in women) may occur in the age group of 35–94 between 2012 and 2022 in Turkey. Feasible interventions in population level policies might prevent approximately 108,000 (62,580–326,700) fewer stroke and IHD deaths. This could result in approximately a 17 % reduction in total stroke and IHD deaths in 2022. Approximately 32 %, 29 %, 11 % and 6 % of that figure could be attributed to a decreased consumption of transfat, dietary salt, saturated fats and fall in smoking prevalence and 22 % could be attributed to increased fruit and vegetable consumption. Feasible improvements in ischemic stroke treatment could prevent approximately 9 % fewer ischemic stroke and IHD deaths by 2022.
Our modeling study suggests that effective and evidence-based food policies at the population level could massively contribute to reduction in ischemic stroke and IHD mortality in a decade and deliver bigger gains compared to healthcare based interventions for primary and secondary prevention.
Electronic supplementary material
The online version of this article (doi:10.1186/s12889-015-2655-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4717543  PMID: 26781488
Stroke; Cardiovascular Diseases; Death; Decision Modeling; Prevention
25.  Recreational physical activity and risk of triple negative breast cancer in the California Teachers Study 
Evidence has accumulated showing that recreational physical activity reduces breast cancer risk. However, it is unclear whether risk reduction pertains to specific receptor-defined subtypes. Moreover, few studies have examined whether changes in the amount of recreational physical activity during adulthood influence breast cancer risk.
A total of 108,907 women, ages 22 to 79 years with no history of breast cancer when joining the California Teachers Study in 1995–1996, completed a baseline questionnaire and were eligible for the study. Through 2012, 5882 women were diagnosed with invasive breast cancer. Breast cancer subtypes were defined by the expression status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Multivariable Cox proportional hazards models provided adjusted hazard ratios (HRs) and 95 % confidence intervals (CIs) for breast cancer overall and ER/PR/HER2-defined subtypes associated with long-term (from high school through age 54 or age at cohort entry, whichever was younger) and baseline (during 3 years prior to baseline) recreational physical activity. Among women who also completed a follow-up questionnaire at 10 years after baseline in 2005–2008 (54,686 women, 1406 with invasive breast cancer), risk associated with changes in the amount of recreational physical activity from baseline to the 10-year follow-up (during 3 years prior to the 10-year follow-up) was determined.
Both long-term and baseline strenuous recreational physical activity were inversely associated with risk of invasive breast cancer (Ptrend ≤0.03). The observed associations were mainly confined to women with triple negative breast cancer (TNBC, ER–/PR–/HER2–, Ptrend ≤0.02) or luminal A-like subtype (ER+ or PR+ plus HER2–) who were former users of menopausal hormone therapy at baseline (Ptrend = 0.02, Phomogeneity of trends ≤0.03). Moreover, women who consistently engaged in the highest level (≥3.51 h/wk/y) of strenuous recreational physical activity between baseline and 10-year follow-up had the lowest risk of breast cancer (HR = 0.71, 95 % CI = 0.52–0.98) when compared to those who were consistently low (≤0.50 h/wk/y).
Strenuous recreational physical activity is associated with lower breast cancer risk, especially TNBC. The benefit may be maximized by consistently engaging in high-intensity recreational physical activity during adulthood.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-016-0723-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4912767  PMID: 27317095
Physical activity; Breast cancer; Triple negative breast cancer; Luminal; Estrogen receptor; Progesterone receptor; HER2; Risk factors; BMI; Menopausal hormone therapy

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