The incidence of breast cancer and changes in the use of hormone replacement therapy: A review of the evidence

Even though a link between hormone replacement therapy (HRT) and breast cancer has been well documented in the epidemiological literature since the 1980s, it was not until publication of the results of the Women's Health Initiative (WHI) study in 2002 and the Million Women Study in 2003 that women and doctors started reconsidering the use of HRT and sales of HRT started to drop. This paper evaluates the impact of the publication of these two landmark studies on the expected and observed changes in the incidence of breast cancer.Between 2001–2002 and 2005–2006, sharp and significant reductions in the incidence of breast cancer of up to 22% were reported in many US and European populations, temporally consistent with the drop in usage of HRT. Declines in the rates of breast cancer were strongest for 50–60-year-old women (those most likely to be current users of HRT), affected mainly ER+ and PR+ cancers (those most strongly associated with HRT use), and were largest among women with the highest pre-decline prevalence of HRT use and the sharpest decline in its use.A considerable amount of scientific evidence supports the hypothesis that the decline in the incidence of breast cancer is in large part attributable to the sudden drop in HRT use following publication of the WHI and Million Women studies. Nevertheless, the problem of how to advise women contemplating HRT use today remains. Medical relief will remain necessary for many women with menopausal complaints, and so new therapeutic options need to be explored.     

US women desire greater professional guidance on hormone and alternative therapies for menopause symptom management

OBJECTIVE: Women increasingly use alternative therapies for menopause symptom relief. We examined 1) current use and perceptions of hormone and alternative therapies for symptom relief among US women, and 2) healthcare provider involvement in women's decision making. DESIGN: An online survey was completed by a national sample of 781 US women aged 40 to 60 years (72% survey completion rate) drawn from the Knowledge Networks panel in June 2004. Nationally representative estimates of women's use and perceptions of hormone and alternative therapies were made by accounting for sampling weights and survey design. RESULTS: Hormone therapy was reported among 263 or 37% of this largely symptomatic sample, of whom 59% had stopped primarily due to concern about its potential risks. Herbal products and soy supplements separately were used among 31% and 13% of symptomatic women, of whom 41% and 67% were current users. Forty-four percent of herb users considered these products helpful with symptom relief. Sampled women generally felt ill informed about proper doses and usage of herbal products. Also, 58% of the sampled women expressed at least some concerns about these products, whereas proven safety was the most important factor when women consider such products. Despite considering healthcare providers the most reliable source of information, sampled women expressed low confidence in their ability to give sufficient information about treatment options for menopause symptoms. CONCLUSIONS: Alternative therapies have become increasing popular and are quickly approaching hormone therapy in frequency as therapies for symptom relief among menopause-age women in the United States. However, large gaps exist between patient expectations and provider preparedness to guide patient decision making.     

Psychosocial factors associated with the use of hormonal replacement therapy in a longitudinal follow-up of Swedish women

Objectives: To follow up a cohort of 1400 women aged 52 years who had replied to a health questionnaire 4 years previously. The follow-up covered general and gynecological health, experience of symptoms, the use of hormone replacement, the reasons for starting HRT and effectiveness of treatment as well as comparison of users and nonusers concerning psychosocial factors and life style. Methods: A questionnaire together with a letter was mailed to the women who had responded previously. The questionnaire covered four different areas: sociodemographic background, general and gynecological health, a 20-item symptom rating scale, and questions concerning work role. Results: A total of 1194 women (85%) responded to the questionnaire; 40% of the women were currently using hormone replacement. The reasons for starting treatment were: relief of somatic (55%) and psychological symptoms (20%), increased wellbeing (5%), to prevent disease (5%) and other reasons,such as keeping young (15%). Positive effects were experienced by 86% and negative effects by 26%. Women using HRT had less frequent vasomotor symptoms, sleep problems and vaginal dryness and were more harmonious than nonusers. There were no differences between HRT users and nonusers regarding negative mood and sexual desire. Women with psychologically demanding and stressful jobs requiring concentration were more likely to use hormone replacement. Conclusions: Swedish women are increasingly willing to start hormone replacement, particularly those who suffer from vasomotor symptoms and who have stressful and psychologically demanding occupations. The majority of these experience relief of symptoms. A certain proportion will suffer from side effects and are likely to discontinue treatment.     

Hormone therapy and coronary heart disease in young women

OBJECTIVE: Because the Women's Health Initiative randomized controlled trial (WHI RCT) primarily studied older women, it is unresolved whether hormone therapy might prevent coronary heart disease in younger women. Given the similarity between our UK General Practice Research Database (GPRD) study of older women and the WHI RCT, the GPRD methodology was used to study a cohort of younger women. DESIGN: Women ages 50 to 55 years were investigated using data from the GPRD to simulate the WHI RCT in a manner similar to our initial study of older women. This study compared 30,102 unexposed and 20,654 exposed women treated with conjugated estrogens and norgestrel. RESULTS: Myocardial infarction was not altered significantly by hormone therapy (adjusted hazard ratio 0.91; 95% CI, 0.69-1.20). Stroke, venous thromboembolic events, breast cancer, and hip fracture were similar to both the GPRD study of older women and the WHI RCT. Although death was decreased in the total cohort, similar to older women, it was not altered significantly in a subset without missing covariate data. CONCLUSION: The similar results of the GPRD studies in younger and older women and between the GPRD and the WHI RCT suggest that hormone therapy does not prevent coronary heart disease in younger postmenopausal women. This study also demonstrates that investigation using a primary care electronic medical record database can expand the generalizability of findings from an RCT.     

Recent reversal of trends in hormone therapy use in a European population

OBJECTIVE: The impact of the Women's Health Initiative (WHI) randomized trial results published in July 2002 indicating that hormone therapy (HT) is potentially harmful for the heart and the mammary gland of naturally postmenopausal women was assessed for the first time in a European population. DESIGN: This study continuously monitored HT use from 1994 through 2003 in a population-based random sample of 5,758 women aged 35 to 74 years residing in Geneva (city and canton), Switzerland, yielding 1,938 naturally postmenopausal women with an intact uterus and 206 artificially postmenopausal women. Women in the former subgroup weighed substantially less than their WHI trial counterparts but were not otherwise at lower risk for cardiovascular disease. RESULTS: Among the naturally postmenopausal women with an intact uterus, current HT use increased from 29% to 46% (P < 0.0001) through July 2002 and then decreased abruptly to 31% in 2003. Current HT use remained stable (range, 38%-46%; trend P = 0.92) among the artificially postmenopausal women. CONCLUSIONS: Successive annual increases from 1994 through 2001 in the prevalence of current HT use by postmenopausal women living in Geneva were dramatically reversed to the level in 1994 just after the results of the WHI trial were published, but only for naturally postmenopausal women with an intact uterus. Approximately one in three of the latter women who stopped using HT may also have lost its beneficial effects on bone health.     

Changing use of hormone therapy among minority women since the Women's Health Initiative

OBJECTIVE: There has been a significant shift in the use of hormone therapy (HT) among nonminority women since the publication of results of the Women's Health Initiative (WHI). Little is known about how the WHI results affected minority populations. This survey measured patterns of HT use among inner city women after publication of the WHI results, identified factors involved in the decision to continue or discontinue HT, and characterized the symptom burden and the experience of women who attempted to discontinue HT. DESIGN: We conducted a cross-sectional survey of 101 English- and Spanish-speaking women in an inner city general internal medicine clinic from August 2003 to April 2004. All women had been taking HT at the time of the publication of the WHI results. The survey included questions on patient-reported experience with HT, symptoms of menopause, and use of alternative treatments. RESULTS: Overall, 101 of 142 (71%) eligible women agreed to participate. The mean age of participants was 60 years; 43% were African American and 46% were Hispanic. The mean duration of HT use was 9.6 years. Three quarters (74%) had heard about the WHI findings, and 87% had attempted to stop taking HT after their publication. The most common reason for attempting to stop HT was concern about an increased risk of cancer or a general increase in risk to health. Of those who stopped HT, the vast majority (85%) reported vasomotor symptoms, and 26% restarted HT, mostly to treat those symptoms. CONCLUSIONS: Nearly all minority women in this small sample attempted to stop HT use after the results of the WHI were published. Restarting HT for treatment of symptoms was common.     

WHI and aftermath: looking beyond the figures

In contrast to the preliminary results of the WHI conjugated equine estrogen plus medroxyprogesterone acetate arm published 2 years ago, the final results from that arm as well as preliminary data from the conjugated equine estrogen-only arm showed that the panic over hormone treatment for menopausal women was unjustified. Moreover, the data for women younger than 60-years-old was even more reassuring. WHI was a study on elderly women starting hormones under the assumption that it may confer cardioprotection. The results of WHI should not be generalized and should not be a reason to withhold hormones in symptomatic perimenopausal or early post-menopausal women who could benefit from that therapy.     

What is the impact of osteoporosis education and bone mineral density testing for postmenopausal women in a managed care setting?

OBJECTIVE: To assess whether osteoporosis education, with and without bone mineral density (BMD) testing, increases the initiation of lifestyle changes and pharmaceutical treatment to prevent osteoporosis. DESIGN: A total of 508 women, aged 54-65, from a large managed care organization who were not on osteoporosis prevention therapy participated in an intervention study. Participants were randomly assigned to either an education class on osteoporosis (n = 301) or education plus BMD (n = 207). A control group of 187 women receiving no intervention were also surveyed to serve as comparison. Group differences and differences based on BMD test result were compared 6 months after education regarding self-reported changes in health behaviors using chi2 tests and logistic regression analyses. RESULTS: Of the 508 intervention participants, 455 (90%) responded to the follow-up survey. Initiation of hormone replacement therapy was reported by 9%, with 5% reporting starting alendronate. More than half reported changes in diet, exercise, or calcium intake. Forty-three percent increased their vitamin D intake. There were no significant group differences in behavior except with regard to pharmaceutical therapy; subjects with education plus BMD were three times more likely than those receiving education only to report starting hormone replacement therapy (p = 0.004). Low BMD scores were associated with increasing vitamin D intake (p = 0.03) and starting medication (p = 0.001). Women in the intervention groups were significantly more likely to report modifying their diet (p < 0.001), calcium (p < 0.01), and vitamin D intake (p < 0.0001) than women in the control group, not exposed to education. CONCLUSION: Education regarding osteoporosis prevention seems to encourage women to make lifestyle changes. The inclusion of BMD testing enhances the likelihood that women will consider pharmaceutical therapy.     

Women's use of hormone replacement therapy for disease prevention; results of a community survey.

This study investigated whether an increased use of hormone replacement therapy (HRT) is attributable to a growing motivation among women to use the therapy for disease prevention. Compared with earlier studies, results from this community survey of women aged 51 to 57 years revealed an increased use of HRT, 60% of women had tried HRT, with a median of four years' duration of use. The most frequently cited primacy use for HRT was symptom relief although many women also took the therapy for the prevention of osteoporosis. While women generally commence HRT for symptom relief the extended use of the therapy is, in part, likely to be attributable to an increased motivation among women to remain on HRT for its 'added' benefit of preventing osteoporosis.     

Care of vaginal symptoms among HIV-infected women

OBJECTIVE: Gynecologic disease is common in HIV-infected women. We examine the sociodemographic, clinical, and provider factors associated with the care of women with vaginal symptoms. METHODS: Women enrolled in the HIV Cost and Services Utilization Study (HCSUS), a nationally representative probability sample of HIV-infected adults, were interviewed between January 1996 and April 1997. Women with vaginal symptoms who sought medical attention were asked, "Did your health care provider examine your vaginal area?" Women were also asked if they received medication for their symptoms. RESULTS: Among 154 women with vaginal symptoms, 127 sought care for their symptoms. Of those who sought care, 48% saw a gynecologist and 52% sought care from nongynecologists, most often their usual HIV care provider. Women who saw a gynecologist for their symptoms were more likely to have received a pelvic examination (92% versus 76%; p =.06) and vaginal fluid collection (98% versus 88%; p =.06) than those who saw their regular HIV provider. Fifteen percent of women received medication for their symptoms without having a pelvic examination; gynecologists were less likely to prescribe without an examination (8% versus 21%; p =.12). CONCLUSION: Gynecologists are more likely to provide adequate care of vaginal symptoms among HIV-infected women than nongynecologists who were HIV care providers. This specialty difference is consistent with quality of care studies for other medical conditions, but the potential gynecologic complications of inadequate evaluation and treatment warrants further investigation.     

Prior hormone therapy and breast cancer risk in the Women's Health Initiative randomized trial of estrogen plus progestin

OBJECTIVES: To assess the extent to which prior hormone therapy modifies the breast cancer risk found with estrogen plus progestin (E+P) in the Women's Health Initiative (WHI) randomized trial. METHODS: Subgroup analyses of prior hormone use on invasive breast cancer incidence in 16,608 postmenopausal women in the WHI randomized trial of E+P over an average 5.6 years of follow-up. RESULTS: Small but statistically significant differences were found between prior HT users and non-users for most breast cancer risk factors but Gail risk scores were similar. Duration of E+P use within the trial (mean 4.4 years, S.D. 2.0) did not vary by prior use. Among 4311 prior users, the adjusted hazard ratio (HR) for E+P versus placebo was 1.96 (95% confidence interval [CI]: 1.17-3.27), significantly different (p=0.03) from that among 12,297 never users (HR 1.02; 95% CI: 0.77-1.36). The interaction between study arm and follow-up time was significant overall (p=0.01) and among never users (p=0.02) but not among prior users (p=0.10). The cumulative incidence over time for the E+P and placebo groups appeared to cross after about 3 years in prior users, and after about 5 years in women with no prior use. No interaction was found with duration (p=0.08) or recency of prior use (p=0.17). Prior hormone use significantly increased the E+P hazard ratio for larger, more advanced tumors. CONCLUSION: A safe interval for combined hormone use could not be reliably defined with these data. However, the significant increase in breast cancer risk in the trial overall after only 5.6 years of follow-up, initially concentrated in women with prior hormone exposure, but with increasing risk over time in women without prior exposure, suggests that durations only slightly longer than those in the WHI trial are associated with increased risk of breast cancer. Longer-term exposure and follow-up data are needed.     

New evidence regarding hormone replacement therapies is urgently required transdermal postmenopausal hormone therapy differs from oral hormone therapy in risks and benefits

Controversies about the safety of different postmenopausal hormone therapies (HTs) started 30 years ago and reached a peak in 2003 after the publication of the results from the Women Health Initiative (WHI) trial and the Million Women Study (MWS) [Writing group for the women's health initiative investigations. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002;288:321-33; Million women study collaborators. Breast cancer and hormone-replacement therapy in the million women study. Lancet 2003;362:419-27]. The single HT formulation used in the WHI trial for non hysterectomized women-an association of oral conjugated equine estrogens (CEE-0.625 mg/day) and a synthetic progestin, medroxyprogesterone acetate (MPA-2.5 mg/day)-increases the risks of venous thromboembolism, cardiovascular disease, stroke and breast cancer. The MWS, an observational study, showed an increased breast cancer risk in users of estrogens combined with either medroxyprogesterone acetate (MPA), norethisterone, or norgestrel. It is unclear and questionable to what extent these results might be extrapolated to other HRT regimens, that differ in their doses, compositions and administration routes, and that were not assessed in the WHI trial and the MWS. Significant results were achieved with the publication of the WHI estrogen-only arm study [Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004;291:1701-1712] in which hormone therapy was reserved to women who had carried out hysterectomy. What emerged from this study will allow us to have some important argument to develop.