Women's Health Initiative

Logo for the Women's Health Initiative (WHI)

The Women's Health Initiative (WHI) was initiated by the U.S. National Institutes of Health (NIH) in 1991. The Women's Health Initiative, which consisted of three clinical trials (CT) and an observational study (OS), was conducted to address major health issues causing morbidity and mortality in postmenopausal women. 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.[1] 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.[2][3]

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.[4]

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.[5][6] 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.[7][8][9] 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.[10][11] 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

Dr. Bernadine Healy, NIH Director (1991-1993)

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).[12] 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.[13]

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.[14]

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[15] and the primary findings are summarized in the following two tables, respectively, with additional detail following subsequently:

Enrollment summary
Intervention
Age Group DM HT w/ E+P HT w/ E-alone CaD OS
50-54 6961 (16%) 2029 (14%) 1396 (15%) 5157 (16%) 12386 (15%)
55-59 11043 (25%) 3492 (23%) 1916 (20%) 8265 (25%) 17321 (20%)
60-69 22713 (52%) 7512 (50%) 4852 (50%) 16520 (51%) 41196 (49%)
70-79 8118 (19%) 3574 (24%) 2575 (26%) 6340 (19%) 22773 (26%)
Total 48835 16608 10739 36282 93676
Abbreviations: E+P: combined estrogen plus progestin therapy. E-alone: estrogen monotherapy.
Summary of findings
CT
Component		 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).[16][17][18] No Increased risk of stroke. No effect on CHD risk.
Increases risk of breast cancer.[19][20][21] 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).[22][23][24][25] No Modest, but non-significant, effects on CVD risk factors.
Reduces risk of invasive colorectal cancer.[26][27][28][29] No Non-significant trend indicated that a longer intervention may yield more definitive results.
Reduces risk of invasive breast cancer.[30][31][32] 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.[33][34][35][36][37][38][39] No A small, but significant, improvement in bone mineral density was identified.
Reduces risk of colorectal cancer.[40][41][42][43] No Study notes that a longer-duration study may yield more definitive results.

Hormone therapy (HT) intervention

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 equine estrogen 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.[44]

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.[45]

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.[46]

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.

Hazard Ratios (HR) and 95% confidence intervals (CIs) for various clinical outcomes in the E+P and E-alone trials

Clinical
Outcome		 Hypothesized
Effect on Risk		 E+P Treatment Group E-alone Treatment Group
HR 95% CI AR HR 95% CI AR
CHD Decreased 1.24 1.00-1.54 +6 0.95 0.79-1.15 -3
Stroke Decreased 1.31 1.02-1.68 +8 1.37 1.09-1.73 +12
Pulmonary embolism Increased 2.13 1.45-3.11 +10 1.37 0.90-2.07 +4
Venous thromboembolism Increased 2.06 1.57-2.70 +18 1.32 0.99-1.75 +8
Breast cancer Increased 1.24 1.02-1.50 +8 0.80 0.62-1.04 -6
Colorectal cancer Decreased 0.56 0.38-0.81 -7 1.08 0.75-1.55 +1
Endometrial cancer - 0.81 0.48-1.36 -1 N/A N/A N/A
Hip fractures Decreased 0.67 0.47-0.96 -5 0.65 0.45-0.94 -7
Total fractures Decreased 0.76 0.69-0.83 -47 0.71 0.64-0.80 -53
Total mortality Decreased 0.98 0.82-1.18 -1 1.04 0.91-1.12 +3
Global index - 1.15 1.03-1.28 +19 1.01 1.09-1.12 +2
Diabetes - 0.79 0.67-0.93 0.88 0.77-1.01
Gallbladder disease Increased 1.59 1.28-1.97 1.67 1.35-2.06
Stress incontinence

(caused by weak pelvic floor muscles)

 - 1.87 1.61-2.18 2.15 1.77-2.82
Urge incontinence

(characterized as an involuntary loss of bladder control, accompanied by sudden urge)

 - 1.15 0.99-1.34 1.32 1.10-1.58
Peripheral artery disease - 0.89 0.63-1.25 1.32 0.99-1.77
Probable dementia Decreased 2.05 1.21-3.48 1.49 0.83-2.66
Abbreviations/Notes: AR, attributable risk per 10,000 person-years. Hazard ratio estimates are based on proportional hazards analysis, stratified by age (five-year intervals), and randomization in the dietary modification (DM) trial. "Global index" is defined for each woman as the time to earliest diagnosis for CHD, stroke, pulmonary embolism, breast cancer, colorectal cancer, endometrial cancer (E+P only), hip fractures, and death from other causes.

Green shading denotes a reduced risk; red shading denotes an elevated risk.

Of all the WHI study findings, the HT findings could be argued to have yielded the farthest-reaching societal and economic[47][48][49] impacts, and received substantial media attention.[1][50][51][52][53] Large reductions in HT prescriptions ensued,[54][55][56][57] resulting in a substantial loss of revenue in sales of this class of drugs, with a presumably commensurate savings to patients and insurers.[58] 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.[59] 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).[2][3]

Dietary modification (DM) intervention

The 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.[60] 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.[61] The trial also did not identify a reduction in colorectal cancer risk attributable to a low-fat dietary pattern.[62]

Calcium/Vitamin D (CaD) intervention

The 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.[63]

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.[64][65] Calcium plus vitamin D was not found to affect the incidence of breast cancer.[66] Finally, an increased risk of kidney stones was observed among those taking calcium plus vitamin D.

Observational study (OS)

The 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,[67] 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:

Study extensions and the WHI at present

The WHI study has been extended twice; these extensions are referred to as "Extension Study 1" (2005-2010) and "Extension Study 2" (2010-2015). 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 115403 of the original WHI participants, or 77% of those eligible from the first study phase. Extension Study 2 was able to enroll 93540 participants, or 87% of those eligible from Extension Study 1.[83]

Long Life Study (LLS)[84]

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.

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.

In addition to the study data, data from genome-wide association studies (GWAS) conducted on participant DNA is available on the NIH-hosted Database of Genotypes and Phenotypes (dbGaP).

Significant Extension Study Findings

Recent 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.

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, but was lost during the late post-intervention phase.[85]

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.[86] These findings highlight the completely different long-term influences estrogen plus progestin have on endometrial cancer and breast cancer.

This type of analysis, conducted more than a decade after the halt of both hormone trials, serves further to demonstrate the long-term value and return on investment yielded by the WHI study.[87]

Publications and Citations

As of September 2015, the WHI has reviewed 2388 writing proposals, of which 1,173 have been published in scientific journals.[88]

According to a 2013 analysis of extramural clinical trials supported by the NHLBI,[89] 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).

Criticisms

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.[90][91]

Most fundamentally, the WHI did not address the major indication for MHT use, relief of symptoms. On the other hand, 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.[92] 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.[93] However, the editor of one of the journals which published the results of the WHI called it a "landmark" study.[94] 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 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.[95][96]

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.[97] 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.[98](1979–present).

Framingham Heart Study - long-term, ongoing cardiovascular study on the residents of Framingham, Massachusetts (1948–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.

Nurses' Health Study - cohort (three cohorts: 1976 and 1989, with a third cohort currently under recruitment[99]) study focusing on the health of female registered nurses.

Footnotes

  1. 1 2 Parker-Pope, Tara (April 9, 2011). "The Women’s Health Initiative and the Body Politic". The New York Times. Retrieved 6 June 2013.
  2. 1 2 Roth, Joshua A.; Etzioni, Ruth; Waters, Teresa M.; Pettinger, Mary; Rossouw, Jacques E.; Anderson, Garnet L.; Chlebowski, Rowan T.; Manson, JoAnn E.; Hlatky, Mark; Johnson, Karen C.; Ramsey, Scott D. (6 May 2014). "Economic Return From the Women's Health Initiative Estrogen Plus Progestin Clinical Trial". Annals of Internal Medicine 160 (9): 594. doi:10.7326/M13-2348.
  3. 1 2 Collins, Francis S. (13 January 2015). "Exceptional Opportunities in Medical Science". JAMA 313 (2): 131. doi:10.1001/jama.2014.16736.
  4. ↑ Rossouw, Jacques; et al. (Mar–Apr 1995). "The Evolution of the Women's Health Initiative: Perspectives from the NIH". J Am Med Womens Assoc 50 (2): 50–55. PMID 7722207.
  5. ↑ 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.
  6. ↑ Black, DM; et al. (June 1992). "Axial and appendicular bone mineral and a woman's lifetime risk of hip fracture". J Bone Min Res 7 (6): 633–638. doi:10.1002/jbmr.5650070607. PMID 1414481.
  7. ↑ Barrett-Connor, Elizabeth; 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.
  8. ↑ "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 (21): 199–208. December 1995. doi:10.1001/jama.273.3.199. PMID 7807658.
  9. ↑ Johnson, Susan; et al. (August 1995). "Recruitment of postmenopausal women in the PEPI Trial. Postmenopausal Estrogen/Progestin Interventions". Controlled Clinical Trials 16 (4): 20–35. PMID 7587217.
  10. ↑ Henderson, MM; Kushi, LH; Thompson, DJ; Gorbach, SL; Clifford, CK; Insull W, Jr; Moskowitz, M; Thompson, RS (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): 115–33. doi:10.1016/0091-7435(90)90014-b. PMID 2193306. Cite uses deprecated parameter |coauthors= (help)
  11. ↑ White, E; Shattuck, AL; Kristal, AR; Urban, N; Prentice, RL; Henderson, MM; Insull W, Jr; Moskowitz, M; Goldman, S; Woods, MN (May–Jun 1992). "Maintenance of a low-fat diet: follow-up of the Women's Health Trial.". Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 1 (4): 315–23. PMID 1338896. Cite uses deprecated parameter |coauthors= (help);
  12. ↑ "NIH Almanac - Past NIH Directors". National Institutes of Health. Retrieved 3 June 2013.
  13. ↑ "Press Release - U.S. Department of Health and Human Services" (PDF). U.S. Department of Health and Human Services. Retrieved 3 June 2013.
  14. ↑ Hays, J; Hunt, JR; Hubbell, FA; Anderson, GL; Limacher, M; Allen, C; Rossouw, JE (Oct 2003). "The Women's Health Initiative recruitment methods and results.". Annals of epidemiology 13 (9 Suppl): S18–77. doi:10.1016/s1047-2797(03)00042-5. PMID 14575939.
  15. ↑ Prentice, RL; Anderson, GL (2008). "The women's health initiative: lessons learned.". Annual review of public health 29: 131–50. doi:10.1146/annurev.publhealth.29.020907.090947. PMID 18348708.
  16. ↑ 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.
  17. ↑ Bush, TL; Barrett-Connor, E; Cowan, LD; Criqui, MH; Wallace, RB; Suchindran, CM; Tyroler, HA; Rifkind, BM (June 1987). "Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the Lipid Research Clinics Program Follow-up Study.". Circulation 75 (6): 1102–9. doi:10.1161/01.cir.75.6.1102. PMID 3568321.
  18. ↑ Grady, D; Rubin, SM; Petitti, DB; Fox, CS; Black, D; Ettinger, B; Ernster, VL; Cummings, SR (Dec 15, 1992). "Hormone therapy to prevent disease and prolong life in postmenopausal women.". Annals of Internal Medicine 117 (12): 1016–37. doi:10.7326/0003-4819-117-12-1016. PMID 1443971.
  19. ↑ 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.
  20. ↑ Steinberg, KK; Thacker, SB; Smith, SJ; Stroup, DF; Zack, MM; Flanders, WD; Berkelman, RL (Apr 17, 1991). "A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer.". JAMA: the Journal of the American Medical Association 265 (15): 1985–90. doi:10.1001/jama.1991.03460150089030. PMID 1826136.
  21. ↑ "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". The Lancet 350 (9084): 1047–1059. 1 October 1997. doi:10.1016/S0140-6736(97)08233-0. PMID 10213546.
  22. ↑ Oh, K; Hu, FB; Manson, JE; Stampfer, MJ; Willett, WC (Apr 1, 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): 672–9. doi:10.1093/aje/kwi085. PMID 15781956.
  23. ↑ Liu, S; Stampfer, MJ; Hu, FB; Giovannucci, E; Rimm, E; Manson, JE; Hennekens, CH; Willett, WC (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): 412–9. PMID 10479204.
  24. ↑ Liu, S; Manson, JE; Lee, IM; Cole, SR; Hennekens, CH; Willett, WC; Buring, JE (Oct 2000). "Fruit and vegetable intake and risk of cardiovascular disease: the Women's Health Study.". The American Journal of Clinical Nutrition 72 (4): 922–8. PMID 11010932.
  25. ↑ Fung, TT; Stampfer, MJ; Manson, JE; Rexrode, KM; Willett, WC; Hu, FB (Sep 2004). "Prospective study of major dietary patterns and stroke risk in women.". Stroke; a journal of cerebral circulation 35 (9): 2014–9. doi:10.1161/01.STR.0000135762.89154.92. PMID 15232120.
  26. ↑ 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 : CCC 1 (1): 81–97; discussion 99–109. doi:10.1007/bf00053187. PMID 2102280.
  27. ↑ McMichael, AJ; Giles, GG (Feb 1, 1988). "Cancer in migrants to Australia: extending the descriptive epidemiological data.". Cancer Research 48 (3): 751–6. PMID 3335035.
  28. ↑ Howe, GR; Benito, E; Castelleto, R; Cornée, J; Estève, J; Gallagher, RP; Iscovich, JM; Deng-ao, J; Kaaks, R; Kune, GA (Dec 16, 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): 1887–96. doi:10.1093/jnci/84.24.1887. PMID 1334153.
  29. ↑ Steinmetz, KA; Potter, JD (Mar 12, 1993). "Food-group consumption and colon cancer in the Adelaide Case-Control Study. I. Vegetables and fruit.". International Journal of Cancer. Journal International Du Cancer 53 (5): 711–9. doi:10.1002/ijc.2910530502. PMID 8449594.
  30. ↑ Freedman, LS; Clifford, C; Messina, M (Sep 15, 1990). "Analysis of dietary fat, calories, body weight, and the development of mammary tumors in rats and mice: a review.". Cancer Research 50 (18): 5710–9. PMID 2203521.
  31. ↑ Howe, GR; Hirohata, T; Hislop, TG; Iscovich, JM; Yuan, JM; Katsouyanni, K; Lubin, F; Marubini, E; Modan, B; Rohan, T (Apr 4, 1990). "Dietary factors and risk of breast cancer: combined analysis of 12 case-control studies.". Journal of the National Cancer Institute 82 (7): 561–9. doi:10.1093/jnci/82.7.561. PMID 2156081.
  32. ↑ Boyd, NF; Stone, J; Vogt, KN; Connelly, BS; Martin, LJ; Minkin, S (Nov 3, 2003). "Dietary fat and breast cancer risk revisited: a meta-analysis of the published literature.". British Journal of Cancer 89 (9): 1672–85. doi:10.1038/sj.bjc.6601314. PMC 2394401. PMID 14583769. Retrieved 21 June 2013.
  33. ↑ Chevalley, T; Rizzoli, R; Nydegger, V; Slosman, D; Rapin, CH; Michel, JP; Vasey, H; Bonjour, JP (September 1994). "Effects of calcium supplements on femoral bone mineral density and vertebral fracture rate in vitamin-D-replete elderly patients.". Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 4 (5): 245–52. doi:10.1007/bf01623348. PMID 7812072.
  34. ↑ 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.
  35. ↑ Shea, B; Wells, G; Cranney, A; Zytaruk, N; Robinson, V; Griffith, L; Ortiz, Z; Peterson, J; Adachi, J; Tugwell, P; Guyatt, G; Osteoporosis Methodology Group and The Osteoporosis Research Advisory, Group (Aug 2002). "Meta-analyses of therapies for postmenopausal osteoporosis. VII. Meta-analysis of calcium supplementation for the prevention of postmenopausal osteoporosis.". Endocrine Reviews 23 (4): 552–9. doi:10.1210/er.2001-7002. PMID 12202470. Cite uses deprecated parameter |coauthors= (help);
  36. ↑ Bischoff-Ferrari, HA; Dawson-Hughes, B; Willett, WC; Staehelin, HB; Bazemore, MG; Zee, RY; Wong, JB (Apr 28, 2004). "Effect of Vitamin D on falls: a meta-analysis.". JAMA: the Journal of the American Medical Association 291 (16): 1999–2006. doi:10.1001/jama.291.16.1999. PMID 15113819.
  37. ↑ Bischoff-Ferrari, HA; Willett, WC; Wong, JB; Giovannucci, E; Dietrich, T; Dawson-Hughes, B (May 11, 2005). "Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials.". JAMA: the Journal of the American Medical Association 293 (18): 2257–64. doi:10.1001/jama.293.18.2257. PMID 15886381.
  38. ↑ Chapuy, MC; Arlot, ME; Duboeuf, F; Brun, J; Crouzet, B; Arnaud, S; Delmas, PD; Meunier, PJ (Dec 3, 1992). "Vitamin D3 and calcium to prevent hip fractures in the elderly women.". The New England Journal of Medicine 327 (23): 1637–42. doi:10.1056/NEJM199212033272305. PMID 1331788.
  39. ↑ Trivedi, DP; Doll, R; Khaw, KT (Mar 1, 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 (Clinical research ed.) 326 (7387): 469. doi:10.1136/bmj.326.7387.469. PMID 12609940.
  40. ↑ Flood, A; Peters, U; Chatterjee, N; Lacey JV, Jr; 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 : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 14 (1): 126–32. PMID 15668485. Cite uses deprecated parameter |coauthors= (help);
  41. ↑ McCullough, ML; Robertson, AS; Rodriguez, C; Jacobs, EJ; Chao, A; Carolyn, J; Calle, EE; Willett, WC; Thun, MJ (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 : CCC 14 (1): 1–12. PMID 12708719.
  42. ↑ 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.
  43. ↑ 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): 788–93. doi:10.1093/ije/27.5.788. PMID 9839734.
  44. ↑ Brinton, Louise A.; Felix, Ashley S. (1 May 2013). "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. PMID 23680641.
  45. ↑ Rossouw, JE; Anderson, GL; Prentice, RL; LaCroix, AZ; Kooperberg, C; Stefanick, ML; Jackson, RD; Beresford, SA; Howard, BV; Johnson, KC; Kotchen, JM; Ockene, J; Writing Group for the Women's Health Initiative, Investigators (Jul 17, 2002). "Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial.". JAMA: the Journal of the American Medical Association 288 (3): 321–33. doi:10.1001/jama.288.3.321. PMID 12117397. Cite uses deprecated parameter |coauthors= (help)
  46. ↑ Anderson, GL; Limacher, M; Assaf, AR; Bassford, T; Beresford, SA; Black, H; Bonds, D; Brunner, R; Brzyski, R; Caan, B; Chlebowski, R; Curb, D; Gass, M; Hays, J; Heiss, G; Hendrix, S; Howard, BV; Hsia, J; Hubbell, A; Jackson, R; Johnson, KC; Judd, H; Kotchen, JM; Kuller, L; LaCroix, AZ; Lane, D; Langer, RD; Lasser, N; Lewis, CE; Manson, J; Margolis, K; Ockene, J; O'Sullivan, MJ; Phillips, L; Prentice, RL; Ritenbaugh, C; Robbins, J; Rossouw, JE; Sarto, G; Stefanick, ML; Van Horn, L; Wactawski-Wende, J; Wallace, R; Wassertheil-Smoller, S; Women's Health Initiative Steering, Committee (Apr 14, 2004). "Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial.". JAMA: the Journal of the American Medical Association 291 (14): 1701–12. doi:10.1001/jama.291.14.1701. PMID 15082697. Cite uses deprecated parameter |coauthors= (help)
  47. ↑ Petersen, Melody (July 10, 2002). "Wyeth Stock Falls 24% After Report". The New York Times. Retrieved 6 June 2013.
  48. ↑ Smith, Aaron (April 27, 2006). "Wyeth faces thousands of Prempro lawsuits". CNN Money. Retrieved 6 June 2013.
  49. ↑ Feeley, Jef (June 19, 2012). "Pfizer Paid $896 Million in Prempro Settlements". Bloomberg. Retrieved 6 June 2013.
  50. ↑ "On second thoughts, let's just go easy on the hormone therapy". The Sydney Morning Herald. July 11, 2002. Retrieved 6 June 2013.
  51. ↑ Kolata, Gina (October 25, 2002). "Drug Agency Weighs Role Of Hormone Replacements". The New York Times. Retrieved 6 June 2013.
  52. ↑ "Landmarks From Two Decades of Study". New York Times. April 9, 2011. Retrieved 6 June 2013.
  53. ↑ Grady, Denise (October 19, 2010). "Breast Cancer Seen as Riskier With Hormone". The New York Times. Retrieved 6 June 2013.
  54. ↑ 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): 424–9. doi:10.1093/fampra/cmq018. PMID 20406789.
  55. ↑ Hersh, AL; Stefanick, ML; Stafford, RS (Jan 7, 2004). "National use of postmenopausal hormone therapy: annual trends and response to recent evidence.". JAMA: the Journal of the American Medical Association 291 (1): 47–53. doi:10.1001/jama.291.1.47. PMID 14709575.
  56. ↑ Hing, E; Brett, KM (Jul 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.
  57. ↑ Wysowski, Diane K.; Governale, Laura A. (1 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.
  58. ↑ "Wyeth Annual Report to Shareholders: 2005". Securities and Exchange Commission (SEC). Retrieved 6 June 2013.
  59. ↑ see details and references in OS section
  60. ↑ Howard, BV; Van Horn, L; Hsia, J; Manson, JE; Stefanick, ML; Wassertheil-Smoller, S; Kuller, LH; LaCroix, AZ; Langer, RD; Lasser, NL; Lewis, CE; Limacher, MC; Margolis, KL; Mysiw, WJ; Ockene, JK; Parker, LM; Perri, MG; Phillips, L; Prentice, RL; Robbins, J; Rossouw, JE; Sarto, GE; Schatz, IJ; Snetselaar, LG; Stevens, VJ; Tinker, LF; Trevisan, M; Vitolins, MZ; Anderson, GL; Assaf, AR; Bassford, T; Beresford, SA; Black, HR; Brunner, RL; Brzyski, RG; Caan, B; Chlebowski, RT; Gass, M; Granek, I; Greenland, P; Hays, J; Heber, D; Heiss, G; Hendrix, SL; Hubbell, FA; Johnson, KC; Kotchen, JM (Feb 8, 2006). "Low-fat dietary pattern and risk of cardiovascular disease: the Women's Health Initiative Randomized Controlled Dietary Modification Trial.". JAMA: the Journal of the American Medical Association 295 (6): 655–66. doi:10.1001/jama.295.6.655. PMID 16467234. Cite uses deprecated parameter |coauthors= (help);
  61. ↑ Prentice, RL; Caan, B; Chlebowski, RT; Patterson, R; Kuller, LH; Ockene, JK; Margolis, KL; Limacher, MC; Manson, JE; Parker, LM; Paskett, E; Phillips, L; Robbins, J; Rossouw, JE; Sarto, GE; Shikany, JM; Stefanick, ML; Thomson, CA; Van Horn, L; Vitolins, MZ; Wactawski-Wende, J; Wallace, RB; Wassertheil-Smoller, S; Whitlock, E; Yano, K; Adams-Campbell, L; Anderson, GL; Assaf, AR; Beresford, SA; Black, HR; Brunner, RL; Brzyski, RG; Ford, L; Gass, M; Hays, J; Heber, D; Heiss, G; Hendrix, SL; Hsia, J; Hubbell, FA; Jackson, RD; Johnson, KC; Kotchen, JM; LaCroix, AZ; Lane, DS; Langer, RD; Lasser, NL; Henderson, MM (Feb 8, 2006). "Low-fat dietary pattern and risk of invasive breast cancer: the Women's Health Initiative Randomized Controlled Dietary Modification Trial.". JAMA: the Journal of the American Medical Association 295 (6): 629–42. doi:10.1001/jama.295.6.629. PMID 16467232. Cite uses deprecated parameter |coauthors= (help);
  62. ↑ Beresford, SA; Johnson, KC; Ritenbaugh, C; Lasser, NL; Snetselaar, LG; Black, HR; Anderson, GL; Assaf, AR; Bassford, T; Bowen, D; Brunner, RL; Brzyski, RG; Caan, B; Chlebowski, RT; Gass, M; Harrigan, RC; Hays, J; Heber, D; Heiss, G; Hendrix, SL; Howard, BV; Hsia, J; Hubbell, FA; Jackson, RD; Kotchen, JM; Kuller, LH; LaCroix, AZ; Lane, DS; Langer, RD; Lewis, CE; Manson, JE; Margolis, KL; Mossavar-Rahmani, Y; Ockene, JK; Parker, LM; Perri, MG; Phillips, L; Prentice, RL; Robbins, J; Rossouw, JE; Sarto, GE; Stefanick, ML; Van Horn, L; Vitolins, MZ; Wactawski-Wende, J; Wallace, RB; Whitlock, E (Feb 8, 2006). "Low-fat dietary pattern and risk of colorectal cancer: the Women's Health Initiative Randomized Controlled Dietary Modification Trial.". JAMA: the Journal of the American Medical Association 295 (6): 643–54. doi:10.1001/jama.295.6.643. PMID 16467233. Cite uses deprecated parameter |coauthors= (help);
  63. ↑ Jackson, RD; LaCroix, AZ; Gass, M; Wallace, RB; Robbins, J; Lewis, CE; Bassford, T; Beresford, SA; Black, HR; Blanchette, P; Bonds, DE; Brunner, RL; Brzyski, RG; Caan, B; Cauley, JA; Chlebowski, RT; Cummings, SR; Granek, I; Hays, J; Heiss, G; Hendrix, SL; Howard, BV; Hsia, J; Hubbell, FA; Johnson, KC; Judd, H; Kotchen, JM; Kuller, LH; Langer, RD; Lasser, NL; Limacher, MC; Ludlam, S; Manson, JE; Margolis, KL; McGowan, J; Ockene, JK; O'Sullivan, MJ; Phillips, L; Prentice, RL; Sarto, GE; Stefanick, ML; Van Horn, L; Wactawski-Wende, J; Whitlock, E; Anderson, GL; Assaf, AR; Barad, D; Women's Health Initiative, Investigators (Feb 16, 2006). "Calcium plus vitamin D supplementation and the risk of fractures.". The New England Journal of Medicine 354 (7): 669–83. doi:10.1056/NEJMoa055218. PMID 16481635. Cite uses deprecated parameter |coauthors= (help);
  64. ↑ Wactawski-Wende, J; Kotchen, JM; Anderson, GL; Assaf, AR; Brunner, RL; O'Sullivan, MJ; Margolis, KL; Ockene, JK; Phillips, L; Pottern, L; Prentice, RL; Robbins, J; Rohan, TE; Sarto, GE; Sharma, S; Stefanick, ML; Van Horn, L; Wallace, RB; Whitlock, E; Bassford, T; Beresford, SA; Black, HR; Bonds, DE; Brzyski, RG; Caan, B; Chlebowski, RT; Cochrane, B; Garland, C; Gass, M; Hays, J; Heiss, G; Hendrix, SL; Howard, BV; Hsia, J; Hubbell, FA; Jackson, RD; Johnson, KC; Judd, H; Kooperberg, CL; Kuller, LH; LaCroix, AZ; Lane, DS; Langer, RD; Lasser, NL; Lewis, CE; Limacher, MC; Manson, JE; Women's Health Initiative, Investigators (Feb 16, 2006). "Calcium plus vitamin D supplementation and the risk of colorectal cancer.". The New England Journal of Medicine 354 (7): 684–96. doi:10.1056/NEJMoa055222. PMID 16481636. Cite uses deprecated parameter |coauthors= (help);
  65. ↑ Prentice, RL; Pettinger, MB; Jackson, RD; Wactawski-Wende, J; Lacroix, AZ; Anderson, GL; Chlebowski, RT; Manson, JE; Van Horn, L; Vitolins, MZ; Datta, M; LeBlanc, ES; Cauley, JA; Rossouw, JE (February 2013). "Health risks and benefits from calcium and vitamin D supplementation: Women's Health Initiative clinical trial and cohort study.". Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 24 (2): 567–80. doi:10.1007/s00198-012-2224-2. PMID 23208074. Cite uses deprecated parameter |coauthors= (help);
  66. ↑ Chlebowski, R. T.; Johnson, K. C.; Kooperberg, C.; Pettinger, M.; Wactawski-Wende, J.; Rohan, T.; Rossouw, J.; Lane, D.; O'Sullivan, M. J.; Yasmeen, S.; Hiatt, R. A.; Shikany, J. M.; Vitolins, M.; Khandekar, J.; Hubbell, F. A. (11 November 2008). "Calcium Plus Vitamin D Supplementation and the Risk of Breast Cancer". JNCI Journal of the National Cancer Institute 100 (22): 1581–1591. doi:10.1093/jnci/djn360. PMC 2673920. PMID 19001601. Retrieved 11 June 2013. Cite uses deprecated parameter |coauthors= (help)
  67. ↑ Langer, RD; White, E; Lewis, CE; Kotchen, JM; Hendrix, SL; Trevisan, M (Oct 2003). "The Women's Health Initiative Observational Study: baseline characteristics of participants and reliability of baseline measures.". Annals of epidemiology 13 (9 Suppl): S107–21. doi:10.1016/s1047-2797(03)00047-4. PMID 14575943.
  68. ↑ Chlebowski, Rowan T.; Kuller, Lewis H.; Prentice, Ross L.; Stefanick, Marcia L.; Manson, JoAnn E.; Gass, Margery; Aragaki, Aaron K.; Ockene, Judith K.; Lane, Dorothy S.; Sarto, Gloria E.; Rajkovic, Aleksandar; Schenken, Robert; Hendrix, Susan L.; Ravdin, Peter M.; Rohan, Thomas E.; Yasmeen, Shagufta; Anderson, Garnet (5 February 2009). "Breast Cancer after Use of Estrogen plus Progestin in Postmenopausal Women". New England Journal of Medicine 360 (6): 573–587. doi:10.1056/NEJMoa0807684. PMID 19196674. Cite uses deprecated parameter |coauthors= (help);
  69. ↑ Chlebowski, RT; Manson, JE; Anderson, GL; Cauley, JA; Aragaki, AK; Stefanick, ML; Lane, DS; Johnson, KC; Wactawski-Wende, J; Chen, C; Qi, L; Yasmeen, S; Newcomb, PA; Prentice, RL (Apr 17, 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): 526–35. doi:10.1093/jnci/djt043. PMID 23543779.
  70. ↑ Luo, Juhua; Cochrane, Barbara B.; Wactawski-Wende, Jean; Hunt, Julie R.; Ockene, Judith K.; Margolis, Karen L. (12 January 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.
  71. ↑ Ravdin, Peter M.; Cronin, Kathleen A.; Howlader, Nadia; Berg, Christine D.; Chlebowski, Rowan T.; Feuer, Eric J.; Edwards, Brenda K.; Berry, Donald A. (19 April 2007). "The Decrease in Breast-Cancer Incidence in 2003 in the United States". New England Journal of Medicine 356 (16): 1670–1674. doi:10.1056/NEJMsr070105. PMID 17442911.
  72. ↑ 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): 1101–7. doi:10.2337/db07-1269. PMID 18223008. line feed character in |title= at position 39 (help);
  73. ↑ Li, Christopher I.; Mirus, Justin E.; Zhang, Yuzheng; Ramirez, Arturo B.; Ladd, Jon J.; Prentice, Ross L.; McIntosh, Martin W.; Hanash, Samir M.; Lampe, Paul D. (19 August 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.
  74. ↑ Li, CI (April 2011). "Discovery and validation of breast cancer early detection biomarkers in preclinical samples.". Hormones & cancer 2 (2): 125–31. doi:10.1007/s12672-010-0061-3. PMID 21761335.
  75. ↑ Evenson, K. R. (15 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.
  76. ↑ Chomistek, AK; Manson, JE; Stefanick, ML; Lu, B; Sands-Lincoln, M; Going, SB; Garcia, L; Allison, MA; Sims, ST; Lamonte, MJ; Johnson, KC; Eaton, CB (Jun 11, 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): 2346–54. doi:10.1016/j.jacc.2013.03.031. PMID 23583242.
  77. ↑ Haring, B; Pettinger, M; Bea, JW; Wactawski-Wende, J; Carnahan, RM; Ockene, JK; Wyler von Ballmoos, M; Wallace, RB; Wassertheil-Smoller, S (May 1, 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. PMID 23635086. Cite uses deprecated parameter |coauthors= (help);
  78. ↑ Luo, J; Margolis, KL; Wactawski-Wende, J; Horn, K; Messina, C; Stefanick, ML; Tindle, HA; Tong, E; Rohan, TE (Mar 1, 2011). "Association of active and passive smoking with risk of breast cancer among postmenopausal women: a prospective cohort study.". BMJ (Clinical research ed.) 342: d1016. doi:10.1136/bmj.d1016. PMID 21363864.
  79. ↑ Li, CI; Chlebowski, RT; Freiberg, M; Johnson, KC; Kuller, L; Lane, D; Lessin, L; O'Sullivan, MJ; Wactawski-Wende, J; Yasmeen, S; Prentice, R (Sep 22, 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): 1422–31. doi:10.1093/jnci/djq316. PMID 20733117.
  80. ↑ Parker, Emily D.; Liu, Simin; Van Horn, Linda; Tinker, Leslie F.; Shikany, James M.; Eaton, Charles B.; Margolis, Karen L. (1 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. Cite uses deprecated parameter |coauthors= (help);
  81. ↑ Sands-Lincoln, M; Loucks, EB; Lu, B; Carskadon, MA; Sharkey, K; Stefanick, ML; Ockene, J; Shah, N; Hairston, KG; Robinson, JG; Limacher, M; Hale, L; Eaton, CB (June 2013). "Sleep Duration, Insomnia, and Coronary Heart Disease Among Postmenopausal Women in the Women's Health Initiative.". Journal of women's health (2002) 22 (6): 477–86. doi:10.1089/jwh.2012.3918. PMID 23651054.
  82. ↑ Neuhouser, ML; Wassertheil-Smoller, S; Thomson, C; Aragaki, A; Anderson, GL; Manson, JE; Patterson, RE; Rohan, TE; van Horn, L; Shikany, JM; Thomas, A; LaCroix, A; Prentice, RL (Feb 9, 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. PMID 19204221. Cite uses deprecated parameter |coauthors= (help);
  83. ↑ "Extension Study 2". Women's Health Initiative. Retrieved 17 June 2013.
  84. ↑ "Long Life Study". Women's Health Initiative. Retrieved 17 June 2013.
  85. ↑ Chlebowski, Rowan T.; Rohan, Thomas E.; Manson, JoAnn E.; Aragaki, Aaron K.; Kaunitz, Andrew; Stefanick, Marcia L.; Simon, Michael S.; Johnson, Karen C.; Wactawski-Wende, Jean; O’Sullivan, Mary J.; Adams-Campbell, Lucile L.; Nassir, Rami; Lessin, Lawrence S.; Prentice, Ross L. (16 April 2015). "Breast Cancer After Use of Estrogen Plus Progestin and Estrogen Alone". JAMA Oncology 1: 296. doi:10.1001/jamaoncol.2015.0494.
  86. ↑ Chlebowski, R. T.; Anderson, G. L.; Sarto, G. E.; Haque, R.; Runowicz, C. D.; Aragaki, A. K.; Thomson, C. A.; Howard, B. V.; Wactawski-Wende, J.; Chen, C.; Rohan, T. E.; Simon, M. S.; Reed, S. D.; Manson, J. E. (14 December 2015). "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.
  87. ↑ Joshi, Purna A.; Goodwin, Pamela J.; Khokha, Rama (16 April 2015). "Progesterone Exposure and Breast Cancer Risk". JAMA Oncology 1: 283. doi:10.1001/jamaoncol.2015.0512.
  88. ↑ "WHI Bibliography Site". Women's Health Initiative. Retrieved 15 September 2015.
  89. ↑ Gordon, David; Taddei-Peters, Wendy; Mascette, Alice; Antman, Melissa; Kaufmann, Peter G.; Lauer, Michael S. (14 November 2013). "Publication of Trials Funded by the National Heart, Lung, and Blood Institute". New England Journal of Medicine 369 (20): 1926–1934. doi:10.1056/NEJMsa1300237.
  90. ↑ Banks, E; Canfell, K (Jul 1, 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): 24–8. doi:10.1093/aje/kwp113. PMID 19468078.
  91. ↑ Prentice, R. L.; Manson, J. E.; Langer, R. D.; Anderson, G. L.; Pettinger, M.; Jackson, R. D.; Johnson, K. C.; Kuller, L. H.; Lane, D. S.; Wactawski-Wende, J.; Brzyski, R.; Allison, M.; Ockene, J.; Sarto, G.; Rossouw, J. E. (25 May 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. Cite uses deprecated parameter |coauthors= (help);
  92. ↑ Epstein, Franklin H.; Mendelsohn, Michael E.; Karas, Richard H. (10 June 1999). "The Protective Effects of Estrogen on the Cardiovascular System". New England Journal of Medicine 340 (23): 1801–1811. doi:10.1056/NEJM199906103402306.
  93. ↑ Santen, RJ; Utian, WH (2010). "Executive Summary: Postmenopausal Hormone Therapy: An Endocrine Society Scientific Statement" (PDF). J Clin Endocrinol Metab 95 (Supplement 1): S1–S66. doi:10.1210/jc.2009-2509. Retrieved Feb 7, 2013.
  94. ↑ DeAngelis, Catherine D. (22 June 2011). "Onward". JAMA: The Journal of the American Medical Association 305 (24): 2575. doi:10.1001/jama.2011.876. we have published important articles such as ... the landmark Women's Health Initiative study
  95. ↑ 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): 172–6. doi:10.1097/AOG.0b013e31827a08c8. PMID 23262943.
  96. ↑ Nelson, H. D.; Walker, M.; Zakher, B.; Mitchell, J. (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.
  97. ↑ The Caerphilly and Speedwell Collaborative Group (1984). "Caerphilly and Speedwell collaborative heart disease studies". Journal of Epidemiology and Public Health 38 (3): 259–262. doi:10.1136/jech.38.3.259. PMC 1052363. PMID 6332166.
  98. ↑ Elwood P, Galante J, Pickering J, et al. (2013). "Healthy Lifestyles Reduce the Incidence of Chronic Diseases and Dementia: Evidence from the Caerphilly Cohort Study". PLOS ONE 8 (12): e81877. doi:10.1371/journal.pone.0081877. PMC 3857242. PMID 24349147.
  99. ↑ "Nurse's Health Study, Phase 3". Retrieved 29 May 2013.

References

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