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Objective: Although joint symptoms are commonly reported after menopause, observational studies examining exogenous estrogen's influence on joint symptoms provide mixed results. Against this background, estrogen-alone effects on joint symptoms were examined in post hoc analyses in the Women's Health Initiative randomized, placebo-controlled, clinical trial., Methods: A total of 10,739 postmenopausal women who have had a hysterectomy were randomized to receive daily oral conjugated equine estrogens (0.625 mg/d) or a matching placebo. The frequency and severity of joint pain and joint swelling were assessed by questionnaire in all participants at entry and on year 1, and in a 9.9% random subsample (n = 1,062) after years 3 and 6. Logistic regression models were used to compare the frequency and severity of symptoms by randomization group. Sensitivity analyses evaluated adherence influence on symptoms., Results: At baseline, joint pain and joint swelling were closely comparable in the randomization groups (about 77% with joint pain and 40% with joint swelling). After 1 year, joint pain frequency was significantly lower in the estrogen-alone group compared with the placebo group (76.3% vs 79.2%, P = 0.001), as was joint pain severity, and the difference in pain between randomization groups persisted through year 3. However, joint swelling frequency was higher in the estrogen-alone group (42.1% vs 39.7%, P = 0.02). Adherence-adjusted analyses strengthen estrogen's association with reduced joint pain but attenuate estrogen's association with increased joint swelling., Conclusions: The current findings suggest that estrogen-alone use in postmenopausal women results in a modest but sustained reduction in the frequency of joint pain.

Background: The findings of the Women's Health Initiative (WHI) estrogen plus progestin (E+P) trial led to a substantial reduction in use of combined hormone therapy (cHT) among postmenopausal women in the United States. The economic effect of this shift has not been evaluated relative to the trial's $260 million cost (2012 U.S. dollars)., Objective: To estimate the economic return from the WHI E+P trial., Design: Decision model to simulate health outcomes for a "WHI scenario" with observed cHT use and a "no-WHI scenario" with cHT use extrapolated from the pretrial period., Data Sources: Primary analyses of WHI outcomes, peer-reviewed literature, and government sources., Target Population: Postmenopausal women in the United States, aged 50 to 79 years, who did not have a hysterectomy., Time Horizon: 2003 to 2012., Perspective: Payer., Intervention: Combined hormone therapy., Outcome Measures: Disease incidence, expenditure, quality-adjusted life-years, and net economic return., Results of Base-Case Analysis: The WHI scenario resulted in 4.3 million fewer cHT users, 126,000 fewer breast cancer cases, 76,000 fewer cardiovascular disease cases, 263,000 more fractures, 145,000 more quality-adjusted life-years, and expenditure savings of $35.2 billion. The corresponding net economic return of the trial was $37.1 billion ($140 per dollar invested in the trial) at a willingness-to-pay level of $100,000 per quality-adjusted life-year., Results of Sensitivity Analysis: The 95% CI for the net economic return of the trial was $23.1 to $51.2 billion., Limitation: No evaluation of indirect costs or outcomes beyond 2012., Conclusion: The WHI E+P trial made high-value use of public funds with a substantial return on investment. These results can contribute to discussions about the role of public funding for large, prospective trials with high potential for public health effects., Primary Funding Source: National Heart, Lung, and Blood Institute.

Objective: Although joint symptoms are commonly reported after menopause, observational studies examining exogenous estrogen's influence on joint symptoms provide mixed results. Against this background, estrogen-alone effects on joint symptoms were examined in post hoc analyses in the Women's Health Initiative randomized, placebo-controlled, clinical trial., Methods: A total of 10,739 postmenopausal women who have had a hysterectomy were randomized to receive daily oral conjugated equine estrogens (0.625 mg/d) or a matching placebo. The frequency and severity of joint pain and joint swelling were assessed by questionnaire in all participants at entry and on year 1, and in a 9.9% random subsample (n = 1,062) after years 3 and 6. Logistic regression models were used to compare the frequency and severity of symptoms by randomization group. Sensitivity analyses evaluated adherence influence on symptoms., Results: At baseline, joint pain and joint swelling were closely comparable in the randomization groups (about 77% with joint pain and 40% with joint swelling). After 1 year, joint pain frequency was significantly lower in the estrogen-alone group compared with the placebo group (76.3% vs 79.2%, P = 0.001), as was joint pain severity, and the difference in pain between randomization groups persisted through year 3. However, joint swelling frequency was higher in the estrogen-alone group (42.1% vs 39.7%, P = 0.02). Adherence-adjusted analyses strengthen estrogen's association with reduced joint pain but attenuate estrogen's association with increased joint swelling., Conclusions: The current findings suggest that estrogen-alone use in postmenopausal women results in a modest but sustained reduction in the frequency of joint pain.

Background: Breast cancer concern is a major reason for the recent marked reduction in use of postmenopausal hormone therapy, although equally effective means of controlling menopausal symptoms are lacking. Single nucleotide polymorphisms (SNP) in the fibroblast growth factor receptor 2 (FGFR2) gene are substantially associated with postmenopausal breast cancer risk and could influence hormone therapy effects., Participants and Methods: We interrogated eight SNPs in intron 2 of the FGFR2 gene for 2,166 invasive breast cancer cases from the Women's Health Initiative clinical trial and one-to-one matched controls to confirm an association with breast cancer risk. We used case-only analyses to examine the dependence of estrogen plus progestin and estrogen-alone odds ratios on SNP genotype., Results: Seven FGFR2 SNPs, including six in a single linkage disequilibrium region, were found to associate strongly (P < 10(-7)) with breast cancer risk. SNP rs3750817 (minor allele T with frequency 0.39) had an estimated per-minor-allele odds ratio of 0.78, and was not in such strong linkage disequilibrium with the other SNPs. The genotype of this SNP related significantly (P < 0.05) to hormone therapy odds ratios. For estrogen plus progestin, the odds ratios (95% confidence intervals) at 0, 1, and 2 minor SNP alleles were 1.52 (1.14-2.02), 1.33 (1.01-1.75), and 0.69 (0.41-1.17), whereas the corresponding values for estrogen alone were 0.74 (0.51-1.09), 0.99 (0.68-1.44), and 0.34 (0.15-0.76)., Conclusions: Postmenopausal women having TT genotype for SNP rs3750817 have a reduced breast cancer risk and seem to experience comparatively favorable effects of postmenopausal hormone therapy.

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

Background: Colorectal cancer incidence was reduced among women assigned to active treatment in the Women's Health Initiative (WHI) estrogen plus progestin-randomized trial, but the interpretation was obscured by an associated later stage of diagnosis. In contrast, the estrogen-alone trial showed no incidence reduction or differential stage at diagnosis. Here, data from the WHI observational study are considered, in conjunction with colorectal cancer mortality data from the hormone therapy trials, in an attempt to clarify postmenopausal hormone therapy effects., Participants and Methods: Postmenopausal women ages 50 to 79 years at WHI enrollment. Estrogen-alone analyses include 21,552 and 10,739 women who were posthysterectomy from the observational study and clinical trial, respectively. Estrogen plus progestin analyses include 32,084 and 16,608 observational study and clinical trial women with uterus. Colorectal cancers were verified by central medical and pathology report review., Results: Hazard ratios (95% confidence intervals) from the WHI observational study were 0.80 (0.53-1.20) for estrogen and 1.15 (0.74-1.79) for estrogen plus progestin, with, respectively, 168 and 175 women diagnosed with colorectal cancer. Delayed diagnosis with estrogen plus progestin is not evident in the observational study. No protective effect on colorectal cancer mortality in the estrogen plus progestin trial is seen over an 8-year intervention and follow-up period., Conclusion: Hazard ratio patterns in the WHI clinical trial and observational study do not provide strong evidence of a clinically important colorectal cancer benefit with either estrogen-alone or estrogen plus progestin over 7 to 8 years of treatment and follow-up.

Background: Clinical trials of postmenopausal hormone therapy (HT) have shown increased risk of coronary heart disease (CHD) in the first few years after initiation of therapy and no overall benefit., Methods: This nested case-control study evaluates a range of inflammatory, lipid, thrombotic, and genetic markers for their association with CHD in the 4 years after randomization and assesses whether any of these markers modified or mediated the initially increased risk associated with HT in postmenopausal women aged 50 to 79 years at baseline. Conjugated equine estrogens, 0.625 mg/d, or placebo was given to 10 739 hysterectomized women, and the same estrogen plus medroxyprogesterone acetate, 2.5 mg/d, was given to 16 608 women with an intact uterus., Results: In multivariate-adjusted analyses of 359 cases and 820 controls in the combined trials, baseline levels of 12 of the 23 biomarkers studied were associated with CHD events: interleukin 6, matrix metalloproteinase 9, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol, triglycerides, D-dimer, factor VIII, von Willebrand factor, leukocyte count, homocysteine, and fasting insulin. Biomarkers tended to be more strongly associated with CHD in the initial 2 years after randomization. The genetic polymorphism glycoprotein IIIa leu33pro was significantly associated with CHD. Baseline low-density lipoprotein cholesterol interacted significantly with HT so that women with higher levels were at higher risk for CHD when given HT (P = .03 for interaction). The levels of several biomarkers were changed by HT, but these changes did not seem to be associated with future CHD events., Conclusions: Several thrombotic, inflammatory, and lipid biomarkers were associated with CHD events in postmenopausal women, but only low-density lipoprotein cholesterol modified the effect of HT. Further research is needed to identify the mechanisms by which HT increases the risk of CHD., Trial Registration: clinicaltrials.gov Identifier: NCT00000611.

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

The Women's Health Initiative trial found a modestly increased risk of invasive breast cancer with daily 0.625-mg conjugated equine estrogens plus 2.5-mg medroxyprogesterone acetate, with most evidence among women who had previously received postmenopausal hormone therapy. In comparison, observational studies mostly report a larger risk increase. To explain these patterns, the authors examined the effects of this regimen in relation to both prior hormone therapy and time from menopause to first use of postmenopausal hormone therapy ("gap time") in the Women's Health Initiative trial and in a corresponding subset of the Women's Health Initiative observational study. Postmenopausal women with a uterus enrolled at 40 US clinical centers during 1993-1998. The authors found that hazard ratios agreed between the two cohorts at a specified gap time and time from hormone therapy initiation. Combined trial and observational study data support an adverse effect on breast cancer risk. Women who initiate use soon after menopause, and continue for many years, appear to be at particularly high risk. For example, for a woman who starts soon after menopause and adheres to this regimen, estimated hazard ratios are 1.64 (95% confidence interval: 1.00, 2.68) over a 5-year period of use and 2.19 (95% confidence interval: 1.56, 3.08) over a 10-year period of use.

Objective: To study the effects of postmenopausal hormone therapy (PHT) on the incidence and severity of rheumatoid arthritis (RA)., Methods: The Women's Health Initiative randomized controlled trials evaluated the effects of unopposed estrogen (E-alone) and estrogen plus progestin (E+P) compared with placebo on a diverse set of health outcomes over 7.1 and 5.6 years, respectively. RA cases were identified using historical and medication data. The hazard of developing RA was estimated using Cox proportional hazards regression models. Disease symptom severity was estimated using the Short Form 36 (SF-36) and self-reported joint pain scores at baseline and after 1 year. Mean changes in severity were compared using linear regression models., Results: Of the 27,347 participants, 63 prevalent cases and 105 incident cases of RA were identified. A nonsignificant reduction in the risk of developing RA (hazard ratio 0.74; 95% confidence interval [95% CI] 0.51, 1.10) was noted with PHT use. PHT use led to improved SF-36 scores in unadjusted analyses (percent change 12.5%; 95% CI -24.45, -0.57) but not after adjustment for relevant covariates (P = 0.33). Nonsignificant improvements in joint pain scores were seen with PHT use (odds ratio [OR] 4.10; 95% CI 0.83, 20.20). PHT did not improve swelling (OR 1.27; 95% CI 0.08, 19.63) or prevent new joint pains (OR 0.72; 95% CI 0.11, 4.68) in RA participants., Conclusion: There were no statistically significant differences in the risk of developing RA or the severity of RA between the PHT and placebo groups.

Background: The Women's Health Initiative (WHI) randomized trial of estrogen plus progestin (E + P) was terminated early based on an assessment of harms exceeding benefits for disease prevention. The results contravened prevailing wisdom and a large body of literature regarding benefits of menopausal hormone therapy. The results and their interpretation have been the subject of considerable debate., Purpose/methods: To describe the process of developing a trial monitoring plan, the key interim and final data, and to explain the choice of statistical methods used in trial monitoring and reporting., Results: A formalized monitoring plan was developed using statistical methods that acknowledged protocol-defined design and analysis plans, input of monitoring board members especially regarding the role of various study outcomes, and multiple comparisons. Major early departures from design assumptions concerning treatment effects indicated a need for additional flexibility in safety monitoring. When the trials were stopped early, questions arose as to how closely the statistical methods in published reports should correspond to those defined by protocol or used in monitoring., Methods: were selected to provide a simple and transparent summary of the primary results, with a cautious interpretation promoted by acknowledgement of multiple testing., Conclusions: Developing a formal trial monitoring plan with a view towards influencing clinical practice is useful for creating consensus among DSMB members regarding the evidence that would justify stopping a trial and the framework to be used to address statistical complexities. Departures from design assumptions typically occur. These reinforce the role of the DSMB in exercising their judgment, and the judicious adaptation of these statistical guidelines in monitoring and reporting trials. In communicating the results in such circumstances, priority should be given to presenting as fair, accurate and transparent a view of the data and findings as current methods and technology allow.

Objective: To estimate the incidence of cytological abnormalities and cervical cancer and to determine the effect of oral estrogen and progestin on cervical cytology among postmenopausal women participating in a multi-institution clinical trial., Methods: The study was a longitudinal analysis of a prospective cohort of 16,608 postmenopausal women (aged 50-79 years) participating in the Women's Health Initiative (WHI) clinical trial of estrogen plus progestin. Eligible participants had a cervical smear within 1 year before randomization and at 3- and 6-year follow-ups. Outcomes measured were low-grade and high-grade squamous intraepithelial lesions (LSIL, HSIL) and cervical cancer at follow-up years 3 and 6., Results: Of 15,733 eligible participants with a uterus, 7,663 were assigned to placebo and 8,070 to estrogen plus progestin. At baseline, 318 women (2%) had low-grade abnormalities on cervical cytology. The annual incidence rate of any new cytological abnormality in the estrogen plus progestin group was significantly higher than that in the placebo group (hazard ratio 1.4, 95% confidence interval [CI] 1.2-1.6). Independent risk factors for HSIL and cervical cancer over a 6-year follow-up (after stratifying for baseline cytologic abnormalities) included sexual activity in the past year while not being married or living as married (hazard ratio 3.5, 95% CI 1.5-8.3). Risk factors did not include age or use of estrogen plus progestin., Conclusion: Use of estrogen plus progestin was associated with increased incidence of any cytologic abnormality, although it had no impact on the incidence of HSIL or cervical cancer. Sexually active older women who are not married or living as married may benefit from continued cervical cancer screening., Clinical Trial Registration: Clinicaltrials.gov, www.clinicaltrials.gov, NCT00000611.

Circumstances in which both randomized controlled trial and observational study data are available provide an important opportunity to identify biases and improve study design and analysis procedures. In addition, joint analyses of data from the two sources can extend clinical trial findings. The US Women's Health Initiative includes randomized controlled trials of use of estrogen by posthysterectomy women and of estrogen plus progestin by women with a uterus, along with corresponding observational study components. In this paper, for coronary heart disease, stroke, and venous thromboembolism, results are first presented from joint analysis of estrogen clinical trial and observational study data to show that residual bias patterns are similar to those previously reported for estrogen plus progestin. These findings support certain combined analyses of the observational data on estrogen and the estrogen plus progestin clinical trial and observational study data to give adjusted observational study estimates of estrogen treatment effects. The resulting treatment effect estimates are compared with corresponding clinical trial estimates, and parallel analyses are also presented for estrogen plus progestin. An application to postmenopausal hormone treatment effects on coronary heart disease among younger women is also provided.

Observational research on postmenopausal hormone therapy suggests a 40-50% reduction in coronary heart disease incidence among women using these preparations. In contrast, the Women's Health Initiative clinical trial of estrogen plus progestin found an elevated incidence over a 5.6-year intervention period through July 7, 2002. Toward explaining this discrepancy, the authors analyzed data from this trial, which included 16,608 postmenopausal women aged 50-79 years, and corresponding data from 53,054 women in the Women's Health Initiative observational study, 33% of whom were estrogen-plus-progestin users at baseline. Estrogen-plus-progestin hazard ratio estimates for coronary heart disease, stroke, and venous thromboembolism in the observational study were 39-48% lower than those in the clinical trial following age adjustment. However, hazard ratios tended to decrease with increasing time from initiation of estrogen-plus-progestin use, and observational study hazard ratio estimates are heavily weighted by longer-term use while clinical trial hazard ratio estimates reflect shorter-term use. Following control for time from estrogen-plus-progestin initiation and confounding, hazard ratio estimates were rather similar for the two cohorts, although there was evidence of some remaining difference for stroke. These analyses have implications for both the design and the analysis of observational studies.

Context: The effects of continuous combined hormone therapy on gynecologic cancers have not been investigated previously in a randomized trial setting., Objective: To determine the possible associations of estrogen plus progestin on gynecologic cancers and related diagnostic procedures., Design, Setting, and Participants: Randomized, double-blind, placebo-controlled trial of 16 608 postmenopausal women, who had not had a hysterectomy at baseline and who had been recruited from 40 US clinical centers between September 1993 and October 1998 (average follow-up, 5.6 years)., Intervention: One tablet per day containing 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate (n = 8506) or placebo (n = 8102)., Main Outcome Measure: Incident invasive cancer of the ovary and endometrium., Results: In 5.6 years of follow-up, there were 32 cases of invasive ovarian cancer, 58 cases of endometrial cancer, 1 case of nonendometrial uterine cancer, 13 cases of cervical cancer, and 7 cases of other gynecologic cancers. The hazard ratio (HR) for invasive ovarian cancer in women assigned to estrogen plus progestin compared with placebo was 1.58 (95% confidence interval [CI], 0.77-3.24). The HR for endometrial cancer was 0.81 (95% CI, 0.48-1.36). No appreciable differences were found in the distributions of tumor histology, stage, or grade for either cancer site. The incidence of other gynecologic cancers was low and did not differ by randomization assignment. More women taking estrogen plus progestin required endometrial biopsies (33% vs 6%; P<.001)., Conclusions: This randomized trial suggests that continuous combined estrogen plus progestin therapy may increase the risk of ovarian cancer while producing endometrial cancer rates similar to placebo. The increased burden of endometrial biopsies required to assess vaginal bleeding further limits the acceptability of this regimen. These data provide additional support for caution in the use of continuous combined hormones.

Context: In the Women's Health Initiative trial of estrogen-plus-progestin therapy, women assigned to active treatment had fewer fractures., Objective: To test the hypothesis that the relative risk reduction of estrogen plus progestin on fractures differs according to risk factors for fractures., Design, Setting, and Participants: Randomized controlled trial (September 1993-July 2002) in which 16 608 postmenopausal women aged 50 to 79 years with an intact uterus at baseline were recruited at 40 US clinical centers and followed up for an average of 5.6 years., Intervention: Women were randomly assigned to receive conjugated equine estrogen, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102)., Main Outcome Measures: All confirmed osteoporotic fracture events that occurred from enrollment to discontinuation of the trial (July 7, 2002); bone mineral density (BMD), measured in a subset of women (n = 1024) at baseline and years 1 and 3; and a global index, developed to summarize the balance of risks and benefits to test whether the risk-benefit profile differed across tertiles of fracture risk., Results: Seven hundred thirty-three women (8.6%) in the estrogen-plus-progestin group and 896 women (11.1%) in the placebo group experienced a fracture (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.69-0.83). The effect did not differ in women stratified by age, body mass index, smoking status, history of falls, personal and family history of fracture, total calcium intake, past use of hormone therapy, BMD, or summary fracture risk score. Total hip BMD increased 3.7% after 3 years of treatment with estrogen plus progestin compared with 0.14% in the placebo group (P<.001). The HR for the global index was similar across tertiles of the fracture risk scale (lowest fracture risk tertile, HR, 1.20; 95% CI, 0.93-1.58; middle tertile, HR, 1.23; 95% CI, 1.04-1.46; highest tertile, HR, 1.03; 95% CI, 0.88-1.24) (P for interaction =.54)., Conclusions: This study demonstrates that estrogen plus progestin increases BMD and reduces the risk of fracture in healthy postmenopausal women. The decreased risk of fracture attributed to estrogen plus progestin appeared to be present in all subgroups of women examined. When considering the effects of hormone therapy on other important disease outcomes in a global model, there was no net benefit, even in women considered to be at high risk of fracture.