Women's Health Initiative Findings Research Articles

Abstract PS07-03: Randomized trials of oestrogen-alone and breast cancer incidence: a meta-analysis

Abstract Background Findings from cohort studies compared with those from the Women's Health initiative (WHI) randomized, placebo-controlled clinical trial regarding estrogen-alone and breast cancer risk are discordant. The WHI randomized trial enrolled 10,729 postmenopausal women with prior hysterectomy, mean age 64 years (33.2% 50-59), no prior breast cancer and a non-suspicious baseline mammogram. After 7.2 years intervention and 16.2 years cumulative follow-up, conjugated equine estrogen (CEE)-alone (vs placebo) significantly reduced breast cancer incidence by 22% (P = 0.005) and significantly reduced breast cancer mortality by 40% (P = 0.04) (Chlebowski JAMA 2020). In contrast, cohort studies had opposite findings, estrogen-alone use was associated with significantly higher breast cancer incidence and significantly higher breast cancer mortality. Therefore, we identified all available estrogen-alone randomized clinical trials where breast cancer findings were reported to conduct a meta-analysis examining the totality of the randomized clinical trial evidence regarding estrogen-alone influence on breast cancer incidence. Methods We conducted PubMed and Google Scholar searches on randomized trials and: estrogen, hormone therapy, and breast cancer, and searches from a prior meta-analyses and reviews. In the current meta-analysis, for trials with published relative risks (RR) and 95% confidence intervals (CI), each log-RR was multiplied by weight = 1/V, where V = variance of the log-RR, and V was derived from the corresponding 95% CI. For smaller trials with only breast cancer numbers, a different method was used, the corresponding log-RR = (O – E)/weight, where O is the observed case number in the oestrogen-alone group and E the corresponding expected case number, E = nP. Findings Ten randomized trials, incorporating WHI findings, and findings from nine smaller trials included 14,272 randomized participants and 591 incident breast cancers. Of 9 smaller trials, 6 required negative baseline screening mammograms; mean entry age: 50 to 56 years in 5 trials and 62 to 71 years in 4 trials. In the nine smaller trials, 1.2% (24 of 2029) vs 2.2% (33 of 1514) randomized to estrogen-alone vs placebo (open label, one trial) were diagnosed with breast cancer, respectively (RR 0.65 95% CI 0.38-1.11, P = 0.12). For 5 trials evaluating estradiol formulations, RR = 0.63 95% CI 0.34-1.16, P = 0.15. In the WHI trial, 4.5% (238 of 5310) vs 5.5% (296 of 5429) randomized to estrogen-alone were diagnosed with breast cancer, respectively (RR 0.78 95% CI 0.65-0.93, P = 0.005)). Combining smaller trials and WHI results, 3.6% (262 of 7339) vs 4.7% (329 of 6943) randomized to estrogen-alone vs placebo were diagnosed with breast cancer, respectively (overall RR 0.77 95% CI 0.65-0.91, P = 0.002). Results from a sensitivity analysis for the smaller trials using exact conditional logistic regression were essentially unchanged (RR 0.64 95% CI 0.35-1.13). Interpretation The totality of randomized clinical trial evidence supports a conclusion that estrogen-alone use, among postmenopausal women with prior hysterectomy, significantly reduces breast cancer incidence. This consistent pattern seen in these randomized trials suggests the WHI CEE-alone findings are not “stand alone” outcomes or due to chance. Citation Format: Rowan Chlebowski, Aaron Aragaki, Kathay Pan, Joanne Mortimer, Karen Johnson, Jean Wactawski-Wende, Meryl LeBoff, Sayeh Lavasani, Dorothy Lane, Rebecca Nelson, JoAnn Manson. Randomized trials of oestrogen-alone and breast cancer incidence: a meta-analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS07-03.

The Women's Health Initiative randomized trials of menopausal hormone therapy and breast cancer: findings in context.

The menopausal hormone therapy (MHT) association with breast cancer has been controversial for more than 40 years. Most recently, findings from cohort studies have been discordant compared with those from the Women's Health Initiative (WHI) randomized trials. In cohort studies, both estrogen therapy and estrogen plus progestin were associated with higher breast cancer incidence. In contrast, in the WHI randomized trials, findings for estrogen plus progestin are concordant with cohort study reports, whereas estrogen therapy significantly reduced breast cancer incidence. In addition, concerns have been raised regarding the WHI findings from both trials. In this report, we briefly summarize findings for MHT on breast cancer from cohort studies and the WHI randomized trials. The report focus is addressing, point-by-point, concerns raised regarding the WHI findings. For cohort studies, we relied on the latest findings from (1) the meta-analysis of the Collaborative Group on Hormonal Factors in Breast Cancer and (2) the Million Women's Study. To identify commentaries and editorials, "Menopause" and "Climacteric" were searched from 2002 to present; PubMed and Google Scholar were searched for commentaries, editorials, and breast cancer, MHT, estrogen, conjugated equine estrogen, estradiol, "hormone replacement therapy," and "HRT." Thirty commentaries challenging WHI findings were identified. All were reviewed, and issues needing response were identified. Findings from the meta-analysis from the Collaborative Group on Hormonal Factors in Breast Cancer and the Million Women Study were summarized and compared with finding in the two WHI randomized trials evaluating estrogen therapy and estrogen plus progestin. Based on the randomized clinical trials, estrogen therapy, for women with prior hysterectomy, decreases breast cancer incidence and mortality. In contrast, estrogen plus progestin increases breast cancer incidence, which persists through two decades. Women considering estrogen plus progestin use for vasomotor symptoms should understand the breast cancer risk.

Estrogen therapy and breast cancer in randomized clinical trials: a narrative review.

In the Women's Health Initiative (WHI) randomized trial with 10,739 postmenopausal women with prior hysterectomy, conjugated equine estrogen (CEE) alone significantly reduced breast cancer incidence and breast cancer mortality. In contrast, epidemiological studies in a meta-analysis from the Collaborative Group on Hormonal Factors in Breast Cancer (Collaborative Group) with 108,647 breast cancers and the Million Women's Study cohort significantly associated estrogen-alone therapy with higher breast cancer incidence and breast cancer mortality. The Collaborative Group included a meta-analysis of five smaller randomized trials and the WHI randomized trial; however, findings were restricted to the Collaborative Group appendix. Our objective is to facilitate understanding of these discordant results. Data sources supporting our review findings include the randomized WHI CEE-alone trial and the meta-analysis of five smaller randomized trials evaluating estrogen alone. We summarize the smaller randomized trials' details of breast cancer relevance and place the findings in clinical context. We review findings of the WHI randomized trial evaluating CEE alone in the context of issues raised by Collaborative Group and the Million Women Study authors. We trace the evolution of the time-from-menopause, "window of opportunity" concept and augment the Collaborative Group meta-analysis by including the most recent WHI findings. Consideration of the smaller randomized trials evaluating estrogen alone with breast cancer signals that the WHI findings of lower breast cancer incidence and lower breast cancer mortality with CEE-alone use are not a "stand-alone" outcome or due to the play of chance. The serial reports of consistent favorable breast cancer findings through 20 years of cumulative follow-up suggest CEE-alone use initiates changes that persist. After full consideration of risks and benefits, randomized trial evidence provides reassurance for postmenopausal women with prior hysterectomy who are close to menopause considering estrogen alone for climacteric symptom management.

Cancer Progress and Priorities: Breast Cancer.

Breast cancer is the most commonly diagnosed invasive cancer among women both globally and within the United States and the number one cause of cancer-related deaths among women globally ([1, 2][1]). Less than 1% of diagnosed breast cancers occur in men ([2][2]) and, therefore, male breast cancer is

The Women's Health Initiative trials of menopausal hormone therapy: lessons learned.

The Women's Health Initiative (WHI) assessed oral conjugated equine estrogens (CEE) taken with or without medroxyprogesterone acetate (MPA) for prevention of chronic disease in postmenopausal women aged 50-79 years. Women with an intact uterus (n = 16,608) were randomized to CEE+ MPA therapy or placebo for a median of 5.6 years; women with hysterectomy (n = 10,739) were randomized to CEE-alone therapy or placebo for a median of 7.2 years. Both cohorts have been followed for 18 years. In the overall study population (mean age, 63 y), neither estrogen-progestin therapy (EPT) nor estrogen-only therapy prevented coronary heart disease or led to a favorable balance of chronic-disease benefits and risks. Subgroup analyses, however, suggest that timing of hormone therapy (HT) initiation influences the relation between HT and coronary risk, as well as its overall benefit-risk balance, with more favorable effects in women who are younger (age < 60 year) or recently menopausal (within 10 year) than in women who are older or further past the menopausal transition. In younger women who entered the trial of estrogen-only therapy with oophorectomy, the intervention was associated with a significant 32% reduction in all-cause mortality over long-term follow-up. WHI findings indicate important differences in HT-related clinical outcomes by age and time since menopause. Systemic HT has an acceptable safety profile for menopause management when initiated among healthy women who are younger (or recently menopausal) and not at elevated risk for cardiovascular disease or breast cancer. Initiation of treatment in older women who are distant from menopause onset, however, should be avoided. Other HT formulations and routes of delivery warrant further study.(WHI clinicaltrials.gov identifier: NCT00000611).

Best practices in care for menopausal patients: 16 years after the Women's Health Initiative.

The Women's Health Initiative (WHI) was a large, randomized clinical trial funded by the National Institutes of Health to determine whether menopause hormone therapy (MHT) prevented heart disease, breast and colorectal cancer, and osteoporotic fractures in postmenopausal women. Two WHI trials were stopped early, and the findings had a profound effect on the clinical practice guidelines related to postmenopausal health. This article provides an overview of the WHI MHT clinical trials and findings, discusses the early stoppage of the trials and subsequent implications, and details the current nomenclature and treatment options for women transitioning through menopause in light of the WHI. This study is based on a comprehensive literature review and an education activity developed by the American Association of Nurse Practitioners. To best serve patients and individualize therapy, clinicians must provide the best estimate of potential risks or benefits to the individual patient. It is important to balance evidence of symptom relief with long-term risks and benefits that fit the patient's characteristics of family and personal health history. Armed with evidence to support various hormonal and non-hormonal options, well-informed clinicians can counsel women about MHT and potentially avoid negative impact on quality of life.

A 17β-Estradiol–Progesterone Oral Capsule for Vasomotor Symptoms in Postmenopausal Women: A Randomized Controlled Trial

(Abstracted from Obstet Gynecol 2018;132:161–170) After the first publication of Women's Health Initiative findings in 2002, many women stopped taking US Food and Drug Administration (FDA)–approved, hormone therapy (HT) and started using non–FDA-approved, “natural” compounded HT believing that it was a safer option. In 2015, it was estimated that 1 million to 2.5 million US women used the unapproved, compounded HT.

What the Women's Health Initiative has taught us about menopausal hormone therapy.

Our understanding of the complex relationship between menopausal hormone therapy (MHT) and cardiovascular disease (CVD) risk has been informed by detailed analyses in the Women's Health Initiative (WHI), the largest randomized, placebo-controlled trial evaluating MHT in postmenopausal women. Although the WHI demonstrated increased risk of CVD events with MHT in the overall cohort, subsequent secondary analyses demonstrated that these risks were influenced by the woman's age and time since menopause, with lower absolute risks and hazard ratios for younger than older women. As MHT is the most effective treatment for the vasomotor symptoms of menopause, it is important to understand its risks and how to conduct risk stratification for symptomatic women. In addition to reviewing the WHI findings, studies pre- and post-WHI are reviewed to describe the relationship between MHT and CVD risk in menopausal women. The absolute risks of adverse cardiovascular events for MHT initiated in women close to menopause are low, and all-cause mortality effects are neutral or even favorable for younger menopausal women. The WHI has advanced and refined our understanding of the relationship between MHT and CVD risk. Although MHT should not be used for CVD prevention, absolute risks of CVD are low when MHT is started close to menopause in healthy women and hazard ratios tend to be lower for younger than older women. For women in early menopause and without contraindications to treatment, the benefits of MHT are likely to outweigh the risks when used for menopausal symptom management.

Further Evidence that Hormone Therapy Is Safe Soon After Menopause

Before the initial Women's Health Initiative (WHI) findings were published in 2002, many clinicians prescribed menopausal hormone therapy (HT)

Menopausal hormone therapy and breast cancer

Observational and randomized controlled trial data have extensively examined the relationship between menopausal hormone therapy (MHT) and risk of developing breast cancer. A highly influential study from the Women's Health Initiative (WHI) in 2002 reported that a MHT regimen of conjugated equine estrogens and medroxyprogesterone acetate increased the risk of breast cancer by 26%. Later reports from the WHI indicated that a MHT regimen with conjugated equine estrogens alone decreased the risk of breast cancer by 23%. Critical re-examination of the WHI study noted that the average participant age was 63, that few women had symptoms, and that the WHI results might not apply to younger, symptomatic women shortly after menopause. Since the original publications, several post hoc analyses and observational studies have stimulated reconsideration of the WHI findings. Emphasis has been directed toward risks in younger women just entering the menopause, the subgroup who are most likely to be considering MHT use.The goal of this treatise is to integrate available mechanistic and clinical information related to the use of estrogen alone or estrogen plus a progestogen for five years or less. These data suggest that estrogen alone neither decreases nor increases risk in younger women initiating therapy close to the time of menopause but decreases risk in older women. Both younger and older women experience an excess risk with estrogen plus a progestogen. The attributable risk in younger women is less in those with a low underlying Gail Model risk score. Effects of MHT on risk largely reflect actions on pre-existing, occult, undiagnosed breast cancers. Tumor kinetic models suggest that the pro-proliferative effects of estrogen plus a progestogen on occult tumors provide a mechanistic explanation for the increased risk with this therapy. Pro-apoptotic effects of estrogen alone may explain the reduction of breast cancer in women starting this therapy at an average age of 63 as reported in the WHI study.This article is part of a Special Issue entitled ‘Menopause’.

Lessons Learned From the Womenʼs Health Initiative Trials of Menopausal Hormone Therapy

We re-evaluate the Women's Health Initiative findings and their implications for clinical practice. Menopausal hormone therapy (HT) was effective for relief of vasomotor symptoms, and the risk of coronary heart disease (CHD) tended to be reduced in women close to menopause compared with the increased risk in women more distant from menopause. In recently menopausal women, short-term absolute risks of stroke and venous thromboembolism were small. Estrogen plus progestin therapy, but not estrogen therapy, increased the risk of breast cancer with a suggestion of greater risk when initiated close to the menopause. Menopausal HT increased the risk of CHD in women more than 20 years distant from menopause, particularly in women with vasomotor symptoms. It remains unknown whether the suggestive benefit for CHD in younger women will translate into benefits or harms if menopausal HT is continued into older ages. Based on Women's Health Initiative data, the use of menopausal HT for fewer than 5 years is a reasonable option for the relief of moderate to severe vasomotor symptoms. The risks seen with estrogen plus progestin therapy suggest careful periodic reassessment of the ongoing therapy needs for women taking estrogen plus progestin therapy. The more favorable profile of estrogen therapy allows for individualized management with respect to duration of use when symptoms persist. For both estrogen therapy and estrogen plus progestin therapy, the baseline risk profile of the individual woman needs to be taken into account. Menopausal HT is not suitable for long-term prevention of CHD given risks of stroke, venous thromboembolism, and breast cancer (for estrogen plus progestin therapy) found in both clinical trials and in observational studies.

Compounded bioidentical menopausal hormone therapy

Although improvement in long-term health is no longer an indication for menopausal hormone therapy, evidence supporting fewer adverse events in younger women, combined with its high overall effectiveness, has reinforced its usefulness for short-term treatment of menopausal symptoms. Menopausal therapy has been provided not only by commercially available products but also by compounding, or creation of an individualized preparation in response to a health care provider's prescription to create a medication tailored to the specialized needs of an individual patient. The Women's Health Initiative findings, coupled with an increase in the direct-to-consumer marketing and media promotion of compounded bioidentical hormonal preparations as safe and effective alternatives to conventional menopausal hormone therapy, have led to a recent increase in the popularity of compounded bioidentical hormones as well as an increase in questions about the use of these preparations. Not only is evidence lacking to support superiority claims of compounded bioidentical hormones over conventional menopausal hormone therapy, but these claims also pose the additional risks of variable purity and potency and lack efficacy and safety data. The Committee on Gynecologic Practice of the American College of Obstetricians and Gynecologists and the Practice Committee of the American Society for Reproductive Medicine provide an overview of the major issues of concern surrounding compounded bioidentical menopausal hormone therapy and provide recommendations for patient counseling.

A decade of postmenopausal hormone therapy prescribing in the United States

Nearly a decade ago, landmark clinical trials revealed an increase in the risks associated with hormone therapy in postmenopausal women, leading to early changes in prescribing patterns. Long-term prescribing patterns in the United States after these trials are unknown. The objective of this study was to describe changes in hormone therapy prescribing including dose, formulation, patient age, and prescriber specialty from 2000 to 2009. A national pharmacy claims database was used to describe the annual prevalence and incidence rates of hormone therapy prescribing from 2000 to 2009 in women 50 years and older. Throughout the decade, a number of prescribing trends were observed: a continuous decline in hormone therapy overall, an initial drop in new therapy that stabilized after 2003, a decline in oral formulations and increase in vaginal formulations, a decline in standard- and high-dose and an increase in low-dose oral formulations, and an increase in the proportion of women who received hormone therapy from gynecologists. Overall prescribing of hormone therapy continued to decline during the past decade, suggesting a long-term impact of the Women's Health Initiative findings. During this same time, treatment regimens shifted to favor vaginal and lower-dose oral formulations.

Stopping menopausal hormone therapy: If breast cancer really decreased, why did colorectal cancer not increase?

ObjectiveThe Women's Health Initiative (WHI) study of postmenopausal hormone therapy (HT) found that estrogen plus progestogen therapy (EPT) decreased colorectal cancer risk. Thus, the decline in EPT use from 2002 to 2003 should have precipitated an increase in the incidence of colorectal cancer. We tested this prediction using the SEER 9 epidemiologic database. MethodsWe analyzed WHI data concerning the effects of EPT and estrogen therapy (ET) on colorectal cancer risks. We also examined HT prescription sales data, as well as SEER 9 colorectal cancer incidences from 2001 to 2004. ResultsIn the WHI study, the incidence of colorectal cancer was comparable in EPT placebo-users, ET users, and ET placebo-users, but significantly lower in EPT users. Assuming that 30% of eligible women used HT in 2001, the decline in EPT sales from 2002 to 2003 of 63% should have increased the incidence of colorectal cancer by 2.8% in the overall population at risk. However, the SEER 9 colorectal cancer incidence fell by 5.9% in this population, which is comparable to the 6.7% decrease observed for invasive breast cancer from 2002 to 2003. ConclusionsDeclining EPT use from 2002 to 2003 should have precipitated an increase in the incidence of colorectal cancer, but the opposite trend was seen in the SEER 9 database during this time. The incidences of invasive breast cancer and colorectal cancer both declined by a similar amount from 2002 to 2003, despite the results of the WHI study predicting opposing trends for the two different types of cancer. Thus, the SEER 9 findings are fundamentally incompatible with expectations from the WHI findings. This implies that reductions in HT use from 2002 to 2003 cannot account for the contemporaneous changes in invasive breast cancer and colorectal cancer incidences. Alternative explanations must be found.

Studies Equivocal on High-Dose Vitamin D

DESTIN, FLA. – More is not necessarily better when it comes to vitamin D. “The optimal intake and blood levels are probably much more moderate than many have led us to believe,” JoAnn E. Manson, MD, DrPH, said at the Congress of Clinical Rheumatology. As a member of the 14-person Institute of Medicine (IOM) committee charged with developing a recently published report on dietary reference intakes of vitamin D and calcium, Dr. Manson assisted in a “rigorous comprehensive review” of more than 1,000 studies. While many researchers and clinicians have argued that people need much higher levels than the 400–800 IU/day intake (depending on age) recommended by the IOM to promote optimal health, the available evidence simply has not borne that out, said Dr. Manson, professor of epidemiology at Harvard University and chief of the division of preventive medicine at Brigham and Women's Hospital, Boston. Although some IOM report naysayers advocate levels up to 6,000 IU/day, it is actually very difficult to find any solid data showing increased benefit with higher doses, she said. In fact, the committee's findings indicate that adequate intake is 400 IU/day for infants through age 12 months, at least 600 IU/day for those aged 1–70 years, and 800 IU/day for those over age 70 years. The upper intake levels are 1,000 IU/day for those aged 0–6 months, 1,500 IU/day for those aged 6–12 months, 2,500 IU/day for those ages 1–3 years, 3,000 IU/day for those ages 4–8 years, and 4,000 IU/day for those over age 8 years, according to the IOM report (J. Clin. Endocrinol. Metab. 2011;96:53–8). The minimum levels represent the intake needed to meet the vitamin D requirements of 97.5% of the population, and they correspond to a serum 25-hydroxyvitamin D (25-OHD) level of 20 ng/mL. At levels above the upper intake level, which correspond to a serum 25-OHD level of about 50 ng/mL, adverse effects have been reported, Dr. Manson said. Emerging evidence suggests that intake resulting in such higher serum 25-OHD levels may be associated with increased all-cause mortality, cancer, cardiovascular disease, falls, and fractures, she noted. National Health and Nutrition Examination Survey data from 2008, for example, showed that age-adjusted mortality was highest among those with serum 25-OHD levels below 19 ng/mL in blacks and below 27.5 ng/mL in the entire cohort, and that mortality decreased with increasing levels – but only to a certain point. At levels in the 50-ng/mL range for blacks, and above 85 ng/mL in the entire cohort, mortality increased steadily. Data on the effects of vitamin D on skeletal health suggest that too much vitamin D can lead to adverse effects; these data provided the strongest basis for the IOM committee's report as they were most plentiful and convincing in terms of showing cause and effect. Evidence regarding numerous other diseases such as cancer, diabetes, and more also were considered. Women's Health Initiative findings, for example, show that adjusted hip fracture rates are highest among those with serum 25-OHD levels of 19.04 ng/mL and those greater than 28.3 ng/mL, and lowest among those between these levels, Dr. Manson said. In older men in the Osteoporotic Fractures in Men study, the adjusted risk of hip fractures was shown to be highest in those with serum 25-OHD levels less than 19 ng/mL (odds ratio, 2.36, compared with those with levels greater than 28 ng/mL), with risk declining steadily in those with levels up to 28 ng/mL (J. Bone Miner. Res. 2010;25:545–53). Other findings indicate the skeletal benefits of vitamin D are dependent on adequate calcium intake, which the committee determined is 1,200 mg/day for people aged 51 years and older. An Agency for Healthcare Research and Quality report in 2009, for example, showed that three randomized controlled trials indicated no significant effect of vitamin D alone on fracture risk, but that one randomized controlled trial showed a benefit in those who received 800 IU of vitamin D3 plus 1,200 mg/day of calcium for 2 years (odds ratio of fractures, 0.80), Dr. Manson said. Studies are currently underway to look closer at the effects of high-dose vitamin D supplementation, but the currently available evidence does not support high doses, she said. Dr. Manson has received funding from the National Institutes of Health to conduct a large-scale randomized trial of vitamin D and omega-3 fatty acids. She made no other relevant disclosure. Sharon Worcester is a freelance writer based in Sterrett, Ala.

Does hormone replacement therapy cause breast cancer? An application of causal principles to three studies

BackgroundBased principally on findings in three studies, the Collaborative Reanalysis (CR), the Women's Health Initiative (WHI), and the Million Women Study (MWS), it is claimed that combined hormone replacement therapy...

What was the immediate impact on population health of the recent fall in hormone replacement therapy prescribing in England? Ecological study

The publication in 2002 of the women's health initiative (WHI) trial revealed long-term risks and benefits of hormone replacement therapy (HRT). Increased cardiovascular disease, venous thromboembolism and breast cancer risks outweighed benefits on hip fracture, colorectal and endometrial cancer. We investigated whether the subsequent 50% fall in HRT use in England impacted on population rates of these outcomes. Time-series analysis of hospital admissions, incidence and mortality amongst women aged 50-69, England 1997-2006. There was no relationship between reduced HRT prescribing after 2002 and trends in breast cancer, colorectal cancer or hip fracture. Amongst 50-59 year olds, the annual percentage change in venous thromboembolism hospitalizations fell from 0.0% [95% confidence interval (CI): -2.3 to 2.3%] between 1997 and 2000 to -5.7% (-7.7 to -3.6%) between 2000 and 2006 (P-value = 0.001); the annual change in endometrial cancer mortality increased from 0.7% (-3.2 to 4.8%) between 1997 and 2003 to 11.0% (0.2 to 22.9%) after 2003 (P-value = 0.07); and previously falling acute myocardial infarction hospitalizations (annual change: -6.8%) and stroke (-3.0%) stabilized (-0.4%) or increased (+0.8%), respectively, around 2001 (P < 0.0001). Although rates of venous thromboembolism (decline) and endometrial cancer mortality (increase) changed in line with WHI findings, the decline in venous thromboembolism may have started before 2002 and increased fatal endometrial cancers could be a chance finding.

Physicians' and Women's Views on Hormone Therapy and Breast Cancer Risk After the WHI: A Qualitative Study

Background: The use of menopausal hormone therapy (HT) has significantly declined since the release of the Women's Health Initiative findings, but to what extent physicians' and women's concerns about breast cancer contributed to this change is unknown. Our study explored physicians' and women's beliefs about hormone therapy and breast cancer risk. Methods: We conducted qualitative in-depth interviews with 22 primary care physicians and 45 female patients at two large integrated health care delivery systems in Washington State and Massachusetts. Results: Concerns about breast cancer risk weighed into the decision-making process for physicians and women in initiating and continuing hormone therapy. For women, control of menopausal symptoms was important and possibly outweighed their concerns about the potential risks of breast cancer. Though concerned about its association with increasing breast cancer risk, physicians were willing to consider hormone therapy to manage women's menopausal symptoms but were frustrated about the lack of available non-hormone therapy alternatives. Most physicians and some women were aware of the Women's Health Initiative, and its findings appeared to influence their beliefs about hormone therapy and breast cancer risk, though doubts remained among both groups about the study findings and implications. Conclusions: Our qualitative study suggests that after the Women's Health Initiative, concerns about breast cancer risk weighed into decisions to initiate and continue hormone therapy for both physicians and women, but menopausal symptoms often directed use.

Provider attributes associated with hormone therapy prescribing frequency

The aim of this study was to identify provider characteristics associated with hormone therapy prescribing. The study design is cross-sectional. In December 2005, we mailed surveys to providers practicing in two integrated healthcare delivery systems located in the northwestern and northeastern United States; 379 responded (74%) and 249 (49% of total) granted access to their automated data. Data included provider demographics, practice characteristics, and perceptions about hormone therapy. Provider-specific annual hormone therapy prescribing frequency was calculated as days supply of hormone therapy filled divided by the number of visits (among women aged 45-80 y). Factors associated with higher rates of hormone therapy prescribing were identified using bivariate and multivariate analyses. We report results separately for primary care providers (internists and family practitioners) and obstetrician/gynecologists because significant correlates differed in these two groups. For both primary care providers and obstetrician/gynecologists, in multivariate analyses, hormone therapy prescribing varied by site (P < or = 0.002) and years at the healthcare organization (P < or = 0.01). For primary care providers only, higher hormone therapy prescribing was associated with reported expert knowledge of the hormone therapy trials (P < or = 0.001). For obstetrician/gynecologists, higher hormone therapy prescription was related to feeling well prepared to counsel women on hormone therapy (P < or = 0.007), believing that the risks of estrogen with progestogen had been exaggerated (P = 0.04), and seeing younger aged patients (P = 0.03). After the release of the Women's Health Initiative findings and practicing under similar clinical guidelines, hormone therapy prescribing is associated with providers' confidence, practice location, and time with a healthcare organization.

Invited Commentary: Hormone Therapy Risks and Benefits--The Women's Health Initiative Findings and the Postmenopausal Estrogen Timing Hypothesis

Worldwide evidence on menopausal hormone therapy shows that it does not reduce coronary heart disease (CHD) risk and that it increases the risks of breast cancer, stroke, and venous thromboembolism. These risks are not offset by reductions in hip fracture risk. Consequently, the Food and Drug Administration and other drug regulatory authorities agree that hormone therapy should be used chiefly for short-term relief of menopausal symptoms. Continuing speculation relates to the "postmenopausal estrogen timing" hypothesis, which proposes that hormone therapy initiated soon after menopause will prevent CHD while therapy started later will have a null or adverse effect. The detailed analyses of Women's Health Initiative data reviewed here specifically address the timing hypothesis. For hormone therapy initiated soon after menopause versus therapy started later, the findings demonstrate 1) similar null or adverse effects on CHD risk; 2) similar adverse effects on the risks of stroke and venous thrombosis; and 3) possibly greater adverse effects on breast cancer risk. Therefore, Women's Health Initiative data do not support the hypothesis of favorable effects in women starting hormone therapy soon after menopause. Hence, the overall trial findings, including net harm for combined estrogen-progestin and the lack of a net benefit for estrogen-only therapy, also apply to women initiating hormone therapy soon after menopause.