The Women's Health Initiative (WHI) was a series of clinical studies initiated by the U.S. National Institutes of Health (NIH) in 1991, to address major health issues causing morbidity and mortality in postmenopausal women. It consisted of three clinical trials (CT) and an observational study (OS). In particular, randomized controlled trials were designed and funded that addressed cardiovascular disease, cancer, and osteoporosis.
In its entirety, the WHI enrolled more than 160,000 postmenopausal women aged 50–79 years (at time of study enrollment) over 15 years, making it one of the largest U.S. prevention studies of its kind, with a budget of $625 million. A 2014 analysis calculated a net economic return on investment of $37.1 billion for the estrogen-plus-progestin arm of the study's hormone trial alone, providing a strong case for the continued use of this variety of large, publicly funded population study. In the years following the WHI, studies have shown a decrease in breast cancer rates in postmenopausal women, attributed to the decline in use of hormone replacement therapy.
Motivation for the expanded study of women's health
In the 1980s, it had become apparent that past biomedical research had focused disproportionately on white men, often neglecting prevention and treatment studies of diseases that are either unique to or more common in women and minorities. In 1985, the Public Health Service Task Force on Women's Health Issues issued recommendations that biomedical and behavioral research should be expanded to provide for the inclusion diseases and conditions identified among women of all age groups. In 1986, the NIH issued recommendations that women be included in all research studies. To further promote the study of women, in 1990, the NIH created the Office of Research on Women's Health.
In 1990, however, a report was published by the General Accounting Office (GAO), at the request of the Congressional Caucus on Women's Issues, which stated that this NIH policy was not being adequately applied to research grant applications. As a consequence, beginning in 1991, NIH strengthened the policy to require, rather than recommend, the inclusion of women in clinical research (when appropriate) in order to obtain funding.
It was these changes in societal attitudes and policy toward women's health research, in addition to the demonstration that such a large study was not only feasible, but could be done economically, that gave rise to the WHI.
WHI study antecedents and demonstration of feasibility for a large-scale intervention study
Among postmenopausal women, cardiovascular disease, cancer, and osteoporosis are the leading causes of morbidity and mortality, as well as impaired quality of life. Among women in all age groups, cancer and cardiovascular disease are the leading causes of mortality. As the incidence of these diseases increases according to age, women over the age of 50 bear much of the disease burden.
It had been generally accepted that postmenopausal estrogen deficiency may play a role in these morbidities, and that dietary, behavioral, and drug interventions may forestall their development. However, these findings were identified on the basis of epidemiologic observational studies alone. Such interventions would require testing through clinical trials before they, along with their full range of risks and benefits, could be used as the basis for setting public health policy and creating prevention guidelines.
However, concerns existed about the feasibility of such a complex clinical trial among participants in this demographic of older women, particularly with respect to sufficient recruitment and adherence to the dietary and hormone-treatment regimens.
In 1987, the NIH funded the Postmenopausal Estrogen/Progestin Intervention (PEPI). The trial followed 875 women who underwent treatment with estrogen, estrogen and progestin, or placebo, and — even quite early in the study — demonstrated both successful recruitment and participant retention/adherence in a hormone therapy (HT) setting. Many of the operational procedures from PEPI, including the study drug dosing, were retained in the larger WHI-HT clinical trial.
In 1984, the NIH provided funding for a feasibility study pertaining to diet adherence, conducted by the Women's Health Trial (WHT). The WHT, which commenced in 1986 and involved 303 women randomized into dietary intervention and control groups, yielded results demonstrating a high degree of adherence on the basis of both food-intake questionnaires and clinical laboratory findings. The WHT did not proceed with its full-scale trial, as it was not awarded further funding from the NIH on the basis of the potential inability of the study to test the hypothesis in a larger cohort of women. In 1990, however, interest in the impact of diet on cancer and cardiovascular disease in women was renewed, and a joint National Cancer Institute (NCI)-National Heart, Lung, and Blood Institute (NHLBI) workshop concluded that a full-scale dietary trial, with a focus on these two diseases, was warranted.
WHI study announced and planning begins
On April 19, 1991, Dr. Bernadine Healy, newly appointed as the first female director of the NIH, announced her plan for the Women's Health Initiative (WHI). Planning for the WHI CT/OS study began that year. In order to promote cross-institutional collaboration, and to prevent the loss of funding to other women's health-related studies, funding was requested and obtained directly from Congress in the form of a discrete line item, with a projected budget of $625 million over the life of the 15-year study.
The NIH awarded the role of Clinical Coordinating Center (CCC) to the Fred Hutchinson Cancer Research Center (FHCRC), located in Seattle, Washington. The CCC's responsibilities included the coordination of the 40 study clinics that would eventually recruit women nationwide, as well as ensuring their consistent adherence to the study design and guidelines.
Design overview, eligibility, and enrollment
In 1991, working groups were formed to determine the study plan for both the clinical trials (CT) and the observational study (OS). These groups included experts from diverse arenas of medicine, public health, and clinical trial design from both within and outside the NIH.
Study organization and implementation
Given the complexity of the WHI study, both in terms of the number of interventions and outcomes studied, as well as the number and geographic distribution of participants and clinical centers, careful orchestration was required. To this end, the WHI maintained a carefully designed organizational structure, along with governance- and science-specific committees and communications channels for staff and investigators to resolve study-related questions and exchange information. As the study launched concurrently with the early stages of modern Internet connectivity, the study centers had to be supplied with computing and networking equipment to connect to the WHI network; WHI-hosted e-mail facilitated the efficient exchange of information among staff and scientists, as well as the transfer of study-related data.
The launch of the study was undertaken in two stages. At first, 16 "vanguard" study centers entered active operation, to evaluate the study protocol and procedures. Once this initial portion of the study was underway, the remaining 24 study centers entered the study around a year later, each assigned to one of the "vanguard" study centers for purposes of mentorship. Study centers were subdivided into four regions, each under the supervision of a regional center, to further facilitate communication and information exchange among study centers.
Eligibility and enrollment
The WHI study recruited postmenopausal women in the 50-79 age range, and sought to be as inclusive as practical. The wide nature of the age range balanced the need to observe the effects of hormone therapy on younger women, while also attempting to capture physical and cognitive outcomes in older populations. In addition, a 20% minority enrollment rate was set for all components, to accurately represent the proportion of minorities within the study demographic (17% at the time of the 1990 U.S. Census). To achieve this, 10 of the 40 WHI clinical centers were designated as minority recruitment centers, with enhanced minority recruitment goals.
Eligibility and exclusion criteria also were defined, both study-wide and component-specific. Global inclusion criteria included postmenopausal women, between 50 and 79 years of age, who were willing and able to provide written consent, and who planned to reside in the study recruitment for a least three years after enrollment. Global exclusion criteria included medical conditions that would be predictive of a survival of less than three years, possessing characteristics or conditions that may diminish study adherence (e.g., substance abuse, mental illness, or cognitive impairment), or concurrent enrollment in another randomized controlled clinical trial.
For the CT, a partial factorial study design was utilized for the investigation of three overlapping interventions (dietary modification, hormone therapy, and calcium/vitamin D supplementation), as this would provide considerable cost efficiencies. Willing study-eligible women were asked to join either the hormone therapy (HT trial), the dietary modification (DM) trial, or both. After one year, willing and eligible CT participants were also asked to join the calcium/vitamin D trial (CaD).
Recruitment goals for the HT, DM, and CaD components of the CT were 27,500, 48,000, and 45,000, respectively, each obtained on the basis of calculations of statistical power with regard to the outcomes of interest for each component.
Participants who either did not qualify for or declined to participate in the CT were, if eligible and willing to consent, enrolled in the observational study (OS), which had an enrollment goal of 100,000.
Study components and primary findings
The WHI study was composed of four study components, to include three overlapping clinical trial (CT) interventions and one observational study (OS). Component enrollment and the primary findings are summarized in the following two tables, respectively, with additional detail following subsequently:
|Age group||DM||HT w/ E+P||HT w/ E-alone||CaD||OS|
|50–54 years||6961 (16%)||2029 (14%)||1396 (15%)||5157 (16%)||12386 (15%)|
|55–59 years||11043 (25%)||3492 (23%)||1916 (20%)||8265 (25%)||17321 (20%)|
|60–69 years||22713 (52%)||7512 (50%)||4852 (50%)||16520 (51%)||41196 (49%)|
|70–79 years||8118 (19%)||3574 (24%)||2575 (26%)||6340 (19%)||22773 (26%)|
|Abbreviations: E+P: combined estrogen plus progestin therapy. E-alone: estrogen monotherapy.|
|Hypothesized Impact on Primary Outcome
Based on previous observational, pilot, and/or laboratory studies
|Supported by WHI CT Findings?||Notes|
|Hormone Therapy||Reduces risk of coronary heart disease (CHD).||No||Increased risk of stroke. No effect on CHD risk.|
|Increases risk of breast cancer.||Varies by regimen||Estrogen-progestin combination therapy increased risk. |
Estrogen-alone therapy showed a possible decrease in risk.
|Dietary Modification||Reduces risks of CHD, stroke, and cardiovascular disease (CVD).||No||Modest, but non-significant, effects on CVD risk factors.|
|Reduces risk of invasive colorectal cancer.||No||Non-significant trend indicated that a longer intervention may yield more definitive results.|
|Reduces risk of invasive breast cancer.||No||Subgroup analyses suggested that the dietary intervention significantly lowered risk of breast cancer among women with a higher baseline percentage of energy from fat.|
|Calcium plus Vitamin D||Reduces risk of hip and other fractures.||No||A small, but significant, improvement in bone mineral density was identified.|
|Reduces risk of colorectal cancer.||No||Study notes that a longer-duration study may yield more definitive results.|
The design of the hormone therapy trial (HT) was approached with the hypothesis that estrogen therapy would result in a decrease in coronary heart disease and osteoporosis-related fractures. As such, the primary outcome of interest was coronary heart disease, as this is a major cause of morbidity and mortality among women, particularly those over age 65, and because, at the time, no clinical trial had been undertaken to prove the cardioprotective effects of HT. Due to the concern over the relationship between HT and elevated breast cancer risk, breast cancer was selected as the primary adverse outcome. Additional outcomes monitored included stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes.
Two regimens were selected, in addition to a placebo group. Women assigned to the intervention group who had previously undergone a hysterectomy were treated with unopposed estrogen, specifically conjugated estrogens (Premarin, manufactured by Wyeth), at a dosage of 0.625 mg/day ("E-alone," n = 5310; placebo, n = 5429). Women with an intact uterus were treated by a combined estrogen plus progestin regimen ("E+P," n = 8506; placebo, n = 8102), specifically the aforementioned estrogen regimen with the addition of 2.5 mg/day of medroxyprogesterone acetate (MPA; Prempro, also manufactured by Wyeth). The addition of progestin has been linked to a marked reduction in the risk for the development of endometrial cancer in women receiving estrogen treatment who have not undergone a hysterectomy.
In addition to the global exclusion criteria, women were ineligible for the HT component if safety was a concern. Such concerns included a breast cancer diagnosis at any time in the past, other cancers (excluding non-melanoma skin cancer) diagnosed within the previous 10 years, or low hematocrit or platelet counts.
HT component findings and ensuing events
The HT component had originally been designed to include a follow-up period of nine years. However, interim monitoring of the combined estrogen/progestin treatment group indicated an increased risk of breast cancer, coronary heart disease, stroke, and pulmonary embolism, which outweighed the evidence indicating a benefit in preventing colorectal cancer and fractures. As a consequence, the HT study pills were stopped in July 2002, with an average follow-up period of 5.2 years. The unopposed estrogen trial was halted in February 2004, after an average follow-up period of 6.8 years, on the basis that unopposed estrogen did not appear to affect the risk of heart disease, the primary outcome, which was in contrast to the findings of previous observational studies. On the other hand, there were indications for an increased risk of stroke. Unopposed estrogen did reduce the risk for osteoporotic fractures and, unlike the estrogen/progestin treatment, showed a decrease in breast cancer risk.
As a consequence of the findings, which indicated that the incurred risks of HT outweigh the identified benefits, the study authors recommended that HT not be prescribed for the purpose of chronic disease prevention in postmenopausal women.
The hypothesized and observed risks of specific clinical outcomes are summarized in the following table. Of particular interest are the contrasts between several of the hypothesized risks and the observed attributable risks, which are instructive in demonstrating the distinct differences between the HT trial findings and those of previous observational studies.
effect on risk
|Estrogen and progestogen
(CEs 0.625 mg/day p.o. + MPA 2.5 mg/day p.o.)
(n = 16,608, with uterus, 5.2–5.6 years follow up)
(CEs 0.625 mg/day p.o.)
(n = 10,739, no uterus, 6.8–7.1 years follow up)
|HR||95% CI||AR||HR||95% CI||AR|
|Coronary heart disease||Decreased||1.24||1.00–1.54||+6 / 10,000 PYs||0.95||0.79–1.15||−3 / 10,000 PYs|
|Stroke||Decreased||1.31||1.02–1.68||+8 / 10,000 PYs||1.37||1.09–1.73||+12 / 10,000 PYs|
|Pulmonary embolism||Increased||2.13||1.45–3.11||+10 / 10,000 PYs||1.37||0.90–2.07||+4 / 10,000 PYs|
|Venous thromboembolism||Increased||2.06||1.57–2.70||+18 / 10,000 PYs||1.32||0.99–1.75||+8 / 10,000 PYs|
|Breast cancer||Increased||1.24||1.02–1.50||+8 / 10,000 PYs||0.80||0.62–1.04||−6 / 10,000 PYs|
|Colorectal cancer||Decreased||0.56||0.38–0.81||−7 / 10,000 PYs||1.08||0.75–1.55||+1 / 10,000 PYs|
|Endometrial cancer||–||0.81||0.48–1.36||−1 / 10,000 PYs||–||–||–|
|Hip fractures||Decreased||0.67||0.47–0.96||−5 / 10,000 PYs||0.65||0.45–0.94||−7 / 10,000 PYs|
|Total fractures||Decreased||0.76||0.69–0.83||−47 / 10,000 PYs||0.71||0.64–0.80||−53 / 10,000 PYs|
|Total mortality||Decreased||0.98||0.82–1.18||−1 / 10,000 PYs||1.04||0.91–1.12||+3 / 10,000 PYs|
|Global index||–||1.15||1.03–1.28||+19 / 10,000 PYs||1.01||1.09–1.12||+2 / 10,000 PYs|
|Peripheral artery disease||–||0.89||0.63–1.25||1.32||0.99–1.77|
|Abbreviations: CEs = conjugated estrogens. MPA = medroxyprogesterone acetate. p.o. = per oral. HR = hazard ratio. AR = attributable risk. PYs = person–years. CI = confidence interval. Notes: Sample sizes (n) include placebo recipients, which were about half of patients. "Global index" is defined for each woman as the time to earliest diagnosis for coronary heart disease, stroke, pulmonary embolism, breast cancer, colorectal cancer, endometrial cancer (estrogen plus progestogen group only), hip fractures, and death from other causes. Sources: See template.|
Of all the WHI study findings, the HT findings could be argued to have yielded the farthest-reaching societal and economic impacts, and received substantial media attention. Large reductions in HT prescriptions ensued, resulting in a substantial loss of revenue in sales of this class of drugs, with a presumably commensurate savings to patients and insurers. More importantly, in subsequent years, studies have shown a decrease in breast cancer rates in postmenopausal women, attributed to the decline in use of HT. In 2014, an analysis was conducted to determine the economic impact of the estrogen-plus-progestin trial findings, which calculated the net economic return on investment to be $37.1 billion, owing to a combination of averted health-related expenditures and increased number of quality-adjusted life years (QALYs).
The United States Preventive Services Task Force, though initially endorsing hormone replacement, in their most recent published recommendation in 2017 discouraged its use for the prevention of chronic diseases such as osteoporosis or cardiovascular disease. When they first evaluated the impact of HRT in 1996, the USPSTF assigned a "B" grade to hormone replacement therapy for use in primary prevention of chronic conditions in postmenopausal women, basing their results on observational studies and short-term trials. A score of "B" carries an official message of, "The USPSTF recommends the service. There is high certainty that the net benefit is moderate, or there is moderate certainty that the net benefit is moderate to substantial." In light of subsequent results from the Heart and Estrogen/progestin Replacement Study (HERS) and the WHI trials, the USPSTF downgraded the scoring to a "D," which corresponds to a message of, "The USPSTF recommends against the service. There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits," and discourages health providers from offering the service or treatment. In 2017, the USPSTF again evaluated the use of HRT, and again assessed a "D" score. The publication of this most recent recommendation against the use of HRT for the treatment of chronic postmenopausal symptoms was accompanied by several companion editorials, lauding the WHI clinical trial's role in preventing patient harm due to HRT administration, noting also the risks inherent to smaller observational studies, which previously had yielded misleading, potentially harmful recommendations to medical practitioners.
It is important to note that this evidence primarily concerns longer-term HRT use for prevention of chronic disease in older women. The USPSTF did not evaluate HRT's use for alleviation of symptoms of menopause, whereas the North American Menopause Society, the American College of Obstetricians and Gynecologists (ACOG), and the Endocrine Society all continue to recommend it as the most effective therapy for short-term treatment of menopausal symptoms in newly-menopausal women who are under the age of 60 year or within 10 years of entering menopause.
The dietary modification (DM) trial was conducted with the purpose of identifying the effects of a low-fat eating pattern; the primary outcome measures were the incidence of invasive breast and colorectal cancers, fatal and nonfatal coronary heart disease (CHD), stroke, and overall cardiovascular disease (CVD), calculated as a composite of CHD and stroke.
Women in the trial were randomly assigned to the dietary intervention group (40%; n = 19541) or the control group (60%; n = 29294). In addition to the global exclusion criteria, component-specific exclusion criteria included prior breast cancer, colorectal cancer, other cancers excluding nonmelanoma skin cancer in the past 10 years, adherence or retention concerns (e.g., a substance abuse history or dementia), or a baseline diet that included a fat intake accounting for less than 32% of total energy intake.
Participants in the intervention group underwent a regimen of trainings, group meetings, and consultations which encouraged low-fat eating habits, targeted to 20% of daily caloric intake, along with increasing the consumption of fruits, vegetables, and grains. Those assigned to the control group were not asked to adopt any specific dietary changes.
DM component findings
The mean follow-up for the DM intervention was 8.1 years. At study years 1 and 6, the dietary fat intake levels for the intervention group were 10.7% and 8.2% less than those of the control group, respectively. The results indicated that, despite some reduction in CVD risk factors (e.g., blood lipids and diastolic blood pressure), there was no significant reduction in the risk of CHD, stroke, or CVD, indicating that a more focused combination of diet and lifestyle interventions may be required to further improve CVD risk factors and reduce overall risk. In addition, no statistically significant reduction in breast cancer risk was identified, although the results approached significance and indicated that longer-term follow-up may yield a more definitive comparison. The trial also did not identify a reduction in colorectal cancer risk attributable to a low-fat dietary pattern.
The calcium/vitamin D (CaD) trial component was designed to test the hypothesis that women taking a combination of calcium and vitamin D will experience a reduced risk of hip and other fractures, as well as breast and colorectal cancer.
Women participating in this intervention were randomly assigned to receive a regimen of 1000 mg calcium in combination with 400 International Units (IU) of vitamin D (n = 18176) or a placebo (n = 18106), and were followed for an average of 7 years, with monitoring for bone density, fractures, and pathologically confirmed cancers as the measures of outcomes. Women in the CaD trial were already participating in the HT trial, the DM trial, or both. In addition to the global exclusion criteria, component-specific exclusion criteria hypercalcemia, renal calculi, corticosteroid use, and calcitriol use.
CaD component findings
Among the intervention cohort, a small but significant improvement in hip bone density was observed, although a significant reduction in hip fractures was not observed. However, subgroup analysis revealed a possible benefit to older women in terms of a reduced risk of hip fractures, attributable to calcium plus vitamin D supplementation.
It was also found that the intervention did not have an effect on the incidence of colorectal cancer, possibly owing to the long latency associated with colorectal cancers. Calcium plus vitamin D was not found to affect the incidence of breast cancer. Finally, an increased risk of kidney stones was observed among those taking calcium plus vitamin D.
The Observational study (OS) study recruited eligible postmenopausal women (n = 93676) who were either ineligible or unwilling to participate in the CT portion of the study, for the purpose of obtaining additional risk factor information, identifying risk-related biomarkers, and serving as a comparative observational assessment to the CT interventions.
Participants underwent an initial baseline screening, including the collection of physical measurements, blood specimens, an inventory of medications and supplements, and completion of questionnaires pertaining to medical history, family history, reproductive history, lifestyle and behavioral factors, and quality of life. In addition, more specific information was collected with regard to the participant's geographic residence history, passive (i.e., "second-hand") smoking exposure in childhood and adulthood, early life exposures, details of physical activity, weight and weight-cycling history, and occupational exposures. In addition to the baseline data collected, OS participants received annual questionnaire mailings to update selected exposures and outcomes, and were expected to make an additional clinic visit, to include an additional blood collection, about three years post-enrollment. It was planned that participants would be followed for an average of 9 years.
The major outcomes of interest for the OS were coronary heart disease, stroke, breast cancer, colorectal cancer, osteoporotic fractures, diabetes, and total mortality. Given the size and diversity of the cohort, taken together with the data and specimen collection being undertaken, it was expected that this cohort could yield insights into a variety of hypotheses, as well as generate new hypotheses with respect to disease etiology in women.
OS component findings
The WHI OS has and continues to yield many findings and new hypotheses, a small sampling of which are highlighted below:
- A decrease in invasive and ductal breast cancer incidences with decreasing estrogen/progestin combination therapy usage among the OS cohort, which served to corroborate the controlled HT CT trial findings. Other cancer surveillance studies have noted the same trend.
- Identification of putative molecular markers which may predispose (and/or aid early detection) certain populations of women to diabetes and breast cancer.
- Recognition that postmenopausal women are less active than they were during their pre-menopausal years, suggesting a possible benefit for interventions at or around perimenopause. Furthermore, this decrease in activity (e.g., prolonged sedentary activity) can lead to an increased CVD risk.
- A correlation between laxative use and an increased risk of falls, for both extrinsic and intrinsic reasons.
- Identification of a positive correlation between active smoking or extensive exposure to second-hand smoke and an increased risk of breast cancer.
- Identification of a potential positive relationship between alcohol use and the risk of developing certain types of hormone-responsive breast cancers.
- An inverse correlation between whole grain consumption and type-2 diabetes, which is in agreement with previous studies; however, this study found the benefit of whole grain consumption to be lost with any history of smoking.
- Insomnia, in combination with a long- (≥10 hours) or short-duration (≤5 hours) sleep pattern, can substantially augment the risk of CVD and CHD.
- A combined analysis of the OS and CT cohorts found no convincing evidence for the influence of multivitamin supplement usage on common cancers, CVD, or total mortality.
- An analysis of outcomes, approximate participant location, and local air quality data found that long-term exposure to fine particulate (PM2.5) air pollution was associated with increased risks of cardiovascular disease and death among postmenopausal women.
Study extensions, new trials, and the WHI at present
The WHI study has received three extensions; these extensions are referred to as "Extension Study 1" (2005-2010), "Extension Study 2" (2010-2015), and the recently undertaken "Extension Study 3" (2015-2020). Participants from the first phase of the WHI study were consented and enrolled, with the intention of collecting additional longitudinal data from subjects involved in all of the original study components. The primary outcomes were the same, although greater emphasis was placed on the investigation of cardiovascular disease and aging. Extension Study 1 enrolled 115,403 of the original WHI participants, or 77% of those eligible from the first study phase. Extension Study 2 was able to enroll 93,540 participants, or 87% of those eligible from Extension Study 1. Preliminary estimates for Extension Study 3 participation, as of September 30, 2015, estimate that 36,115 of the Clinical Trial participants and 45,271 Observational Study participants remain active in the WHI study, for a total of 81,386 or 87% of those previously enrolled in Extension Study 2.
A subsample of the Extension Study 2 participants (n = 7875), aged 63–99 and meeting other eligibility criteria, were consented into the Long Life Study (LLS), the purpose of which was to establish new baselines from which new studies in disease and aging can work. In-person visits were conducted to assess and collect physical and functional measurements, as well as blood to replenish the WHI biospecimen repository and determine current CBC parameters for these participants. The LLS completed its in-person visits and blood collections in May 2013.
A large subset of the LLS participants (n ≈ 7400) were further enrolled in the Objective Physical Activity and Cardiovascular Health in Women (OPACH) study, the purpose of which was to assess physical activity in women capable of ambulation. These women were asked to maintain a week-long sleep log, wear an accelerometer for a week, and keep track of falls on a month basis for one year. The goal was to establish a stronger correlation between physical activity and cardiovascular disease and total mortality.
COcoa Supplement and Multivitamin Outcomes Study (COSMOS)
The COcoa Supplement and Multivitamin Outcomes Study (COSMOS) at Brigham and Women's Hospital and the Fred Hutchinson Cancer Research Center (Seattle, WA) was a four-year clinical trial with more than 21,000 women and men, recruited from across the U.S. The study was supported by Mars and Pfizer. The objective of the study was to investigate whether either cocoa flavanols (600 mg/day) or a common multivitamin affects the risk of developing heart disease, stroke, and cancer. First results showed no effect on the pre-registered primary endpoints (incidences of heart disease and cancer), but they did show an effect on secondary endpoints with a reduction in heart disease mortality for cocoa flavanols and a reduction of lung cancer risk for multivitamins.
Women's Health Initiative Strong & Healthy (WHISH)
The Women's Health Initiative Strong and Healthy Study (WHISH), started in 2015 and expected to last four years, seeks to examine the impact of physical activity in older women on certain outcomes such as heart disease and metrics including maintaining an independent lifestyle. The study has enrolled nearly 50,000 participants as of October 2016, whose assigned interventions will include varying physical activity routines, which are monitored by mail and via phone, using an interactive voice response (IVR) system.
Other ancillary studies
Public health investigators and biostatisticians can apply to use WHI study data in conjunction with their investigations. As of June 2013, nearly 450 Ancillary Studies have been proposed. Newly generated data from these Ancillary Studies must be submitted to the WHI, which in turn provides a richer data resource for subsequent studies.
Significant extension study findings
Analysis during the post-intervention period following the estrogen-plus-progestin trial continues to reveal the strong association between estrogen- plus-progestin usage and breast cancer risk. Following the halt of the estrogen-plus-progestin trial, there was a sharp decrease in breast cancer risk in the early post-intervention period, though the hazard ratio remained greater than 1, followed by a sustained risk during the late post-intervention period that was significantly greater than 1. It is hypothesized that the initial decrease was due to the resulting change in the hormone environment, while the subsequent persistent increase in breast cancer incidence may be attributed to the persistence of oncogenic mutations and subsequent expansion of these mutation-harboring cell lineages. The most recent update, published July 28, 2020 in JAMA, reported that increased breast cancer risk has persisted among women randomized to estrogen plus progestin compared with placebo (hazard ratio [HR], 1.28; 95%CI, 1.13 -1.45; P-value < 0.001).
In contrast, breast cancer risk was significantly lower for the estrogen-alone group compared to placebo during the post-intervention period. Specifically, the reduction of breast cancer incidence persisted throughout the early post-intervention phase. Lower breast cancer risk among the estrogen-alone group remained for the most recent update (HR, 0.78; 95%CI, 0.65-0.93; P-value = 0.005). In addition, statistically significantly lower breast cancer mortality was reported (HR, 0.60; 95%CI, 0.37-0.97; P = 0.04).
Regarding endometrial cancer, although estrogen-plus-progestin use during the intervention period suggested a reduction in cancer incidence, the difference became statistically significant with additional follow-up from the extension period. These findings highlight the completely different long-term influences estrogen plus progestin have on endometrial cancer and breast cancer.
According to a cumulative 18-year follow-up analysis published in 2017, it was found that, among 27,347 postmenopausal women who had originally participated in the WHI hormone therapy trials, interventions using estrogen-plus-progestin and estrogen-alone were not associated with increased or decreased risk of all-cause, cardiovascular, or total cancer mortality.
Of note, mortality is a rather limited summary because it does not include non-fatal CVD and non-fatal cancer events that may have long term consequences on health and quality of life. Post-menopausal women considering initiation of HT and their clinicians should refer to previous WHI publications for a complete summary of risks for fatal and non-fatal events.
The Dietary Modification intervention has also yielded new findings, after nearly two decades of follow-up. During the dietary intervention period (median, 8.1 years), it was found that a low-fat dietary pattern led to a lower incidence of death (from all causes) after breast cancer (40 deaths versus 94 in the "normal diet" arm; HR, 0.65; 95% CI, 0.45 to 0.94, P = .02.). After a median 16.1 years of cumulative follow-up (inclusive of the intervention period), further analysis showed that this benefit persisted (234 deaths versus 443 in the "normal diet" arm; HR, 0.82; 95% CI, 0.70 to 0.96 with P = .01). A more recent update, with 19.6 years of cumulative follow-up, reported the persistent reduction of death (from all-causes) after breast cancer continued (359 v 652 deaths; HR, 0.85; 95% CI, 0.74 to 0.96; P = .01) and a statistically significant reduction in deaths as a result of breast cancer (breast cancer followed by death directly attributed to the breast cancer) emerged (132 v 251 deaths; HR, 0.79; 95% CI, 0.64 to 0.97; P = .02).
Another recent analysis of Dietary Modification intervention outcomes showed a 30% reduction in coronary heart disease (CHD) risk among women having normal blood pressure (n = 23,248) and partaking in a low-fat dietary pattern (122 versus 256 CHD events; HR, 0.70; 95% CI, 0.56 to 0.87 during the intervention period). Participants with existing cardiovascular disease at baseline (n = 1,656) were at higher risk of developing coronary heart disease, both during the intervention and extended follow-up periods (101 versus 116 CHD events, HR, 1.47; 95% CI, 1.12 to 1.93; and 36 versus 44, HR, 1.61 95% CI 1.02 to 2.55, respectively). The increased among women with prior CVD was likely due to post-randomization confounding, resulting in some difficulty in interpretation. Women in the diet intervention group were more likely to report changes in statin use (either cessation or initiation) post-randomization than women in the comparison group.
Secondary analyses concluded that the dietary intervention did not increase risk of diabetes, but instead slowed progression. During the trial, intervention group women had lower rates of initiation of insulin therapy (HR, 0.74; 95% CI, 0.59 to 0.94; P = 0.01) and through cumulative follow-up (HR, 0.88; 95% CI 0.78 to 0.99; P = 0.04).
These types of analysis, conducted more than a decade after the halt of the intervention trials, serves further to demonstrate the long-term value and return on investment yielded by the WHI study.
Publications and citations
According to a 2013 analysis of extramural clinical trials supported by the NHLBI, the components of the WHI study have been some of the most frequently cited in the literature, with the E+P trial ranking first among all NHLBI-sponsored clinical trials, alone averaging 812.5 citations annually (total average annual number of citations for the WHI study interventions, 1233.3). In addition, the WHI study component findings were found to reach publication in a timely manner, despite the study's negative trial findings (see NEJM Supplementary Appendix for detailed findings).
Awards and accolades
In 2015, the WHI study was awarded the 2015 Team Science Award from the Association for Clinical and Translational Science (ACTS), "given in recognition of the WHI team's success in the translation of research discoveries into clinical applications and, eventually, widespread clinical practice."
In April 2016, the American Association for Cancer Research (AACR), the oldest and largest research society of its kind, awarded the WHI study the 2016 Team Science Award in recognition of its more than 20 years of work, which ultimately "singularly changed the face of women's medicine around the world."
Criticisms of the WHI's design and findings
The WHI trial was limited by low adherence, high attrition, inadequate power to detect risks for some outcomes, and evaluation of few regimens. Subsequent to publication of the WHI, controversy arose regarding the applicability of its findings to women just entering menopause. To be properly double blinded, the study required that women not be perimenopausal or have symptoms of menopause. As the average age of menopause is 51, this resulted in an older study population, with an average age of 63. Only 3.5% of the women were 50–54 years of age, the time when women usually decide whether to initiate hormonal therapy. Further analysis of WHI data, however, demonstrated that there is no gained preventive benefit in starting hormone therapy soon after menopause.
Most fundamentally, the WHI did not address the major indication for MHT use: relief of symptoms. Rather, the stated goal of the HT component was to test the long-term cardiovascular-protective effects (rather than treatment of menopausal symptoms) of HT in postmenopausal women, which had been supported by previous observational studies in terms of how it reduces atherosclerotic diseases by lowering serum lipid levels and promoting vasodilation. In an expert consensus statement from The Endocrine Society, evidence from the WHI trial was weighted less than that of a randomized controlled trial according to the GRADE system criteria because of mitigating factors: large dropout rate; lack of adequate representation of applicable group of women (i.e. those initiating therapy at the time of menopause); and modifying influences from prior hormone use. However, the editor of one of the journals which published the results of the WHI called it a "landmark" study. The double blinding limited validity of study results due to its effects on patient exclusion criteria. The dominant majority of participants were Caucasian, and tended to be slightly overweight and former smokers, with the necessary health risks for which these demographics predispose. Furthermore, the focus of the WHI study was disease prevention. Most women take hormone therapy to treat symptoms of menopause rather than for disease prevention and therefore the risks and benefits of hormone therapy in the general population differ from those of the women included in the WHI. Despite these concerns, the original findings of the WHI trial have been accepted by reputable journals, and have withstood the scrutiny of subsequent reanalysis of the study data.
Other large-scale public health studies
Atherosclerosis Risk in Communities (ARIC) study - cohort study of 15,792 men and women in four U.S. communities, which began in 1987, and seeks to identify the underlying causes of atherosclerosis and the resulting clinical outcomes.
Caerphilly Heart Disease Study - cohort study of 2,512 men, set up in a representative population sample drawn from a small town in South Wales, UK. Study has collected wide-ranging data and has focused on risk factors that predict vascular disease, diabetes, cognitive impairment and dementia — and the benefits of living a healthy lifestyle.(1979–present).
Multi-Ethnic Study of Atherosclerosis (MESA) - cohort study of approximately 6,000 men and women in six U.S. communities, which started in 2000, with the purpose of identifying the subclinical (i.e., asymptomatic) characteristics of cardiovascular disease, as well as risk factors that predict progression to a clinical disease state.
- Parker-Pope T (April 9, 2011). "The Women's Health Initiative and the Body Politic". The New York Times. Retrieved 6 June 2013.
- Roth JA, Etzioni R, Waters TM, Pettinger M, Rossouw JE, Anderson GL, et al. (May 2014). "Economic return from the Women's Health Initiative estrogen plus progestin clinical trial: a modeling study". Annals of Internal Medicine. 160 (9): 594–602. doi:10.7326/M13-2348. PMC 4157355. PMID 24798522.
- Collins FS (January 2015). "Exceptional opportunities in medical science: a view from the National Institutes of Health". JAMA. 313 (2): 131–132. doi:10.1001/jama.2014.16736. PMC 5101937. PMID 25585318.
- see details and references in OS section
- Rossouw JE, Finnegan LP, Harlan WR, Pinn VW, Clifford C, McGowan JA (Mar–Apr 1995). "The evolution of the Women's Health Initiative: perspectives from the NIH". Journal of the American Medical Women's Association. 50 (2): 50–55. PMID 7722207.
- National Center for Health Statistics: Vital Statistics of the United States, volume II, Part B. Washington, DC: DHSS Public Health Service. 1990. pp. 90–1102.
- Black DM, Cummings SR, Genant HK, Nevitt MC, Palermo L, Browner W (June 1992). "Axial and appendicular bone density predict fractures in older women". Journal of Bone and Mineral Research. 7 (6): 633–638. doi:10.1002/jbmr.5650070607. PMID 1414481. S2CID 3007572.
- Barrett-Connor E, Slone S, Greendale G, Kritz-Silverstein D, Espeland M, Johnson SR, et al. (July 1997). "The Postmenopausal Estrogen/Progestin Interventions Study: primary outcomes in adherent women". Maturitas. 27 (3): 261–274. doi:10.1016/s0378-5122(97)00041-8. PMID 9288699.
- "Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI Trial". JAMA. 273 (3): 199–208. January 1995. doi:10.1001/jama.273.3.199. PMID 7807658.
- Johnson S, Mebane-Sims I, Hogan PE, Stoy DB (August 1995). "Recruitment of postmenopausal women in the PEPI Trial. Postmenopausal Estrogen/Progestin Interventions". Controlled Clinical Trials. 16 (4 Suppl): 20S–35S. doi:10.1016/0197-2456(95)91155-4. PMID 7587217.
- Henderson MM, Kushi LH, Thompson DJ, Gorbach SL, Clifford CK, Insull W, et al. (March 1990). "Feasibility of a randomized trial of a low-fat diet for the prevention of breast cancer: dietary compliance in the Women's Health Trial Vanguard Study". Preventive Medicine. 19 (2): 115–133. doi:10.1016/0091-7435(90)90014-B. PMID 2193306.
- White E, Shattuck AL, Kristal AR, Urban N, Prentice RL, Henderson MM, et al. (May–June 1992). "Maintenance of a low-fat diet: follow-up of the Women's Health Trial". Cancer Epidemiology, Biomarkers & Prevention. 1 (4): 315–323. PMID 1338896.
- "NIH Almanac — Past NIH Directors". National Institutes of Health. Retrieved 3 June 2013.
- "Press Release — U.S. Department of Health and Human Services" (PDF). U.S. Department of Health and Human Services. Retrieved 3 June 2013.
- Darby A (8 November 2017). "Bernadine Healy (1944–2011)". Embryo Project Encyclopedia. Arizona State University, Arizona Board of Regents. ISSN 1940-5030.
- Hays J, Hunt JR, Hubbell FA, Anderson GL, Limacher M, Allen C, Rossouw JE (October 2003). "The Women's Health Initiative recruitment methods and results". Annals of Epidemiology. 13 (9 Suppl): S18–S77. doi:10.1016/s1047-2797(03)00042-5. PMID 14575939.
- Prentice RL, Anderson GL (2008). "The women's health initiative: lessons learned". Annual Review of Public Health. 29: 131–150. doi:10.1146/annurev.publhealth.29.020907.090947. PMID 18348708.
- Stampfer MJ, Colditz GA (January 1991). "Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence". Preventive Medicine. 20 (1): 47–63. doi:10.1016/0091-7435(91)90006-p. PMID 1826173.
- Bush TL, Barrett-Connor E, Cowan LD, Criqui MH, Wallace RB, Suchindran CM, et al. (June 1987). "Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the Lipid Research Clinics Program Follow-up Study". Circulation. 75 (6): 1102–1109. doi:10.1161/01.cir.75.6.1102. PMID 3568321.
- Grady D, Rubin SM, Petitti DB, Fox CS, Black D, Ettinger B, et al. (December 1992). "Hormone therapy to prevent disease and prolong life in postmenopausal women". Annals of Internal Medicine. 117 (12): 1016–1037. doi:10.7326/0003-4819-117-12-1016. PMID 1443971.
- Dupont WD, Page DL (January 1991). "Menopausal estrogen replacement therapy and breast cancer". Archives of Internal Medicine. 151 (1): 67–72. doi:10.1001/archinte.151.1.67. PMID 1824675.
- Steinberg KK, Thacker SB, Smith SJ, Stroup DF, Zack MM, Flanders WD, Berkelman RL (April 1991). "A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer". JAMA. 265 (15): 1985–1990. doi:10.1001/jama.1991.03460150089030. PMID 1826136.
- "Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Collaborative Group on Hormonal Factors in Breast Cancer". Lancet. 350 (9084): 1047–1059. October 1997. doi:10.1016/S0140-6736(97)08233-0. PMID 10213546. S2CID 54389746.
- Oh K, Hu FB, Manson JE, Stampfer MJ, Willett WC (April 2005). "Dietary fat intake and risk of coronary heart disease in women: 20 years of follow-up of the nurses' health study". American Journal of Epidemiology. 161 (7): 672–679. doi:10.1093/aje/kwi085. PMID 15781956.
- Liu S, Stampfer MJ, Hu FB, Giovannucci E, Rimm E, Manson JE, et al. (September 1999). "Whole-grain consumption and risk of coronary heart disease: results from the Nurses' Health Study". The American Journal of Clinical Nutrition. 70 (3): 412–419. doi:10.1093/ajcn/70.3.412. PMID 10479204.
- Liu S, Manson JE, Lee IM, Cole SR, Hennekens CH, Willett WC, Buring JE (October 2000). "Fruit and vegetable intake and risk of cardiovascular disease: the Women's Health Study". The American Journal of Clinical Nutrition. 72 (4): 922–928. doi:10.1093/ajcn/72.4.922. PMID 11010932.
- Fung TT, Stampfer MJ, Manson JE, Rexrode KM, Willett WC, Hu FB (September 2004). "Prospective study of major dietary patterns and stroke risk in women". Stroke. 35 (9): 2014–2019. doi:10.1161/01.STR.0000135762.89154.92. PMID 15232120.
- Prentice RL, Sheppard L (July 1990). "Dietary fat and cancer: consistency of the epidemiologic data, and disease prevention that may follow from a practical reduction in fat consumption". Cancer Causes & Control. 1 (1): 81–97, discussion 99–109. doi:10.1007/bf00053187. PMID 2102280. S2CID 23968699.
- McMichael AJ, Giles GG (February 1988). "Cancer in migrants to Australia: extending the descriptive epidemiological data". Cancer Research. 48 (3): 751–756. PMID 3335035.
- Howe GR, Benito E, Castelleto R, Cornée J, Estève J, Gallagher RP, et al. (December 1992). "Dietary intake of fiber and decreased risk of cancers of the colon and rectum: evidence from the combined analysis of 13 case-control studies". Journal of the National Cancer Institute. 84 (24): 1887–1896. doi:10.1093/jnci/84.24.1887. PMID 1334153. S2CID 24292694.
- Steinmetz KA, Potter JD (March 1993). "Food-group consumption and colon cancer in the Adelaide Case-Control Study. I. Vegetables and fruit". International Journal of Cancer. 53 (5): 711–719. doi:10.1002/ijc.2910530502. PMID 8449594. S2CID 41556761.
- Freedman LS, Clifford C, Messina M (September 1990). "Analysis of dietary fat, calories, body weight, and the development of mammary tumors in rats and mice: a review". Cancer Research. 50 (18): 5710–5719. PMID 2203521.
- Howe GR, Hirohata T, Hislop TG, Iscovich JM, Yuan JM, Katsouyanni K, et al. (April 1990). "Dietary factors and risk of breast cancer: combined analysis of 12 case-control studies". Journal of the National Cancer Institute. 82 (7): 561–569. doi:10.1093/jnci/82.7.561. PMID 2156081.
- Boyd NF, Stone J, Vogt KN, Connelly BS, Martin LJ, Minkin S (November 2003). "Dietary fat and breast cancer risk revisited: a meta-analysis of the published literature". British Journal of Cancer. 89 (9): 1672–1685. doi:10.1038/sj.bjc.6601314. PMC 2394401. PMID 14583769.
- Chevalley T, Rizzoli R, Nydegger V, Slosman D, Rapin CH, Michel JP, et al. (September 1994). "Effects of calcium supplements on femoral bone mineral density and vertebral fracture rate in vitamin-D-replete elderly patients". Osteoporosis International. 4 (5): 245–252. doi:10.1007/bf01623348. PMID 7812072. S2CID 25980969.
- Cumming RG (October 1990). "Calcium intake and bone mass: a quantitative review of the evidence". Calcified Tissue International. 47 (4): 194–201. doi:10.1007/bf02555919. PMID 2146986. S2CID 189914090.
- Shea B, Wells G, Cranney A, Zytaruk N, Robinson V, Griffith L, et al. (August 2002). "Meta-analyses of therapies for postmenopausal osteoporosis. VII. Meta-analysis of calcium supplementation for the prevention of postmenopausal osteoporosis". Endocrine Reviews. 23 (4): 552–559. doi:10.1210/er.2001-7002. PMID 12202470.
- Bischoff-Ferrari HA, Dawson-Hughes B, Willett WC, Staehelin HB, Bazemore MG, Zee RY, Wong JB (April 2004). "Effect of Vitamin D on falls: a meta-analysis". JAMA. 291 (16): 1999–2006. doi:10.1001/jama.291.16.1999. PMID 15113819.
- Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T, Dawson-Hughes B (May 2005). "Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials". JAMA. 293 (18): 2257–2264. doi:10.1001/jama.293.18.2257. PMID 15886381.
- Chapuy MC, Arlot ME, Duboeuf F, Brun J, Crouzet B, Arnaud S, et al. (December 1992). "Vitamin D3 and calcium to prevent hip fractures in elderly women". The New England Journal of Medicine. 327 (23): 1637–1642. doi:10.1056/NEJM199212033272305. PMID 1331788.
- Trivedi DP, Doll R, Khaw KT (March 2003). "Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial". BMJ. 326 (7387): 469. doi:10.1136/bmj.326.7387.469. PMC 150177. PMID 12609940.
- Flood A, Peters U, Chatterjee N, Lacey JV, Schairer C, Schatzkin A (January 2005). "Calcium from diet and supplements is associated with reduced risk of colorectal cancer in a prospective cohort of women". Cancer Epidemiology, Biomarkers & Prevention. 14 (1): 126–132. doi:10.1158/1055-9922.214.171.124. PMID 15668485. S2CID 28435636.
- McCullough ML, Robertson AS, Rodriguez C, Jacobs EJ, Chao A, Carolyn J, et al. (February 2003). "Calcium, vitamin D, dairy products, and risk of colorectal cancer in the Cancer Prevention Study II Nutrition Cohort (United States)". Cancer Causes & Control. 14 (1): 1–12. doi:10.1023/A:1022591007673. PMID 12708719. S2CID 11682517.
- Terry P, Baron JA, Bergkvist L, Holmberg L, Wolk A (2002). "Dietary calcium and vitamin D intake and risk of colorectal cancer: a prospective cohort study in women". Nutrition and Cancer. 43 (1): 39–46. doi:10.1207/S15327914NC431_4. PMID 12467133. S2CID 45003595.
- Marcus PM, Newcomb PA (October 1998). "The association of calcium and vitamin D, and colon and rectal cancer in Wisconsin women". International Journal of Epidemiology. 27 (5): 788–793. doi:10.1093/ije/27.5.788. PMID 9839734.
- Brinton LA, Felix AS (July 2014). "Menopausal hormone therapy and risk of endometrial cancer". The Journal of Steroid Biochemistry and Molecular Biology. 142: 83–89. doi:10.1016/j.jsbmb.2013.05.001. PMC 3775978. PMID 23680641.
- Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. (July 2002). "Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial". JAMA. 288 (3): 321–333. doi:10.1001/jama.288.3.321. PMID 12117397.
- Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, et al. (April 2004). "Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial". JAMA. 291 (14): 1701–1712. doi:10.1001/jama.291.14.1701. PMID 15082697.
- Petersen M (July 10, 2002). "Wyeth Stock Falls 24% After Report". The New York Times. Retrieved 6 June 2013.
- Smith A (April 27, 2006). "Wyeth faces thousands of Prempro lawsuits". CNN Money. Retrieved 6 June 2013.
- Feeley J (June 19, 2012). "Pfizer Paid $896 Million in Prempro Settlements". Bloomberg. Retrieved 6 June 2013.
- "On second thoughts, let's just go easy on the hormone therapy". The Sydney Morning Herald. July 11, 2002. Retrieved 6 June 2013.
- Kolata G (October 25, 2002). "Drug Agency Weighs Role Of Hormone Replacements". The New York Times. Retrieved 6 June 2013.
- Christie B (April 9, 2011). "Landmarks From Two Decades of Study". New York Times. Retrieved 6 June 2013.
- Grady D (October 19, 2010). "Breast Cancer Seen as Riskier With Hormone". The New York Times. Retrieved 6 June 2013.
- Lagro-Janssen A, Knufing MW, Schreurs L, van Weel C (August 2010). "Significant fall in hormone replacement therapy prescription in general practice". Family Practice. 27 (4): 424–429. doi:10.1093/fampra/cmq018. PMID 20406789.
- Hersh AL, Stefanick ML, Stafford RS (January 2004). "National use of postmenopausal hormone therapy: annual trends and response to recent evidence". JAMA. 291 (1): 47–53. doi:10.1001/jama.291.1.47. PMID 14709575.
- Hing E, Brett KM (July 2006). "Changes in U.S. prescribing patterns of menopausal hormone therapy, 2001-2003". Obstetrics and Gynecology. 108 (1): 33–40. doi:10.1097/01.AOG.0000220502.77153.5a. PMID 16816053. S2CID 36112529.
- Wysowski DK, Governale LA (March 2005). "Use of menopausal hormones in the United States, 1992 through June, 2003". Pharmacoepidemiology and Drug Safety. 14 (3): 171–176. doi:10.1002/pds.985. PMID 15386701. S2CID 40103990.
- "Wyeth Annual Report to Shareholders: 2005". Securities and Exchange Commission (SEC). Retrieved 6 June 2013.
- Grossman DC, Curry SJ, Owens DK, Barry MJ, Davidson KW, Doubeni CA, et al. (December 2017). "Hormone Therapy for the Primary Prevention of Chronic Conditions in Postmenopausal Women: US Preventive Services Task Force Recommendation Statement". JAMA. 318 (22): 2224–2233. doi:10.1001/jama.2017.18261. PMID 29234814.
- US Preventive Services Task Force (1996). Postmenopausal Hormone Prophylaxis. Williams & Wilkins.
- "Grade Definitions - US Preventive Services Task Force". www.uspreventiveservicestaskforce.org. Retrieved 2017-12-13.
- Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E (August 1998). "Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group". JAMA. 280 (7): 605–613. doi:10.1001/jama.280.7.605. PMID 9718051.
- U.S. Preventive Services Task Force (May 2005). "Hormone therapy for the prevention of chronic conditions in postmenopausal women: recommendations from the U.S. Preventive Services Task Force". Annals of Internal Medicine. 142 (10): 855–860. doi:10.7326/0003-4819-142-10-200505170-00011. PMID 15897536.
- Wenger NK (February 2018). "Menopausal Hormone Therapy for the Primary Prevention of Chronic Conditions: Unfulfilled Expectations". JAMA Cardiology. 3 (2): 99–101. doi:10.1001/jamacardio.2017.4575. PMID 29234780.
- Grady D (February 2018). "Evidence for Postmenopausal Hormone Therapy to Prevent Chronic Conditions: Success, Failure, and Lessons Learned". JAMA Internal Medicine. 178 (2): 185–186. doi:10.1001/jamainternmed.2017.7861. PMID 29234779.
- Lewis CE, Wellons MF (December 2017). "Menopausal Hormone Therapy for Primary Prevention of Chronic Disease". JAMA. 318 (22): 2187–2189. doi:10.1001/jama.2017.16974. PMID 29234792.
- "Menopausal hormone therapy: where are we now? - bpacnz". bpac.org.nz. Retrieved 2020-09-27.
- Howard BV, Van Horn L, Hsia J, Manson JE, Stefanick ML, Wassertheil-Smoller S, et al. (February 2006). "Low-fat dietary pattern and risk of cardiovascular disease: the Women's Health Initiative Randomized Controlled Dietary Modification Trial". JAMA. 295 (6): 655–666. doi:10.1001/jama.295.6.655. PMID 16467234.
- Prentice RL, Caan B, Chlebowski RT, Patterson R, Kuller LH, Ockene JK, et al. (February 2006). "Low-fat dietary pattern and risk of invasive breast cancer: the Women's Health Initiative Randomized Controlled Dietary Modification Trial". JAMA. 295 (6): 629–642. doi:10.1001/jama.295.6.629. PMID 16467232.
- Beresford SA, Johnson KC, Ritenbaugh C, Lasser NL, Snetselaar LG, Black HR, et al. (February 2006). "Low-fat dietary pattern and risk of colorectal cancer: the Women's Health Initiative Randomized Controlled Dietary Modification Trial". JAMA. 295 (6): 643–654. doi:10.1001/jama.295.6.643. PMID 16467233.
- Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE, et al. (February 2006). "Calcium plus vitamin D supplementation and the risk of fractures". The New England Journal of Medicine. 354 (7): 669–683. doi:10.1056/NEJMoa055218. PMID 16481635. S2CID 23195632.
- Wactawski-Wende J, Kotchen JM, Anderson GL, Assaf AR, Brunner RL, O'Sullivan MJ, et al. (February 2006). "Calcium plus vitamin D supplementation and the risk of colorectal cancer". The New England Journal of Medicine. 354 (7): 684–696. doi:10.1056/NEJMoa055222. PMID 16481636. S2CID 20826870.
- Prentice RL, Pettinger MB, Jackson RD, Wactawski-Wende J, Lacroix AZ, Anderson GL, et al. (February 2013). "Health risks and benefits from calcium and vitamin D supplementation: Women's Health Initiative clinical trial and cohort study". Osteoporosis International. 24 (2): 567–580. doi:10.1007/s00198-012-2224-2. PMC 3557387. PMID 23208074.
- Chlebowski RT, Johnson KC, Kooperberg C, Pettinger M, Wactawski-Wende J, Rohan T, et al. (November 2008). "Calcium plus vitamin D supplementation and the risk of breast cancer". Journal of the National Cancer Institute. 100 (22): 1581–1591. doi:10.1093/jnci/djn360. PMC 2673920. PMID 19001601.
- Langer RD, White E, Lewis CE, Kotchen JM, Hendrix SL, Trevisan M (October 2003). "The Women's Health Initiative Observational Study: baseline characteristics of participants and reliability of baseline measures". Annals of Epidemiology. 13 (9 Suppl): S107–S121. doi:10.1016/s1047-2797(03)00047-4. PMID 14575943.
- Chlebowski RT, Kuller LH, Prentice RL, Stefanick ML, Manson JE, Gass M, et al. (February 2009). "Breast cancer after use of estrogen plus progestin in postmenopausal women". The New England Journal of Medicine. 360 (6): 573–587. doi:10.1056/NEJMoa0807684. PMC 3963492. PMID 19196674.
- Chlebowski RT, Manson JE, Anderson GL, Cauley JA, Aragaki AK, Stefanick ML, et al. (April 2013). "Estrogen plus progestin and breast cancer incidence and mortality in the Women's Health Initiative Observational Study". Journal of the National Cancer Institute. 105 (8): 526–535. doi:10.1093/jnci/djt043. PMC 3691942. PMID 23543779.
- Luo J, Cochrane BB, Wactawski-Wende J, Hunt JR, Ockene JK, Margolis KL (February 2013). "Effects of menopausal hormone therapy on ductal carcinoma in situ of the breast". Breast Cancer Research and Treatment. 137 (3): 915–925. doi:10.1007/s10549-012-2402-0. PMID 23315265. S2CID 5861369.
- Ravdin PM, Cronin KA, Howlader N, Berg CD, Chlebowski RT, Feuer EJ, et al. (April 2007). "The decrease in breast-cancer incidence in 2003 in the United States". The New England Journal of Medicine. 356 (16): 1670–1674. doi:10.1056/NEJMsr070105. PMID 17442911.
- Hsu YH, Niu T, Song Y, Tinker L, Kuller LH, Liu S (April 2008). "Genetic variants in the UCP2-UCP3 gene cluster and risk of diabetes in the Women's Health Initiative Observational Study". Diabetes. 57 (4): 1101–1107. doi:10.2337/db07-1269. PMID 18223008.
- Li CI, Mirus JE, Zhang Y, Ramirez AB, Ladd JJ, Prentice RL, et al. (September 2012). "Discovery and preliminary confirmation of novel early detection biomarkers for triple-negative breast cancer using preclinical plasma samples from the Women's Health Initiative observational study". Breast Cancer Research and Treatment. 135 (2): 611–618. doi:10.1007/s10549-012-2204-4. PMC 3439142. PMID 22903690.
- Li CI (April 2011). "Discovery and validation of breast cancer early detection biomarkers in preclinical samples". Hormones & Cancer. 2 (2): 125–131. doi:10.1007/s12672-010-0061-3. PMC 3228358. PMID 21761335.
- Evenson KR, Wilcox S, Pettinger M, Brunner R, King AC, McTiernan A (November 2002). "Vigorous leisure activity through women's adult life: the Women's Health Initiative Observational Cohort Study". American Journal of Epidemiology. 156 (10): 945–953. doi:10.1093/aje/kwf132. PMID 12419767.
- Chomistek AK, Manson JE, Stefanick ML, Lu B, Sands-Lincoln M, Going SB, et al. (June 2013). "Relationship of sedentary behavior and physical activity to incident cardiovascular disease: results from the Women's Health Initiative". Journal of the American College of Cardiology. 61 (23): 2346–2354. doi:10.1016/j.jacc.2013.03.031. PMC 3676694. PMID 23583242.
- Haring B, Pettinger M, Bea JW, Wactawski-Wende J, Carnahan RM, Ockene JK, et al. (May 2013). "Laxative use and incident falls, fractures and change in bone mineral density in postmenopausal women: results from the Women's Health Initiative". BMC Geriatrics. 13 (1): 38. doi:10.1186/1471-2318-13-38. PMC 3645973. PMID 23635086.
- Luo J, Margolis KL, Wactawski-Wende J, Horn K, Messina C, Stefanick ML, et al. (March 2011). "Association of active and passive smoking with risk of breast cancer among postmenopausal women: a prospective cohort study". BMJ. 342: d1016. doi:10.1136/bmj.d1016. PMC 3047002. PMID 21363864.
- Li CI, Chlebowski RT, Freiberg M, Johnson KC, Kuller L, Lane D, et al. (September 2010). "Alcohol consumption and risk of postmenopausal breast cancer by subtype: the women's health initiative observational study". Journal of the National Cancer Institute. 102 (18): 1422–1431. doi:10.1093/jnci/djq316. PMC 2943525. PMID 20733117.
- Parker ED, Liu S, Van Horn L, Tinker LF, Shikany JM, Eaton CB, Margolis KL (June 2013). "The association of whole grain consumption with incident type 2 diabetes: the Women's Health Initiative Observational Study". Annals of Epidemiology. 23 (6): 321–327. doi:10.1016/j.annepidem.2013.03.010. PMC 3662533. PMID 23608304.
- Sands-Lincoln M, Loucks EB, Lu B, Carskadon MA, Sharkey K, Stefanick ML, et al. (June 2013). "Sleep duration, insomnia, and coronary heart disease among postmenopausal women in the Women's Health Initiative". Journal of Women's Health. 22 (6): 477–486. doi:10.1089/jwh.2012.3918. PMC 3678565. PMID 23651054.
- Neuhouser ML, Wassertheil-Smoller S, Thomson C, Aragaki A, Anderson GL, Manson JE, et al. (February 2009). "Multivitamin use and risk of cancer and cardiovascular disease in the Women's Health Initiative cohorts". Archives of Internal Medicine. 169 (3): 294–304. doi:10.1001/archinternmed.2008.540. PMC 3868488. PMID 19204221.
- Miller KA, Siscovick DS, Sheppard L, Shepherd K, Sullivan JH, Anderson GL, Kaufman JD (February 2007). "Long-term exposure to air pollution and incidence of cardiovascular events in women". The New England Journal of Medicine. 356 (5): 447–458. doi:10.1056/nejmoa054409. PMID 17267905.
- "Extension Study 2". Women's Health Initiative. Retrieved 17 June 2013.
- Internal e-mail communication.
- "Long Life Study". Women's Health Initiative. Retrieved 17 June 2013.
- "Participant News — COcoa Supplement and Multivitamin Outcomes Study (COSMOS) Trial". www.whi.org. Women's Health Initiative. Archived from the original on November 29, 2016. Retrieved 2016-11-28.
- "COcoa Supplement and Multivitamin Outcomes Study (COSMOS) Trial". www.whi.org. Women's Health Institute. Archived from the original on November 29, 2016. Retrieved 2016-11-28.
- Sesso HD, Manson JE, Aragaki AK, Rist PM, Johnson LG, Friedenberg G, et al. (June 2022). "Effect of cocoa flavanol supplementation for the prevention of cardiovascular disease events: the COcoa Supplement and Multivitamin Outcomes Study (COSMOS) randomized clinical trial". The American Journal of Clinical Nutrition. 115 (6): 1490–1500. doi:10.1093/ajcn/nqac055. PMC 9170467. PMID 35294962.
- Sesso HD, Rist PM, Aragaki AK, Rautiainen S, Johnson LG, Friedenberg G, et al. (June 2022). "Multivitamins in the prevention of cancer and cardiovascular disease: the COcoa Supplement and Multivitamin Outcomes Study (COSMOS) randomized clinical trial". The American Journal of Clinical Nutrition. 115 (6): 1501–1510. doi:10.1093/ajcn/nqac056. PMC 9170475. PMID 35294969.
- "Women's Health Initiative Strong and Healthy Study — Tabular View — ClinicalTrials.gov". clinicaltrials.gov.
- "dbGaP". NCBI. Retrieved 2020-02-18.
- Chlebowski RT, Anderson GL, Aragaki AK, Manson JE, Stefanick ML, Pan K, et al. (July 2020). "Association of Menopausal Hormone Therapy With Breast Cancer Incidence and Mortality During Long-term Follow-up of the Women's Health Initiative Randomized Clinical Trials". JAMA. 324 (4): 369–380. doi:10.1001/jama.2020.9482. PMC 7388026. PMID 32721007.
- Chlebowski RT, Rohan TE, Manson JE, Aragaki AK, Kaunitz A, Stefanick ML, et al. (June 2015). "Breast Cancer After Use of Estrogen Plus Progestin and Estrogen Alone: Analyses of Data From 2 Women's Health Initiative Randomized Clinical Trials". JAMA Oncology. 1 (3): 296–305. doi:10.1001/jamaoncol.2015.0494. PMC 6871651. PMID 26181174.
- Chlebowski RT, Anderson GL, Sarto GE, Haque R, Runowicz CD, Aragaki AK, et al. (March 2016). "Continuous Combined Estrogen Plus Progestin and Endometrial Cancer: The Women's Health Initiative Randomized Trial". Journal of the National Cancer Institute. 108 (3): djv350. doi:10.1093/jnci/djv350. PMC 5072373. PMID 26668177.
- Manson JE, Aragaki AK, Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, et al. (September 2017). "Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women's Health Initiative Randomized Trials". JAMA. 318 (10): 927–938. doi:10.1001/jama.2017.11217. PMC 5728370. PMID 28898378.
- "Big study finds no rise in death risk among women who took hormone therapy". Fred Hutch. Retrieved 2017-10-18.
- Chlebowski RT, Aragaki AK, Anderson GL, Thomson CA, Manson JE, Simon MS, et al. (September 2017). "Low-Fat Dietary Pattern and Breast Cancer Mortality in the Women's Health Initiative Randomized Controlled Trial". Journal of Clinical Oncology. 35 (25): 2919–2926. doi:10.1200/JCO.2016.72.0326. PMC 5578391. PMID 28654363.
- Chlebowski RT, Aragaki AK, Anderson GL, Pan K, Neuhouser ML, Manson JE, et al. (May 2020). "Dietary Modification and Breast Cancer Mortality: Long-Term Follow-Up of the Women's Health Initiative Randomized Trial". Journal of Clinical Oncology. 38 (13): 1419–1428. doi:10.1200/JCO.19.00435. PMC 7193750. PMID 32031879.
- Prentice RL, Aragaki AK, Van Horn L, Thomson CA, Beresford SA, Robinson J, et al. (July 2017). "Low-fat dietary pattern and cardiovascular disease: results from the Women's Health Initiative randomized controlled trial". The American Journal of Clinical Nutrition. 106 (1): 35–43. doi:10.3945/ajcn.117.153270. PMC 5486201. PMID 28515068.
- Howard BV, Aragaki AK, Tinker LF, Allison M, Hingle MD, Johnson KC, et al. (April 2018). "A Low-Fat Dietary Pattern and Diabetes: A Secondary Analysis From the Women's Health Initiative Dietary Modification Trial". Diabetes Care. 41 (4): 680–687. doi:10.2337/dc17-0534. PMC 5860839. PMID 29282203.
- Joshi PA, Goodwin PJ, Khokha R (June 2015). "Progesterone Exposure and Breast Cancer Risk: Understanding the Biological Roots". JAMA Oncology. 1 (3): 283–285. doi:10.1001/jamaoncol.2015.0512. PMID 26181171.
- "WHI Bibliography Site". Women's Health Initiative. Retrieved 12 September 2018.
- Gordon D, Taddei-Peters W, Mascette A, Antman M, Kaufmann PG, Lauer MS (November 2013). "Publication of trials funded by the National Heart, Lung, and Blood Institute". The New England Journal of Medicine. 369 (20): 1926–1934. doi:10.1056/NEJMsa1300237. PMC 3928673. PMID 24224625.
- "Good news at Fred Hutch". Fred Hutch. 16 April 2015.
- "Association for Clinical and Translational Science : Previous Meeting Awards". www.actscience.org.
- "AACR Team Science Award: 2016 Women's Health Initiative Team". American Association for Cancer Research. Archived from the original on 3 December 2016.
- "AACR Team Science Award".
- "Good News at Fred Hutch". Fred Hutch.
- "Women's Health Initiative receives AACR Team Science Award". EurekAlert!.
- Banks E, Canfell K (July 2009). "Invited Commentary: Hormone therapy risks and benefits--The Women's Health Initiative findings and the postmenopausal estrogen timing hypothesis". American Journal of Epidemiology. 170 (1): 24–28. doi:10.1093/aje/kwp113. PMID 19468078.
- Prentice RL, Manson JE, Langer RD, Anderson GL, Pettinger M, Jackson RD, et al. (July 2009). "Benefits and risks of postmenopausal hormone therapy when it is initiated soon after menopause". American Journal of Epidemiology. 170 (1): 12–23. doi:10.1093/aje/kwp115. PMC 2733042. PMID 19468079.
- Mendelsohn ME, Karas RH (June 1999). "The protective effects of estrogen on the cardiovascular system". The New England Journal of Medicine. 340 (23): 1801–1811. doi:10.1056/NEJM199906103402306. PMID 10362825.
- Santen RJ, Allred DC, Ardoin SP, Archer DF, Boyd N, Braunstein GD, et al. (July 2010). "Postmenopausal hormone therapy: an Endocrine Society scientific statement". The Journal of Clinical Endocrinology and Metabolism. 95 (7 Suppl 1): s1–s66. doi:10.1210/jc.2009-2509. PMC 6287288. PMID 20566620.
- Deangelis CD (June 2011). "Onward". JAMA. 305 (24): 2575–2576. doi:10.1001/jama.2011.876. PMID 21693750.
we have published important articles such as ... the landmark Women's Health Initiative study
- Rossouw JE, Manson JE, Kaunitz AM, Anderson GL (January 2013). "Lessons learned from the Women's Health Initiative trials of menopausal hormone therapy". Obstetrics and Gynecology. 121 (1): 172–176. doi:10.1097/AOG.0b013e31827a08c8. PMC 3547645. PMID 23262943.
- Nelson HD, Walker M, Zakher B, Mitchell J (July 2012). "Menopausal hormone therapy for the primary prevention of chronic conditions: a systematic review to update the U.S. Preventive Services Task Force recommendations". Annals of Internal Medicine. 157 (2): 104–113. doi:10.7326/0003-4819-157-2-201207170-00466. PMID 22786830.
- The Caerphilly and Speedwell Collaborative Group (September 1984). "Caerphilly and Speedwell collaborative heart disease studies". Journal of Epidemiology and Community Health. 38 (3): 259–262. doi:10.1136/jech.38.3.259. PMC 1052363. PMID 6332166.
- Elwood P, Galante J, Pickering J, Palmer S, Bayer A, Ben-Shlomo Y, et al. (2013). "Healthy lifestyles reduce the incidence of chronic diseases and dementia: evidence from the Caerphilly cohort study". PLOS ONE. 8 (12): e81877. Bibcode:2013PLoSO...881877E. doi:10.1371/journal.pone.0081877. PMC 3857242. PMID 24349147.
- "Nurse's Health Study, Phase 3". Brigham and Women's Hospital. Retrieved 29 May 2013.
- "Design of the Women's Health Initiative clinical trial and observational study. The Women's Health Initiative Study Group". Controlled Clinical Trials. 19 (1): 61–109. February 1998. doi:10.1016/S0197-2456(97)00078-0. PMID 9492970.
- Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, et al. (April 2004). "Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial". JAMA. 291 (14): 1701–1712. doi:10.1001/jama.291.14.1701. PMID 15082697.
- Manson JE, Chlebowski RT, Stefanick ML, Aragaki AK, Rossouw JE, Prentice RL, et al. (October 2013). "Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials". JAMA. 310 (13): 1353–1368. doi:10.1001/jama.2013.278040. PMC 3963523. PMID 24084921.
- Nabel EG (October 2013). "The Women's Health Initiative--a victory for women and their health". JAMA. 310 (13): 1349–1350. doi:10.1001/jama.2013.278042. PMID 24084919.
- Prentice RL, Anderson GL (2008). "The women's health initiative: lessons learned". Annual Review of Public Health. 29: 131–150. doi:10.1146/annurev.publhealth.29.020907.090947. PMID 18348708.