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.     

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.     

HRT and gynaecologic cancer after WHI: old stuff or new doubts?

Previous studies had shown that there is little concern about endometrial cancer risk with hormone replacement therapy (HRT), whereas the risk of ovarian cancer is still debated. A new paper based on the women's health initiative (WHI) study devoted to gynaecologic cancers has been published in the October 2003 issue of JAMA, leading to the conclusion that also for endometrial and ovarian cancer risk, as the first WHI publication did for breast cancer risk, the previous large studies have been confirmed. About follow-up the authors conclude that, "The increased burden of endometrial biopsies required to assess vaginal bleeding further limits the acceptability of this regimen." These conclusions deserve a thorough analysis and must be read in the light of the burden of available epidemiological and clinical data and of recommended clinical practice. In the WHI trial the use of continuous combined HRT has resulted in a considerable increase of both imaging and invasive exams, to investigate women with bleeding or spotting, but the findings of these exams have been invariably negative. As far as, all published studies agree on the fact that continuous combined HRT either has no effect or significantly reduces the risk of both endometrial hyperplasia and cancer, there should be no reason to close-watching endometrium of women using this regimen with a different strategy from that employed on any healthy woman.     

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.     

Potential age-dependent effects of estrogen on neural injury

In 2000, approximately 10 million women were receiving hormone replacement therapy (HRT) for alleviation of menopausal symptoms. A number of prior animal studies suggested that HRT may be neuroprotective and cardioprotective. Then, in 2003, reports from the Women's Health Initiative (WHI) indicated that long-term estrogen/progestin supplementation led to increased incidence of stroke. A second branch of the WHI in women with prior hysterectomy found an even stronger correlation between estrogen supplementation alone and stroke incidence. Follow-up analyses of the data, as well as data from other smaller clinical trials, have also demonstrated increased stroke severity in women receiving HRT or estrogen alone. This review examines the studies indicating that estrogen is neuroprotectant in animal models and explores potential reasons why this may not be true in postmenopausal women. Specifically, age-related differences in estrogen receptors and estrogenic actions in the brain are discussed, with the conclusion that animal models of disease must closely mimic human disease to produce clinically relevant results.     

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.     

Climacteric symptoms and knowledge about hormone replacement therapy among Hong Kong Chinese women aged 40-60 years

OBJECTIVES: To evaluate the use of hormone replacement therapy (HRT), the prevalence of climacteric symptoms, and the knowledge about HRT. METHODS: A prospective study was conducted by telephone interview among a randomly selected population-based sample of 978 Hong Kong Chinese women aged 40-60 years. RESULTS: Of 414 women with a history of either natural or surgical menopause, 22 (5.3%) and 17 (4.1%), respectively, were either past or current users of HRT. The climacteric symptom scores of premenopausal women were significantly lower than those of perimenopausal women, but were comparable with those of postmenopausal women. The commonest climacteric symptom was 'muscle and joint pains' which was reported in 553 (56.6%) women, while only 228 (23.3%) and 151 (15.4%) women reported hot flushes and night sweating, respectively. Moreover, only 230 (23.5%) women realized that HRT could relieve menopausal symptoms and only 33 (3.4%) women were aware that HRT was protective against osteoporosis. In general, women with more climacteric symptoms, who had ever used HRT, and those with higher education level and higher family income, had better knowledge about HRT. CONCLUSIONS: Postmenopausal Hong Kong Chinese women have a low HRT usage rate and the majority of them are lacking of the knowledge about HRT.     

Five-year compliance with hormone replacement therapy in postmenopausal Chinese women in Hong Kong

Objectives: To assess 5-year compliance with hormone replacement therapy (HRT) in Hong Kong Chinese women and the reasons for long-term compliance or non-compliance. Methods: A telephone survey using a standardized questionnaire was conducted in 187 postmenopausal women who had commenced HRT in a referral-only specialist clinic of a university teaching hospital 5 years previously. Over this 5-year period, the cohort had been referred out to primary care doctors once they had become stabilized on treatment. Results: The 5-year compliance rate was 71.1%. The overall compliance rates were nearly the same from 2 and 5 years. ‘Doctors’ advice’ was the most important reason for maintenance of long-term compliance, accounting for 88.0% of all compliant cases. The most frequent reason for non-compliance was that of the experience of side effects. Other important reasons were fear of cancer, fear of other side effects, and discouragement from other doctors. Overall, 16.0% of women expressed concern regarding potential side effects or risk of breast cancer. Younger age at menopause and at time of initial consultation, shorter duration of menopause at presentation and previous history of hysterectomy were associated with a higher degree of compliance at 5 years. Presence or absence of menopausal symptoms, on the other hand, was not a significant factor. Conclusions: The 5-year compliance rate in this cohort of Hong Kong Chinese women was comparable to that reported from predominantly Caucasian populations. The physicians’ role in encouraging postmenopausal women to achieve long-term HRT compliance was observed.