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Original Investigation |

Menopausal Hormone Therapy and Health Outcomes During the Intervention and Extended Poststopping Phases of the Women’s Health Initiative Randomized Trials FREE

JoAnn E. Manson, MD, DrPH1; Rowan T. Chlebowski, MD, PhD2; Marcia L. Stefanick, PhD3; Aaron K. Aragaki, MS4; Jacques E. Rossouw, MD5; Ross L. Prentice, PhD4; Garnet Anderson, PhD4; Barbara V. Howard, PhD6; Cynthia A. Thomson, PhD, RD7; Andrea Z. LaCroix, PhD4; Jean Wactawski-Wende, PhD8; Rebecca D. Jackson, MD9; Marian Limacher, MD10; Karen L. Margolis, MD, MPH11; Sylvia Wassertheil-Smoller, PhD12; Shirley A. Beresford, PhD4; Jane A. Cauley, DrPH13; Charles B. Eaton, MD, MS14; Margery Gass, MD, NCMP15; Judith Hsia, MD16; Karen C. Johnson, MD, MPH17; Charles Kooperberg, PhD4; Lewis H. Kuller, MD, DrPH13; Cora E. Lewis, MD, MSPH18; Simin Liu, MD, ScD19; Lisa W. Martin, MD20; Judith K. Ockene, PhD21; Mary Jo O’Sullivan, MD22; Lynda H. Powell, PhD23; Michael S. Simon, MD, MPH24; Linda Van Horn, PhD, RD25; Mara Z. Vitolins, DrPH, RD26; Robert B. Wallace, MD, MSc27
[+] Author Affiliations
1Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
2Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California
3Stanford Prevention Research Center, Stanford, California
4Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
5National Heart, Lung, and Blood Institute, Bethesda, Maryland
6MedStar Health Research Institute and Georgetown/Howard Universities Center for Clinical and Translational Sciences, Washington, DC
7Mel & Enid Zuckerman College of Public Health, University of Arizona, Tucson
8Department of Social and Preventive Medicine, State University of New York, Buffalo
9Division of Endocrinology, Diabetes and Metabolism, Ohio State University, Columbus
10University of Florida, Gainesville/Jacksonville
11HealthPartners Institute for Education and Research, Minneapolis, Minnesota
12Albert Einstein College of Medicine, New York, New York
13Department of Epidemiology, University of Pittsburgh, School of Public Health, Pittsburgh, Pennsylvania
14Department of Family Medicine and Epidemiology, Alpert Medical School of Brown University, Providence, Rhode Island
15North American Menopause Society, Cleveland Clinic and Case Western Reserve University School of Medicine, Cleveland, Ohio
16Clinical Research, AstraZeneca, Wilmington, Delaware
17Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis
18Department of Medicine, University of Alabama, Birmingham
19Departments of Epidemiology and Medicine, Brown University, Providence, Rhode Island
20Cardiology Division, George Washington University School of Medicine and Health Sciences, Washington, DC
21Preventive and Behavioral Medicine, University of Massachusetts Medical School, Worcester
22Department of Obstetrics and Gynecology, Division of Research, University of Miami, Miami, Florida
23Department of Preventive Medicine, Rush University Medical Center, Chicago, Illinois
24Wayne State University, Karmanos Cancer Institute, Detroit, Michigan
25Northwestern University Feinberg School of Medicine, Chicago, Illinois
26Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, North Carolina
27Department of Epidemiology, University of Iowa College of Public Health, Iowa City
JAMA. 2013;310(13):1353-1368. doi:10.1001/jama.2013.278040.
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Published online

Importance  Menopausal hormone therapy continues in clinical use but questions remain regarding its risks and benefits for chronic disease prevention.

Objective  To report a comprehensive, integrated overview of findings from the 2 Women’s Health Initiative (WHI) hormone therapy trials with extended postintervention follow-up.

Design, Setting, and Participants  A total of 27 347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers.

Interventions  Women with an intact uterus received conjugated equine estrogens (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) (n = 8506) or placebo (n = 8102). Women with prior hysterectomy received CEE alone (0.625 mg/d) (n = 5310) or placebo (n = 5429). The intervention lasted a median of 5.6 years in CEE plus MPA trial and 7.2 years in CEE alone trial with 13 years of cumulative follow-up until September 30, 2010.

Main Outcomes and Measures  Primary efficacy and safety outcomes were coronary heart disease (CHD) and invasive breast cancer, respectively. A global index also included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death.

Results  During the CEE plus MPA intervention phase, the numbers of CHD cases were 196 for CEE plus MPA vs 159 for placebo (hazard ratio [HR], 1.18; 95% CI, 0.95-1.45) and 206 vs 155, respectively, for invasive breast cancer (HR, 1.24; 95% CI, 1.01-1.53). Other risks included increased stroke, pulmonary embolism, dementia (in women aged ≥65 years), gallbladder disease, and urinary incontinence; benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Most risks and benefits dissipated postintervention, although some elevation in breast cancer risk persisted during cumulative follow-up (434 cases for CEE plus MPA vs 323 for placebo; HR, 1.28 [95% CI, 1.11-1.48]). The risks and benefits were more balanced during the CEE alone intervention with 204 CHD cases for CEE alone vs 222 cases for placebo (HR, 0.94; 95% CI, 0.78-1.14) and 104 vs 135, respectively, for invasive breast cancer (HR, 0.79; 95% CI, 0.61-1.02); cumulatively, there were 168 vs 216, respectively, cases of breast cancer diagnosed (HR, 0.79; 95% CI, 0.65-0.97). Results for other outcomes were similar to CEE plus MPA. Neither regimen affected all-cause mortality. For CEE alone, younger women (aged 50-59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index (nominal P < .05 for trend by age). Absolute risks of adverse events (measured by the global index) per 10 000 women annually taking CEE plus MPA ranged from 12 excess cases for ages of 50-59 years to 38 for ages of 70-79 years; for women taking CEE alone, from 19 fewer cases for ages of 50-59 years to 51 excess cases for ages of 70-79 years. Quality-of-life outcomes had mixed results in both trials.

Conclusions and Relevance  Menopausal hormone therapy has a complex pattern of risks and benefits. Findings from the intervention and extended postintervention follow-up of the 2 WHI hormone therapy trials do not support use of this therapy for chronic disease prevention, although it is appropriate for symptom management in some women.

Trial Registration  clinicaltrials.gov Identifier: NCT00000611

Figures in this Article

The Women’s Health Initiative (WHI) trials were designed to determine the benefits and risks of hormone therapy when taken for chronic disease prevention by predominantly healthy postmenopausal women.13 Although originally prescribed primarily to treat vasomotor symptoms, menopausal hormone therapy had been increasingly viewed as a way to prevent many chronic diseases of aging, including coronary heart disease (CHD) and cognitive impairment.4,5 At least 40% of postmenopausal women in the United States were using hormone therapy shortly before the publication of the initial WHI findings.6 Even though observational studies had suggested net benefit for hormone therapy use,4,5 no previous large-scale randomized prevention trial had addressed the balance of risks and benefits. In this context, the WHI hormone therapy trials were conceived and the most commonly used hormone therapy formulations in the United States at that time, conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) and CEE alone, were chosen as the interventions.1

Findings from the 2 hormone therapy trials have been published in numerous journals during the past decade2,3,715 (a full listing of previous reports appears in the Supplement), but no previous WHI publication has synthesized results for primary, secondary, and quality-of-life outcomes of the 2 trials during their intervention and postintervention phases. In addition, for some end points, analyses have not been previously stratified by age or time since menopause. The goal of this report is to provide a comprehensive, integrated overview of findings from the 2 WHI hormone therapy trials with extended postintervention follow-up (median, 13 years of cumulative follow-up) and stratification by age and other important variables.

Study Design

Details of the 2 WHI hormone therapy trial designs and outcome adjudication procedures have been published.13 Briefly, 27 347 postmenopausal women aged 50 to 79 years were recruited from 1993 to 1998 at 40 US clinical centers; 16 608 women with a uterus were randomized to oral CEE (0.625 mg/d) plus MPA (2.5 mg/d) (Prempro) or placebo and 10 739 women with prior hysterectomy were randomized to oral CEE (0.625 mg/d) alone (Premarin) or placebo. The primary efficacy and safety outcomes of the trial were CHD and invasive breast cancer, respectively. The sample sizes were based on power to detect effects on these outcomes.1

Institutional review board approval was obtained at each clinical center and all participants provided written informed consent. Race and ethnicity were self-reported. Postintervention follow-up through September 30, 2010, is based on 81.1% of surviving participants who provided additional written informed consent. Following stopping of the interventions, fewer than 4% of women reported personal use of hormone therapy. Comparisons during the postintervention phase need to be interpreted in the context of possible selection due to effects in the preceding intervention phase and partial consent to further follow-up after 2005.

Statistical Analysis

For each trial, intervention phase analyses included all randomized participants according to their randomization assignment until last intervention contact, using time-to-event methods based on the intention-to-treat principle. A global index of the monitored clinical events was calculated as time to first event for CHD, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, endometrial cancer (for CEE plus MPA only), hip fractures, and death from all other causes.

Hazard ratios (HRs) were estimated using Cox proportional hazards models stratified by age, prior disease (if appropriate), and randomization status in the WHI dietary modification trial. Models were constructed for each clinical end point with women contributing follow-up time until the end of the study phase, date of their first relevant clinical event, death, or withdrawal from the study, whichever came first. Comparisons during the postintervention phase include randomized participants in active follow-up and at risk for an initial diagnosis of the relevant outcome. Cumulative results represent overall findings. The HRs may exhibit time dependencies within or between phases, as previously reported.14,15

All statistical tests are 2-sided and nominal P values of .05 or less are regarded as significant. The P values do not adjust for multiple outcomes, sequential monitoring, or multiple subgroup comparisons due to the large number of tests conducted; therefore, the P values should be interpreted cautiously. Inference on subgroup analyses rely primarily on tests for interaction, which are also subject to multiple testing limitations when a large number of tests are conducted. Subgroup analyses, stratifying on age and time since menopause, are reported for most outcomes. Tests were based on a 1 degree of freedom for trend in which models included a randomization group × baseline group interaction term, which was coded ordinally.

Adherence sensitivity analyses, conducted by censoring follow-up 6 months after nonadherence (taking <80% of study pills or starting nonprotocol hormone therapy), included time-varying weights (inversely proportional to the estimated probability of continued adherence) in proportional hazards models that adjusted for changes in the distribution of sample characteristics during follow-up. For secondary and quality-of-life outcomes, results are provided for the intervention phase and, when available, for the postintervention and cumulative follow-up period.

Additional analyses were conducted among women with no prior hormone therapy use before entry as well as stratified by vasomotor symptoms at enrollment. All statistical analyses were conducted using SAS software version 9.3 (SAS Institute Inc) and R software version 2.15 (R Foundation for Statistical Computing).

Baseline Characteristics

Baseline characteristics for the 2 randomization groups in each trial were well balanced according to demographic and disease risk factors (Table). However, several differences are seen when comparing characteristics between trials. Compared with CEE plus MPA trial participants, women in the CEE alone trial were more racially diverse, more distant from menopause onset, had less favorable cardiovascular risk profiles, and more commonly had oophorectomy and prior hormone therapy use.

Table Graphic Jump LocationTable.  Baseline Characteristics of Participants in the 2 WHI Hormone Therapy Trials

The intervention phase of the CEE plus MPA trial ended on July 7, 2002 (after a median of 5.6 years [interquartile range {IQR}, 4.8-6.5 years]) due to increased breast cancer risk and an unfavorable risk-to-benefit ratio with CEE plus MPA.2 The intervention phase of the CEE alone trial ended on February 29, 2004 (after a median of 7.2 years [IQR, 6.4-8.1 years]) due to increased stroke incidence that was not offset by lower CHD risk in the hormone therapy group.3 Some HRs differ slightly from those previously reported due to the more complete outcome ascertainment in the present report. After the intervention phases ended, the follow-up phases continued through September 30, 2010, among surviving participants who provided additional written consent. The cumulative results reported herein include a median postintervention follow-up of 8.2 years (IQR, 6.6-8.2 years) for the CEE plus MPA trial and a median cumulative follow-up of 13.2 years (IQR, 10.5-14.2 years); for the CEE alone trial, the median postintervention follow-up was 6.6 years (IQR, 3.8-6.6 years) and the median cumulative follow-up was 13.0 years (IQR, 9.1-14.1 years) (Figure 1).

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Figure 1.
Women’s Health Initiative Trials of Menopausal Hormone Therapy Through Extended Follow-up

There were 342 306 women who were ineligible or unwilling to participate in the hormone therapy trials. The postintervention phase began on the day after participants were instructed to stop study medication use and continued through the original trial completion date. During the extension phase, there was follow-up for those who provided additional consent (conjugated equine estrogens plus medroxyprogesterone acetate or placebo trial: 83% of those eligible and 2.8% dropped out; conjugated equine estrogens alone or placebo trial: 78% of those eligible and 3.0% dropped out).

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Primary End Points in the 2 Trials: Intervention, Postintervention, and Cumulative Results

The intervention results for CHD and invasive breast cancer (the primary efficacy and safety outcomes, respectively) in the 2 trials are presented in Figure 2. The higher absolute risks for these and other major health outcomes among women in older compared with younger age groups appear in Figure 3. Results for the postintervention and cumulative follow-up phases appear in Figure 4 and eFigure 1 in Supplement. The figures include the number of incident cases (events), absolute risk differences (cases per 10 000 person-years for each end point in the CEE plus MPA or CEE alone groups minus the placebo groups), HRs, 95% confidence intervals, and forest plots of the HRs and 95% confidence intervals for the 2 trials.

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Figure 2.
Health Outcomes in the Overall Study Population in the Women’s Health Initiative Hormone Therapy Trials During the Intervention Phase

CABG indicates coronary artery bypass graft; CEE, conjugated equine estrogens; HR, hazard ratio; MI, myocardial infarction; MPA, medroxyprogesterone acetate; NA, not applicable due to hysterectomy; NR, not reported due to small numbers; PCI, percutaneous coronary intervention; PY, person-years. aPercentages are annualized. bDifference in estimated absolute excess risks (hormone therapy minus placebo). cIndicates CEE alone or CEE plus MPA. dExcludes non–melanoma skin cancer. eIn women aged 65 years or older. fIn women not reporting condition at baseline. gCollected at year 1. hIn symptomatic women aged 50 to 54 years.

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Figure 3.
Absolute Risks of Health Outcomes by 10-Year Age Groups in the Women’s Health Initiative Hormone Therapy Trials During the Intervention Phase

None of the age interactions were statistically significant (at the P < .05 level), except for colorectal cancer, all-cause mortality, myocardial infarction, and the global index in the CEE alone trial (details appear in Figure 5). CEE indicates conjugated equine estrogens; MPA, medroxyprogesterone acetate.

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Figure 4.
Postintervention Health Outcomes and Overall Combined Outcomes (Cumulative Follow-up) in the Overall Study Population in the Women’s Health Initiative Hormone Therapy Trials

The all cardiovascular events outcome is defined in the Results section. CABG indicates coronary artery bypass graft; CEE, conjugated equine estrogens; HR, hazard ratio; MI, myocardial infarction; MPA, medroxyprogesterone acetate; NA, not applicable because women have had hysterectomy; NR, not reported due to small numbers; PCI, percutaneous coronary intervention; PY, person-years. aThe percentages are annualized. bDifference in estimated absolute excess risks (CEE plus MPA or CEE alone minus placebo). cIndicates CEE alone or CEE plus MPA. dExcludes non–melanoma skin cancer. eIncludes participants who did not report a prevalent condition at baseline.

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Coronary Heart Disease

Coronary heart disease was defined as nonfatal myocardial infarction (MI) or coronary death. Results for total MI, which was a secondary end point, are reported separately below.

Intervention Phase

Results for CHD differed between the 2 trials (Figure 2). Women assigned to CEE plus MPA had an HR of 1.18 (95% CI, 0.95-1.45) compared with placebo. The HR at year 1 was 1.80 (95% CI, 1.08-2.99), but was less elevated or neutral in subsequent years (P = .03 for trend by time). Women assigned to CEE alone had an HR of 0.94 (95% CI, 0.78-1.14) compared with placebo; the HRs did not differ appreciably by year since randomization (P = .21 for trend by time).

Postintervention and Cumulative Follow-up Phases

The postintervention results in both trials were neutral (Figure 4). During cumulative 13-year follow-up, the HRs for CHD were 1.09 (95% CI, 0.96-1.24) for CEE plus MPA and 0.94 (95% CI, 0.82-1.09) for CEE alone compared with the placebo groups (Figure 4).

Stratified Analyses by Age and Time Since Menopause

In the CEE plus MPA trial, the HRs were similar by age (Figure 5); however, there was a nonsignificant difference by time since menopause onset compared with the placebo group (P = .08 for trend), with significantly elevated risk among women who were more than 20 years past menopause onset (eFigure 2 in Supplement). In the CEE alone trial, a nonsignificant but lower CHD risk in younger women was suggested compared with the placebo group (P = 0.08 for trend; Figure 5). Statistically significant differences by age or proximity to menopause for MI are described later.

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Figure 5.
Health Outcomes in the Women’s Health Initiative Hormone Therapy Trials During the Intervention Phase According to 10-Year Age Groups at Randomization

CABG indicates coronary artery bypass graft; CEE, conjugated equine estrogens; HR, hazard ratio; MI, myocardial infarction; MPA, medroxyprogesterone acetate; NA, not applicable because women have had hysterectomy; PCI, percutaneous coronary intervention; PY, person-years. aThe percentages are annualized. bDifference in estimated absolute excess risks (CEE plus MPA or CEE alone minus placebo). cFor trend by age group. dIndicates CEE alone or CEE plus MPA. eExcludes non–melanoma skin cancer.

Graphic Jump Location
Invasive Breast Cancer
Intervention Phase

Results for invasive breast cancer differed between the 2 trials. Women assigned to CEE plus MPA had an HR of 1.24 (95% CI, 1.01-1.53) for breast cancer compared with the placebo group (Figure 2). The HRs progressively increased by time since randomization (P = .005 for time trend), with cancer cases diagnosed at more advanced stages.16 In contrast, women assigned to CEE alone had an HR of 0.79 (95% CI, 0.61-1.02) compared with the placebo group and the HRs did not differ by time since randomization.

Postintervention and Cumulative Follow-up

The HR for invasive breast cancer with CEE plus MPA remained statistically significantly elevated during postintervention and cumulative follow-up compared with the placebo group (HR for cumulative follow-up, 1.28 [95% CI, 1.11-1.48]; Figure 4 and eFigure 1 in Supplement); however, more detailed time-dependent analyses identified risk attenuation with time since cessation of hormone therapy use.17 For women assigned to CEE alone, the risk reduction became statistically significant during cumulative follow-up (HR, 0.79 [95% CI, 0.65-0.97]; Figure 4).

Stratified Analyses

No appreciable differences by age or time since menopause onset emerged (Figure 5 and Figure 6; eFigure 2 in Supplement).

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Figure 6.
Health Outcomes in the Women’s Health Initiative Hormone Therapy Trials for the Overall Combined Phases (Cumulative Follow-up) According to 10-Year Age Groups at Randomization

CABG indicates coronary artery bypass graft; CEE, conjugated equine estrogens; HR, hazard ratio; MI, myocardial infarction; MPA, medroxyprogesterone acetate; NA, not applicable because women have had hysterectomy; PCI, percutaneous coronary intervention; PY, person-years. aThe percentages are annualized. bDifference in estimated absolute excess risks (CEE plus MPA or CEE alone minus placebo). cFor trend by age group. dIndicates CEE alone or CEE plus MPA. eExcludes non–melanoma skin cancer.

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Other End Points in the Global Index: Intervention and Postintervention Results
Stroke
Intervention Phase

Stroke risk was increased with CEE plus MPA (HR, 1.37) and with CEE alone (HR, 1.35) compared with the placebo groups (Figure 2), reflecting increased ischemic but not hemorrhagic stroke risk.10,11

Postintervention and Cumulative Follow-up

The postintervention results were neutral in both trials (eFigure 1 in Supplement). Cumulatively, the HRs for stroke were higher in the hormone therapy groups compared with the placebo groups in both trials (HR, 1.16 for CEE plus MPA; HR, 1.15 for CEE alone) (Figure 4).

Stratified Analyses

No appreciable differences by subgroups were seen in either trial (Figures 5-6 and eFigure 2 in Supplement).

Pulmonary Embolism
Intervention Phase

A statistically significant increase in pulmonary embolism risk was seen in women assigned to CEE plus MPA (HR, 1.98) compared with the placebo group (Figure 2), whereas the increase in pulmonary embolism risk was not statistically significant in women assigned to CEE alone (HR, 1.35).

Postintervention and Cumulative Follow-up

Poststopping results were neutral in both trials (eFigure 1 in Supplement). Cumulatively, the HRs were 1.26 (95% CI, 1.00-1.59) for CEE plus MPA and 1.15 (95% CI, 0.87-1.51) for CEE alone compared with the placebo groups (Figure 4).

Stratified Analyses

No appreciable differences by age or time since menopause onset were seen in either trial (Figures 5-6 and eFigure 2 in Supplement).

Colorectal Cancer
Intervention Phase

Results for colorectal cancer differed between the 2 trials. For women assigned to CEE plus MPA, the HR was 0.62 (95% CI, 0.43-0.89) compared with the placebo group (Figure 2), but the cancer cases were diagnosed at a more advanced stage.18 For women assigned to CEE alone, hormone therapy did not affect colorectal cancer incidence (HR, 1.15; 95% CI, 0.81-1.64).

Postintervention and Cumulative Follow-up

Poststopping and cumulative HRs were neutral in both trials (Figure 4 and eFigure 1 in Supplement).

Stratified Analyses

For women assigned to CEE alone, results were more adverse in older compared with younger women (P = .02 for trend), but age differences were not apparent for those assigned to CEE plus MPA (Figure 5).

Endometrial Cancer
Intervention Phase

Women in the CEE plus MPA group compared with the placebo group had an HR of 0.83 (95% CI, 0.49-1.40; Figure 2).

Postintervention and Cumulative Follow-up

A reduced risk of endometrial cancer with CEE plus MPA emerged postintervention (HR, 0.58; 95% CI, 0.40-0.86) compared with the placebo group (eFigure 1 in Supplement) and for cumulative follow-up (HR, 0.67 [95% CI, 0.49-0.91]; Figure 4).

Hip Fracture
Intervention Phase

Women in the CEE plus MPA and CEE alone groups compared with the placebo groups had statistically significant 33% reductions in hip fracture (Figure 2).

Postintervention and Cumulative Follow-up

The risk reductions were attenuated in both trials postintervention (eFigure 1 in Supplement); however, a significant fracture benefit persisted over 13 years for women assigned to CEE plus MPA (HR, 0.81 [95% CI, 0.68-0.97]; Figure 4).

Stratified Analyses

Results in the CEE alone trial were more favorable for women with greater time since menopause onset (eFigure 2 in Supplement).

All-Cause Mortality
Intervention Phase

Neither CEE plus MPA nor CEE alone affected all-cause mortality (Figure 2).

Postintervention and Cumulative Follow-up

All-cause mortality remained neutral postintervention and during cumulative follow-up in both trials (Figure 4). The cumulative follow-up HR was 0.99 (95% CI, 0.91-1.08) for CEE plus MPA compared with placebo and 0.99 (95% CI, 0.90-1.10) for CEE alone compared with placebo (Figure 4).

Stratified Analyses

In both trials, patterns of more favorable results for all-cause mortality in younger than older women were apparent during the intervention phase. Among women aged 50 to 59 years, the HRs were 0.67 (95% CI, 0.43-1.04) in the CEE plus MPA trial and 0.70 (95% CI, 0.46-1.09) in the CEE alone trial; however, the HRs ranged from 1.01 to 1.21 among women aged 60 to 79 years (Figure 5). The nominal P value for trend by age was only significant (P = .04) in the CEE alone trial. Trends with time since menopause onset were similar but not significant (eFigure 2 in Supplement).

Global Index
Intervention Phase

Overall, the health risks of CEE plus MPA significantly outweighed the benefits. For the global index of monitored events, which included the outcomes listed above, the HR was elevated for CEE plus MPA at 1.12 (95% CI, 1.02-1.24) compared with placebo (Figure 2). In absolute terms, for every 10 000 women taking CEE plus MPA per year, there were 6 more coronary events, 9 more strokes, 9 more pulmonary emboli, 9 more cases of breast cancer, 6 fewer cases of colorectal cancer, 1 fewer case of endometrial cancer, 6 fewer hip fractures, and 1 fewer death, yielding a net effect of 20 additional adverse events per 10 000 person-years (Figure 2 and Figure 3). The corresponding HR for the global index for CEE alone was 1.03 (95% CI, 0.93-1.13) with a net of 4 adverse events.

Postintervention and Cumulative Follow-up

Because most risks became attenuated after stopping therapy, the global index was neutral for both trials postintervention and cumulatively (Figure 4 and eFigure 1 in Supplement).

Stratified Analyses

The global index HR for women assigned to CEE plus MPA was not modified by age (P > .99 for trend); however, for women assigned to CEE alone, the HR was more favorable in younger women (P = .02 for trend; Figure 5). The absolute risks of adverse events were lower in both trials in younger than older women. For CEE plus MPA compared with placebo, women aged 50 to 59 years had 12 more adverse events per 10 000 person-years; 60 though 69 years, 22 more; and 70 to 79 years, 38 more. For CEE alone compared with placebo, women aged 50 to 59 years had 19 fewer adverse events per 10 000 person-years, whereas women aged 70 to 79 years had 51 more adverse events per 10 000 person-years (Figure 5).

Effect modification by age for CEE alone was more pronounced during cumulative follow-up (P = .01 for trend by age). Compared with placebo, there were 26 fewer adverse events per 10 000 person-years among women aged 50 to 59 years assigned to CEE alone and 33 more adverse events per 10 000 person-years among those aged 70 to 79 years (Figure 6).

Secondary End Points in the 2 Trials: Intervention and Postintervention Results

The results for other clinical end points in the trial are summarized herein but more details are available in the Supplement.

Myocardial Infarction

Overall, results for MI were similar to those for CHD (Figure 2). However, differences by age or time since menopause onset emerged during the intervention phase of both trials. For CEE plus MPA, statistically significant differences were apparent by time since menopause onset (HRs were 0.91, 1.16, and 1.99 with increasing decade past menopause onset, respectively; P = .01 for trend; eFigure 2 in Supplement) but not by age (Figure 5). For CEE alone, the HRs increased with increasing decade of age (HRs of 0.55 for 50-59 years, 0.95 for 60-69 years, and 1.24 for 70-79 years; P = .02 for trend; Figure 5 and eFigure 3 in Supplement). Cumulatively, the differences by time since menopause onset for CEE plus MPA persisted (P = .02 for trend) and the differences by age for CEE alone became more pronounced (P = .007 for trend; Figure 6).

Other Secondary Cardiovascular Disease Outcomes

Results for coronary artery bypass graft or percutaneous coronary intervention were neutral in both trials; findings for deep vein thrombosis generally paralleled those for pulmonary embolism (Figure 2 and Figure 4). The all cardiovascular events outcome in Figure 2 includes MI, stroke, coronary artery bypass graft or percutaneous coronary intervention, angina, heart failure, carotid artery disease, peripheral vascular disease, venous thromboembolism, and cardiovascular death. The HRs were significantly elevated for total cardiovascular events during the intervention phase of both trials, but were neutral during the postintervention phase. For cardiovascular death, results were neutral throughout the trial phases (Figure 2, Figure 4, and eFigure 1 in Supplement).

Secondary Cancer Outcomes

The incidence of lung and ovarian cancer did not differ significantly between randomization groups (Figure 2 and Figure 4). An adverse effect of CEE plus MPA, but not CEE alone, on lung cancer mortality has been observed in the WHI.19,20 Neither intervention was associated with total cancer incidence (ie, all cancer types in Figure 2 and Figure 4); the cumulative HR was 1.04 (95% CI, 0.96-1.12) for CEE plus MPA and 0.93 (95% CI, 0.84-1.04) for CEE alone (Figure 4). Women aged 50 to 59 years in the CEE alone group had a lower cumulative incidence of total cancer compared with the placebo group (HR, 0.80 [95% CI, 0.64-0.99]; ie, all cancer types in Figure 6), but age interactions were not significant.

During the intervention phase, total cancer mortality did not differ between randomization groups in either trial (Figure 2); during cumulative follow-up, the HRs were 1.07 (95% CI, 0.93-1.23) for CEE plus MPA and 0.95 (95% CI, 0.81-1.13) for CEE alone. When examined by age, the HRs for total cancer mortality in the CEE alone trial were more adverse for women older than 70 years (HRs for increasing age groups were 0.77, 0.77, 1.36; P = .05 for trend; eFigure 3 in Supplement), but this trend was not significant in cumulative results (eFigure 4 in Supplement). No effect modification by age or time since menopause onset was detected for cancer mortality in the CEE plus MPA trial.

Clinical Vertebral and Total Fractures

In both trials, results for clinical vertebral and total fractures paralleled those for hip fracture (Figure 2 and eFigure 3 in Supplement).

Dementia

A subset of WHI participants aged 65 years or older at enrollment underwent cognitive testing in the WHI memory study.21,22 The HRs for probable dementia were 2.01 (95% CI, 1.19-3.42) during the intervention phase of the CEE plus MPA trial and 1.47 (95% CI, 0.85-2.52) for the CEE alone trial (Figure 2). For women aged 50 to 55 years at randomization, cognitive assessments that were conducted an average of 7.2 years postintervention showed neutral results.23

Self-reported End Points, Self-reported Symptoms, and Quality-of-Life Outcomes in the 2 Trials

In both trials, women assigned hormone therapy had significantly lower rates of treated diabetes than women assigned placebo (HR, 0.81 [95% CI, 0.70-0.94] for CEE plus MPA and 0.86 [95% CI, 0.76-0.98] for CEE alone; Figure 2). However, rates of gallbladder disease were approximately 50% higher among women assigned to hormone therapy in both trials (Figure 2). Self-reported urinary incontinence24 (at least once/week) was also higher in women assigned to CEE plus MPA (HR, 1.49; 95% CI, 1.36-1.63) or CEE alone (HR, 1.61; 95% CI, 1.46-1.79) than in those assigned to placebo (Figure 2) and were attenuated but still higher poststopping in both trials (eFigure 1 in Supplement). The reductions in diabetes dissipated postintervention in both trials (Figure 4 and eFigure 1 in Supplement), whereas the HRs for gallbladder disease were attenuated but still elevated for CEE plus MPA and became neutral for CEE alone. No significant differences by age group were observed for these outcomes.

Among younger women (aged 50-54 years) experiencing moderate or severe hot flashes, night sweats, or both at enrollment (n = 979), those in both the CEE plus MPA and CEE alone groups had substantial reductions in symptoms (64% and 28%, respectively, vs placebo at 1 year; Figure 2). In the overall cohort, women assigned to CEE plus MPA and CEE alone reported less sleep disturbances (assessed by a 5-item validated scale25,26), but more breast tenderness than in those receiving placebo (Figure 2 and eFigure 5 in Supplement). Women receiving CEE plus MPA were less likely to have joint pain than those receiving placebo.

Regarding health-related quality of life (RAND 36-Item Short Form Health Survey),9,27 treatment with CEE plus MPA compared with placebo was associated with a small but statistically significant benefit for physical functioning, role physical, bodily pain, and general health, and neutral results for the other subscales at 1 year (eFigure 5 in Supplement). Treatment with CEE alone was associated with nominally significant adverse effects for social functioning and emotional role (eFigure 5 in Supplement). No significant differences in depressive symptom scores were observed. Postintervention symptoms of breast tenderness were similar between treatment groups in both trials but the direction of some of the other associations was reversed (eFigure 1 in Supplement), particularly joint pain. Additional information about other patient-reported outcomes appears in the Supplement.

Additional Analyses Conducted in the 2 Trials
Women Without Prerandomization Use of Hormone Therapy

Approximately one-quarter of CEE plus MPA trial participants and half of CEE alone trial participants had used hormone therapy prior to randomization. To simulate first initiation of hormone therapy in clinical practice, secondary analyses were conducted to assess women without hormone therapy use prior to randomization, stratified by age group (eFigure 6 in Supplement). The age-stratified findings remained similar to the primary analysis for the CEE plus MPA trial, but were slightly more favorable for younger women in the CEE alone trial. Among women aged 50 to 59 years without prior hormone therapy use, the global index was significantly better for those assigned CEE alone compared with placebo (HR, 0.71; 95% CI, 0.50-0.99). There were 40 fewer adverse events per 10 000 person-years in this age group in the CEE alone group compared with 34 excess events per 10 000 person-years among women aged 70 to 79 years.

Analyses Stratified by Vasomotor Symptoms at Baseline

Women aged 70 to 79 years with moderate to severe vasomotor symptoms at baseline assigned to CEE plus MPA had an HR for CHD of 5.79 (95% CI, 1.29-25.97), whereas women in younger age groups (with or without vasomotor symptoms) did not have significantly elevated CHD risks (eFigure 7 in Supplement). Similarly, women aged 70 to 79 years who had moderate to severe vasomotor symptoms and were assigned to CEE alone had an HR for CHD of 4.34 (95% CI, 1.43-13.14) compared with women assigned placebo, whereas women in younger age groups (with or without vasomotor symptoms) had no excess risk. Thus, CHD risk with both hormone therapy regimens was particularly high in the small group of women aged 70 years or older with moderate to severe vasomotor symptoms (n = 392; 4.8% and 8.7% of women in this age group in the CEE plus MPA and CEE alone trials, respectively), but the 3-way interactions by age and vasomotor symptoms were nominally significant only when CEE was taken alone (P = .04). Such interactions were not observed for other disease outcomes.

Sensitivity Analyses Censoring for Noncompliance With Study Pills

Secondary analyses among adherent women (censoring women within 6 months of reporting <80% compliance with study pills) were generally similar to intention-to-treat results but tended to accentuate the findings in each trial. For example, the intervention phase adherence-adjusted HR for CHD was 1.32 (95% CI, 1.00-1.75) in the CEE plus MPA trial and 0.85 (95% CI, 0.64-1.14) in the CEE alone trial, whereas the HR for breast cancer was 1.52 (95% CI, 1.15-2.00) in the CEE plus MPA trial and 0.58 (95% CI, 0.39-0.84) in the CEE alone trial.

Other Analyses

A detailed presentation of biomarker findings and analyses stratified by other baseline characteristics is beyond the scope of this article. However, several additional analyses with potential relevance to clinical decision making about hormone therapy appear in the Supplement.

This report provides a comprehensive overview of findings from the intervention and extended postintervention phases of the CEE plus MPA and CEE alone trials of the WHI, representing 13 years of cumulative follow-up. Key findings include differences in the benefit-to-risk profile for CEE plus MPA compared with CEE alone, and the role of age, time since menopause onset, and other factors in modifying the effects of hormone therapy on some outcomes.

Overall, the risks of CEE plus MPA therapy during the intervention phase outweighed the benefits. Most risks and benefits from CEE plus MPA dissipated postintervention; however, cardiovascular disease events remained nonsignificantly elevated, a reduction in endometrial cancer emerged, hip fractures remained cumulatively reduced, and breast cancer HRs remained above unity. Among women with prior hysterectomy, the benefits and risks of CEE alone therapy during the intervention phase were more balanced, with increased risks of stroke and venous thrombosis, reduced risk of hip and total fractures, and a nonsignificant reduction in invasive breast cancer. A significant decrease in breast cancer emerged postintervention among women assigned CEE alone, but most other outcomes were neutral. Thus, breast cancer findings were divergent between the 2 trials and, for both cancer and cardiovascular disease outcomes, results tended to be more adverse for CEE plus MPA than for CEE alone.

The effects of hormone therapy on clinical outcomes were influenced in some cases by age or time since onset of menopause. For CEE alone during the intervention phase, results were more favorable for younger than older women for all-cause mortality, MI, deaths due to cancer, and the global index. Both regimens, however, were associated with increased risk of stroke, venous thrombosis, gallbladder disease, and urinary incontinence, without clear differences by age. For CEE plus MPA, invasive breast cancer was an additional adverse effect and, although risk of MI varied by time since menopause onset, the overall risks outweighed the benefits across all age groups.

The potential influence of age or time since menopause onset on the relationship between hormone therapy and vascular disease has received considerable attention.2832 It has been postulated that estrogen may slow down the early stages of atherosclerosis and have favorable endothelial effects in women with recent onset of menopause but have adverse and plaque-destabilizing effects on advanced atherosclerotic lesions.28,32 Overall, the WHI findings suggest that hormone therapy has a harmful effect on CHD risk among older women, whereas the results in younger women remain inconclusive. Lower absolute risks of adverse events with hormone therapy in younger women, however, lead to lower attributable risks in these age groups. Whether menopausal hormone therapy has a particularly adverse effect on coronary risk in older women with vasomotor symptoms remains unclear.3335 These symptoms have been associated with higher coronary risk in some reports,33,35 and have been previously linked to adverse outcomes with hormone therapy among women with prevalent CHD.36 Due to the small sizes of these subgroups in the WHI and other studies, however, further research is needed.

Treatment with CEE plus MPA increased breast cancer incidence and cancer cases were diagnosed at a higher cancer stage, likely reflecting diagnostic delay due to interference with mammographic detection.37 Although a residual elevation in breast cancer risk was seen with CEE plus MPA postintervention, analyses demonstrated year-to-year reductions in HRs after stopping hormone therapy. In contrast, the significant reduction in breast cancer seen with CEE alone38,39 was unexpected and differs from the results of many observational studies.40,41 Although differential mammography use in those with hormone therapy use compared with those with nonuse of hormone therapy in observational studies may explain some of the differences, the opposite findings for CEE alone compared with CEE plus MPA in the randomized trials points to a determinant influence of progestin on the breast epithelium.42 Full discussion of the complex processes mediating these differences43,44 is beyond the scope of this report.

Fewer colorectal cancer cases were diagnosed during the CEE plus MPA intervention phase but the cancer cases were diagnosed at a higher stage, potentially reflecting differential detection (Supplement).18 Treatment with CEE plus MPA reduced the risk of endometrial cancer; however, both hormone therapy regimens may increase ovarian cancer risk.45 Women treated with CEE plus MPA had increased rates of death from (but not incidence of) lung cancer, whereas no effect on these outcomes was seen in women treated with CEE alone.20 Neither treatment with CEE plus MPA nor CEE alone influenced total cancer incidence or total cancer mortality.

Both CEE plus MPA and CEE alone reduced diabetes risk during the intervention phase, which is when improvements in measured glucose and insulin levels also were documented46,47; however, the risk reductions dissipated postintervention. Both regimens increased risks for venous thrombosis and gallbladder disease. Among participants aged 65 years or older, hormone therapy increased probable dementia risk, with results for CEE plus MPA more adverse than for CEE alone. Women aged 50 to 54 years with moderate to severe vasomotor symptoms at baseline experienced symptom reductions with hormone therapy, and women overall had fewer sleep disturbances and joint pain, although incidence of rheumatoid arthritis was not reduced.48 Overall, results for self-reported symptoms with both interventions were mixed and few additional quality-of-life benefits were observed.

Despite the large size and numerous strengths of the WHI randomized hormone therapy trials, some limitations warrant consideration. Only 1 dose, formulation, and route of administration in each trial was assessed; thus, results are not necessarily generalizable to other hormone preparations. Event information collected poststopping represents unblinded reporting and nearly 20% of surviving participants did not consent to extended follow-up. Multiple outcomes and subgroups (some with low power) were examined, potentially leading to both false-positive and false-negative results. Thus, the nominal P values and 95% confidence intervals presented herein should be interpreted cautiously.

In summary, current WHI findings based on results from the intervention, postintervention, and cumulative follow-up phases do not support the use of either CEE plus MPA or CEE alone for chronic disease prevention. The risks of CEE plus MPA outweigh the benefits irrespective of a woman’s age; however, a more favorable risk-to-benefit ratio was seen in younger women with prior hysterectomy who received CEE alone. Increased risks of stroke and venous thrombosis, as well as gallstones and urinary incontinence, in both younger and older women remain a concern with both regimens. Even though hormone therapy is a reasonable option for the management of moderate to severe menopausal symptoms among generally healthy women during early menopause, the risks associated with hormone therapy, in conjunction with the multiple testing limitations attending subgroup analyses, preclude a recommendation in support of its use for disease prevention even among younger women. Current findings also suggest caution when considering hormone therapy treatment in older age groups, even in the presence of persistent vasomotor symptoms, given the high risk of CHD and other outcomes associated with hormone therapy use in this setting.

Corresponding Author: JoAnn E. Manson, MD, DrPH, Brigham and Women’s Hospital, Harvard Medical School, 900 Commonwealth Ave, Third Floor, Boston, MA 02215 (jmanson@rics.bwh.harvard.edu).

Author Contributions: Dr Manson and Mr Aragaki had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design : Manson, Stefanick, Rossouw, Prentice, Anderson, Howard, Thompson, Wactawski-Wende, Eaton, Johnson, Kooperberg, Lewis, Liu, Powell, Wallace.

Acquisition of data: Manson, Chlebowski, Stefanick, Prentice, Anderson, Howard, LaCroix, Wactawski-Wende, Jackson, Limacher, Wassertheil-Smoller, Beresford, Gass, Hsia, Johnson, Kooperberg, Lewis, Liu, Ockene, O’Sullivan, Powell, Van Horn, Vitolins, Wallace.

Analysis and interpretation of data: Manson, Chlebowski, Stefanick, Aragaki, Rossouw, Prentice, Anderson, Howard, LaCroix, Jackson, Limacher, Margolis, Wassertheil-Smoller, Beresford, Cauley, Hsia, Johnson, Kooperberg, Kuller, Liu, Martin, Powell, Simon, Van Horn, Vitolins.

Drafting of the manuscript: Manson, Aragaki, Rossouw.

Critical revision of the manuscript for important intellectual content: Manson, Chlebowski, Stefanick, Aragaki, Rossouw, Prentice, Anderson, Howard, Thomson, LaCroix, Wactawski-Wende, Jackson, Limacher, Margolis, Wassertheil-Smoller, Beresford, Cauley, Eaton, Gass, Hsia, Johnson, Kooperberg, Kuller, Lewis, Liu, Martin, Ockene, O’Sullivan, Powell, Simon, Van Horn, Vitolins, Wallace.

Statistical analysis: Manson, Aragaki, Prentice, LaCroix, Kooperberg, Liu.

Obtained funding: Manson, Stefanick, Rossouw, Prentice, Anderson, Howard, LaCroix, Wactawski-Wende, Jackson, Limacher, Wassertheil-Smoller, Hsia, Johnson, Lewis, Ockene, Powell, Wallace.

Administrative, technical, or material support: Manson, Chlebowski, Stefanick, Rossouw, Prentice, Thomson, Wactawski-Wende, Jackson, Limacher, Wassertheil-Smoller, Beresford, Cauley, Eaton, Hsia, Johnson, Lewis, O’Sullivan, Simon, Van Horn.

Study supervision: Chlebowski, Rossouw, Prentice, Anderson, Wactawski-Wende, Beresford, Wallace.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Chlebowski reported receiving consulting fees or honoraria from Novartis, Amgen, and AstraZeneca; fees for participation in review activities from Pfizer; payment for lectures from Novartis; and payment for educational activities from Educational Concepts Group. Drs Stefanick, Prentice, LaCroix, Wactawski-Wende, Limacher, Margolis, Wassertheil-Smoller, Beresford, Cauley, Johnson, Lewis, Martin, and O’Sullivan reported receiving institutional grant support from the National Institutes of Health. Dr Howard reported receiving an institutional grant from MedStar Health. Dr Jackson reported receiving consulting fees from Merck for educational materials on clinical trial methods; and a pending institutional grant from Pfizer for health education activities using electronic health records. Dr Wassertheil-Smoller also reported receiving payment for data and safety monitoring board activities related to the Olagen Collagen Matrix Study of glaucoma. Dr Gass reported serving as the executive director of the North American Menopause Society. Dr Liu reported receiving consulting fees from Stanford University; receiving an institutional patent at the University of California, Los Angeles; and receiving royalties from UptoDate Inc. Dr Ockene reported receiving consulting fees from the Research Foundation for the State University of New York, Buffalo. No other disclosures were reported.

Funding/Support: The Women’s Health Initiative is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 321115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. Wyeth-Ayerst donated the study drugs.

Role of the Sponsor: The Women’s Health Initiative (WHI) project office at the National Heart, Lung, and Blood Institute (NHLBI), which was the sponsor, had a role in the design and conduct of the study; interpretation of the data; review and approval of the manuscript; and decision to submit the manuscript for publication. Decisions concerning the above, as well as data collection, management, and analysis, resided with committees composed of WHI investigators and included NHLBI representatives.

A Short List of Women’s Health Initiative Investigators:

Program Office: Jacques Rossouw, Shari Ludlam, Dale Burwen, Joan McGowan, Leslie Ford, and Nancy Geller (National Heart, Lung, and Blood Institute, Bethesda, Maryland).

Clinical Coordinating Center: Garnet Anderson, Ross Prentice, Andrea LaCroix, and Charles Kooperberg (Fred Hutchinson Cancer Research Center, Seattle, Washington).

Investigators and Academic Centers: JoAnn E. Manson (Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts); Barbara V. Howard (MedStar Health Research Institute/Howard University, Washington, DC); Marcia L. Stefanick (Stanford Prevention Research Center, Stanford, California); Rebecca Jackson (Ohio State University, Columbus); Cynthia A. Thomson (University of Arizona, Tucson/Phoenix); Jean Wactawski-Wende (State University of New York, Buffalo); Marian Limacher (University of Florida, Gainesville/Jacksonville); Robert Wallace (University of Iowa, Iowa City/Davenport); Lewis Kuller (University of Pittsburgh, Pittsburgh, Pennsylvania); Sally Shumaker (Wake Forest University School of Medicine, Winston-Salem, North Carolina).

Women’s Health Initiative Memory Study: Sally Shumaker (Wake Forest University School of Medicine, Winston-Salem, North Carolina).

Additional Information: A full list of all the investigators who have contributed to Women’s Health Initiative science appears at https://cleo.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Long%20List.pdf.

Additional Contributions: We thank the Women’s Health Initiative investigators, staff, and the trial participants for their outstanding dedication and commitment.

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Bonds  DE, Lasser  N, Qi  L,  et al.  The effect of conjugated equine oestrogen on diabetes incidence: the Women’s Health Initiative randomised trial. Diabetologia. 2006;49(3):459-468.
PubMed   |  Link to Article
Walitt  B, Pettinger  M, Weinstein  A,  et al; Women’s Health Initiative Investigators.  Effects of postmenopausal hormone therapy on rheumatoid arthritis: the Women’s Health Initiative randomized controlled trials. Arthritis Rheum. 2008;59(3):302-310.
PubMed   |  Link to Article

Figures

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Figure 1.
Women’s Health Initiative Trials of Menopausal Hormone Therapy Through Extended Follow-up

There were 342 306 women who were ineligible or unwilling to participate in the hormone therapy trials. The postintervention phase began on the day after participants were instructed to stop study medication use and continued through the original trial completion date. During the extension phase, there was follow-up for those who provided additional consent (conjugated equine estrogens plus medroxyprogesterone acetate or placebo trial: 83% of those eligible and 2.8% dropped out; conjugated equine estrogens alone or placebo trial: 78% of those eligible and 3.0% dropped out).

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Figure 2.
Health Outcomes in the Overall Study Population in the Women’s Health Initiative Hormone Therapy Trials During the Intervention Phase

CABG indicates coronary artery bypass graft; CEE, conjugated equine estrogens; HR, hazard ratio; MI, myocardial infarction; MPA, medroxyprogesterone acetate; NA, not applicable due to hysterectomy; NR, not reported due to small numbers; PCI, percutaneous coronary intervention; PY, person-years. aPercentages are annualized. bDifference in estimated absolute excess risks (hormone therapy minus placebo). cIndicates CEE alone or CEE plus MPA. dExcludes non–melanoma skin cancer. eIn women aged 65 years or older. fIn women not reporting condition at baseline. gCollected at year 1. hIn symptomatic women aged 50 to 54 years.

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Figure 3.
Absolute Risks of Health Outcomes by 10-Year Age Groups in the Women’s Health Initiative Hormone Therapy Trials During the Intervention Phase

None of the age interactions were statistically significant (at the P < .05 level), except for colorectal cancer, all-cause mortality, myocardial infarction, and the global index in the CEE alone trial (details appear in Figure 5). CEE indicates conjugated equine estrogens; MPA, medroxyprogesterone acetate.

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Figure 4.
Postintervention Health Outcomes and Overall Combined Outcomes (Cumulative Follow-up) in the Overall Study Population in the Women’s Health Initiative Hormone Therapy Trials

The all cardiovascular events outcome is defined in the Results section. CABG indicates coronary artery bypass graft; CEE, conjugated equine estrogens; HR, hazard ratio; MI, myocardial infarction; MPA, medroxyprogesterone acetate; NA, not applicable because women have had hysterectomy; NR, not reported due to small numbers; PCI, percutaneous coronary intervention; PY, person-years. aThe percentages are annualized. bDifference in estimated absolute excess risks (CEE plus MPA or CEE alone minus placebo). cIndicates CEE alone or CEE plus MPA. dExcludes non–melanoma skin cancer. eIncludes participants who did not report a prevalent condition at baseline.

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Figure 5.
Health Outcomes in the Women’s Health Initiative Hormone Therapy Trials During the Intervention Phase According to 10-Year Age Groups at Randomization

CABG indicates coronary artery bypass graft; CEE, conjugated equine estrogens; HR, hazard ratio; MI, myocardial infarction; MPA, medroxyprogesterone acetate; NA, not applicable because women have had hysterectomy; PCI, percutaneous coronary intervention; PY, person-years. aThe percentages are annualized. bDifference in estimated absolute excess risks (CEE plus MPA or CEE alone minus placebo). cFor trend by age group. dIndicates CEE alone or CEE plus MPA. eExcludes non–melanoma skin cancer.

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Figure 6.
Health Outcomes in the Women’s Health Initiative Hormone Therapy Trials for the Overall Combined Phases (Cumulative Follow-up) According to 10-Year Age Groups at Randomization

CABG indicates coronary artery bypass graft; CEE, conjugated equine estrogens; HR, hazard ratio; MI, myocardial infarction; MPA, medroxyprogesterone acetate; NA, not applicable because women have had hysterectomy; PCI, percutaneous coronary intervention; PY, person-years. aThe percentages are annualized. bDifference in estimated absolute excess risks (CEE plus MPA or CEE alone minus placebo). cFor trend by age group. dIndicates CEE alone or CEE plus MPA. eExcludes non–melanoma skin cancer.

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Tables

Table Graphic Jump LocationTable.  Baseline Characteristics of Participants in the 2 WHI Hormone Therapy Trials

References

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PubMed   |  Link to Article
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PubMed   |  Link to Article
Anderson  GL, Limacher  M, Assaf  AR,  et al; Women’s Health Initiative Steering Committee.  Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA. 2004;291(14):1701-1712.
PubMed   |  Link to Article
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PubMed   |  Link to Article
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PubMed   |  Link to Article
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PubMed   |  Link to Article
Manson  JE, Hsia  J, Johnson  KC,  et al; Women’s Health Initiative Investigators.  Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003;349(6):523-534.
PubMed   |  Link to Article
Chlebowski  RT, Hendrix  SL, Langer  RD,  et al; WHI Investigators.  Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative randomized trial. JAMA. 2003;289(24):3243-3253.
PubMed   |  Link to Article
Hays  J, Ockene  JK, Brunner  RL,  et al; Women’s Health Initiative Investigators.  Effects of estrogen plus progestin on health-related quality of life. N Engl J Med. 2003;348(19):1839-1854.
PubMed   |  Link to Article
Wassertheil-Smoller  S, Hendrix  SL, Limacher  M,  et al; WHI Investigators.  Effect of estrogen plus progestin on stroke in postmenopausal women: the Women’s Health Initiative: a randomized trial. JAMA. 2003;289(20):2673-2684.
PubMed   |  Link to Article
Hendrix  SL, Wassertheil-Smoller  S, Johnson  KC,  et al; WHI Investigators.  Effects of conjugated equine estrogen on stroke in the Women’s Health Initiative. Circulation. 2006;113(20):2425-2434.
PubMed   |  Link to Article
Jackson  RD, Wactawski-Wende  J, LaCroix  AZ,  et al; Women’s Health Initiative Investigators.  Effects of conjugated equine estrogen on risk of fractures and BMD in postmenopausal women with hysterectomy: results from the Women’s Health Initiative randomized trial. J Bone Miner Res. 2006;21(6):817-828.
PubMed   |  Link to Article
Hsia  J, Langer  RD, Manson  JE,  et al; Women’s Health Initiative Investigators.  Conjugated equine estrogens and coronary heart disease: the Women’s Health Initiative. Arch Intern Med. 2006;166(3):357-365.
PubMed   |  Link to Article
Heiss  G, Wallace  R, Anderson  GL,  et al; WHI Investigators.  Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin. JAMA. 2008;299(9):1036-1045.
PubMed   |  Link to Article
LaCroix  AZ, Chlebowski  RT, Manson  JE,  et al; WHI Investigators.  Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA. 2011;305(13):1305-1314.
PubMed   |  Link to Article
Chlebowski  RT, Anderson  G, Pettinger  M,  et al; Women’s Health Initiative Investigators.  Estrogen plus progestin and breast cancer detection by means of mammography and breast biopsy [published correction appears in Arch Intern Med. 2008;168(9):935]. Arch Intern Med. 2008;168(4):370-377.
PubMed   |  Link to Article
Chlebowski  RT, Kuller  LH, Prentice  RL,  et al; WHI Investigators.  Breast cancer after use of estrogen plus progestin in postmenopausal women. N Engl J Med. 2009;360(6):573-587.
PubMed   |  Link to Article
Chlebowski  RT, Wactawski-Wende  J, Ritenbaugh  C,  et al; Women’s Health Initiative Investigators.  Estrogen plus progestin and colorectal cancer in postmenopausal women. N Engl J Med. 2004;350(10):991-1004.
PubMed   |  Link to Article
Chlebowski  RT, Schwartz  AG, Wakelee  H,  et al; Women’s Health Initiative Investigators.  Oestrogen plus progestin and lung cancer in postmenopausal women (Women’s Health Initiative trial): a post-hoc analysis of a randomised controlled trial. Lancet. 2009;374(9697):1243-1251.
PubMed   |  Link to Article
Chlebowski  RT, Anderson  GL, Manson  JE,  et al.  Lung cancer among postmenopausal women treated with estrogen alone in the Women’s Health Initiative randomized trial. J Natl Cancer Inst. 2010;102(18):1413-1421.
PubMed   |  Link to Article
Shumaker  SA, Legault  C, Rapp  SR,  et al; WHIMS Investigators.  Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA. 2003;289(20):2651-2662.
PubMed   |  Link to Article
Shumaker  SA, Legault  C, Kuller  L,  et al; Women’s Health Initiative Memory Study.  Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women’s Health Initiative Memory Study. JAMA. 2004;291(24):2947-2958.
PubMed   |  Link to Article
Espeland  MA, Shumaker  SA, Leng  I,  et al; for the WHIMSY Study Group.  Long-term effects on cognitive function of postmenopausal hormone therapy prescribed to women aged 50 to 55 years. JAMA Intern Med. 2013;173(15):1429-1436.
PubMed   |  Link to Article
Hendrix  SL, Cochrane  BB, Nygaard  IE,  et al.  Effects of estrogen with and without progestin on urinary incontinence. JAMA. 2005;293(8):935-948.
PubMed   |  Link to Article
Levine  DW, Kripke  DF, Kaplan  RM,  et al.  Reliability and validity of the Women’s Health Initiative insomnia rating scale. Psychol Assess. 2003;15(2):137-148.
PubMed   |  Link to Article
Levine  DW, Dailey  ME, Rockhill  B, Tipping  D, Naughton  MJ, Shumaker  SA.  Validation of the Women’s Health Initiative insomnia rating scale in a multicenter controlled clinical trial. Psychosom Med. 2005;67(1):98-104.
PubMed   |  Link to Article
Brunner  RL, Gass  M, Aragaki  A,  et al; Women’s Health Initiative Investigators.  Effects of conjugated equine estrogen on health-related quality of life in postmenopausal women with hysterectomy: results from the Women’s Health Initiative randomized clinical trial. Arch Intern Med. 2005;165(17):1976-1986.
PubMed   |  Link to Article
Mendelsohn  ME, Karas  RH.  Molecular and cellular basis of cardiovascular gender differences. Science. 2005;308(5728):1583-1587.
PubMed   |  Link to Article
North American Menopause Society.  Estrogen and progestogen use in postmenopausal women: 2010 position statement of the North American Menopause Society. Menopause. 2010;17(2):242-255.
PubMed   |  Link to Article
Writing Group on behalf of Workshop Consensus Group; International Menopause Society Consensus Statement.  Aging, menopause, cardiovascular disease and HRT. Climacteric. 2009;12(5):368-377.
PubMed   |  Link to Article
Santen  RJ, Allred  DC, Ardoin  SP,  et al; Endocrine Society.  Postmenopausal hormone therapy: an Endocrine Society scientific statement. J Clin Endocrinol Metab. 2010;95(7)(suppl 1):s1-s66.
PubMed   |  Link to Article
Mikkola  TS, Clarkson  TB.  Estrogen replacement therapy, atherosclerosis, and vascular function. Cardiovasc Res. 2002;53(3):605-619.
PubMed   |  Link to Article
Gast  GC, Pop  VJ, Samsioe  GN,  et al.  Vasomotor menopausal symptoms are associated with increased risk of coronary heart disease. Menopause. 2011;18(2):146-151.
PubMed
Lantto  H, Haapalahti  P, Tuomikoski  P,  et al.  Vasomotor hot flashes and heart rate variability: a placebo-controlled trial of postmenopausal hormone therapy. Menopause. 2012;19(1):82-88.
PubMed   |  Link to Article
Gast  GC, Pop  VJ, Samsioe  GN,  et al.  Hormone therapy and coronary heart disease risk by vasomotor menopausal symptoms. Maturitas. 2011;70(4):373-378.
PubMed   |  Link to Article
Huang  AJ, Sawaya  GF, Vittinghoff  E, Lin  F, Grady  D.  Hot flushes, coronary heart disease, and hormone therapy in postmenopausal women. Menopause. 2009;16(4):639-643.
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Chlebowski  RT, Anderson  GL.  Changing concepts: menopausal hormone therapy and breast cancer. J Natl Cancer Inst. 2012;104(7):517-527.
PubMed   |  Link to Article
Stefanick  ML, Anderson  GL, Margolis  KL,  et al; WHI Investigators.  Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA. 2006;295(14):1647-1657.
PubMed   |  Link to Article
Anderson  GL, Chlebowski  RT, Aragaki  AK,  et al.  Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomised placebo-controlled trial. Lancet Oncol. 2012;13(5):476-486.
PubMed   |  Link to Article
Collaborative Group on Hormonal Factors in Breast Cancer.  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. Lancet. 1997;350(9084):1047-1059.
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Beral  V; Million Women Study Collaborators.  Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003;362(9382):419-427.
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Kim  JJ, Kurita  T, Bulun  SE.  Progesterone action in endometrial cancer, endometriosis, uterine fibroids, and breast cancer. Endocr Rev. 2013;34(1):130-162.
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Jordan  VC, Ford  LG.  Paradoxical clinical effect of estrogen on breast cancer risk: a “new” biology of estrogen-induced apoptosis. Cancer Prev Res (Phila). 2011;4(5):633-637.
PubMed   |  Link to Article
Anderson  GL, Judd  HL, Kaunitz  AM,  et al; Women’s Health Initiative Investigators.  Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women’s Health Initiative randomized trial. JAMA. 2003;290(13):1739-1748.
PubMed   |  Link to Article
Margolis  KL, Bonds  DE, Rodabough  RJ,  et al; Women’s Health Initiative Investigators.  Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women’s Health Initiative hormone trial. Diabetologia. 2004;47(7):1175-1187.
PubMed   |  Link to Article
Bonds  DE, Lasser  N, Qi  L,  et al.  The effect of conjugated equine oestrogen on diabetes incidence: the Women’s Health Initiative randomised trial. Diabetologia. 2006;49(3):459-468.
PubMed   |  Link to Article
Walitt  B, Pettinger  M, Weinstein  A,  et al; Women’s Health Initiative Investigators.  Effects of postmenopausal hormone therapy on rheumatoid arthritis: the Women’s Health Initiative randomized controlled trials. Arthritis Rheum. 2008;59(3):302-310.
PubMed   |  Link to Article
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Multimedia

Supplement.

List of previous WHI publications

eFigure 1. Number of events (annualized %), difference in absolute risks per 10,000 person-years, and hazard ratios (95%CI) for various health outcomes in the overall study population in the WHI Hormone Therapy Trials (post-intervention phase). The total cardiovascular disease outcome is defined in the legend for Figure 2.

eFigure 2. Number of events (annualized %), difference in absolute risks per 10,000 person-years, and hazard ratios (95%CI) for various health outcomes in the WHI Hormone Therapy Trials (intervention phase) according to time since menopause (10-year groups) at randomization.

eFigure 3. Number of events (annualized %), difference in absolute risks per 10,000 person-years, and hazard ratios (95%CI) for secondary endpoints in the WHI Hormone Therapy Trials (intervention phase) according to 10-year age groups at randomization. The total cardiovascular disease outcome is defined in the legend for Figure 2.

eFigure 4. Number of events (annualized %), difference in absolute risks per 10,000 person-years, and hazard ratios (95%CI) for secondary endpoints in the WHI Hormone Therapy Trials (overall combined phases, cumulative followup) according to 10-year age groups at randomization. The total cardiovascular disease outcome is defined in the legend for Figure 2.

eFigure 5. Mean (95% CI) and effect sizes for other health-related quality of life variables in the WHI Hormone Therapy Trials by randomization arm at Year 1 (intervention phase).

eFigure 6. Number of events (annualized %), difference in absolute risks per 10,000 person-years, and hazard ratios (95%CI) for various health outcomes in the WHI Hormone Therapy Trials (intervention phase) among women with no prior HT Use according to 10-year age groups at randomization.

eFigure 7. Number of Events (annualized %) and hazard ratios (95%CI) for CHD in the WHI Hormone Therapy Trials (intervention phase) according to vasomotor symptoms and age at randomization.

Secondary and patient-reported outcomes in the two trials

Additional analyses addressing risk stratification

Additional discussion of the breast cancer findings

References

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