Issues to debate on the Women's Health Initiative (WHI) study. Hormone replacement therapy: an epidemiological dilemma?

In July 2002 the data of the prematurely stopped Estrogen plus Progestin study of the Women's Health Initiative (WHI) were presented in the Journal of the American Medical Association. The results of the Heart and Estrogen/Progestin Replacement Study (HERS/HERS II) were published in the same issue. The results of WHI for healthy postmenopausal women often are interpreted to be in analogy with the HERS/HERS II results for postmenopausal women with established coronary heart disease. As a result of HERS/HERS II and WHI, use of HRT in general became questionable. This is an unjustified judgement of HRT in general. This synoptic review and criticism of both studies will show the methodological weaknesses and their consequences and the reasons for limited generalizability of the study results from WHI and HERS/HERS II on normal HRT users.     

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.     

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.     

Hormone replacement therapy and acute coronary outcomes: methodological issues between randomized and observational studies

A large number of observational studies, supported by animal and basic research studies, have shown a protective effect of hormone replacement therapy (HRT) on acute coronary outcomes. The recent large randomized Women's Health Initiative (WHI) study reported the opposite result, i.e. a small risk increase of 29% for acute coronary outcomes under estrogen-progestin treatment. Possible methodological reasons for these discrepancies are discussed. Despite randomization, the reported small increase in risk in the WHI study could be spurious because of differential unblinding of HRT users, which could have resulted in higher detection rates of otherwise clinically unrecognized acute myocardial infarction in these women. We show that altering diagnostic patterns because of unblinding could lower the crude rate ratio of 1.28 to 1.02. In the observational studies, the protective effect may have been exaggerated due to a healthy user bias and to the inappropriate choice of the reference group. Using an alternative reference group, the combined rate ratio of 0.67 was increased to 0.82. The diametrical effects of HRT on acute coronary outcomes found between the observational studies and the WHI Study may be a result not only of bias in the observational studies, but also of bias in the WHI Study.     

Influence of HRT on prognostic factors for breast cancer: a systematic review after the Women's Health Initiative trial

INTRODUCTION: Mortality due to breast cancer has been reported to be the same or even lower in HRT users than in non-users. This has been attributed to earlier diagnosis and to better prognosis. Nevertheless, more advanced disease in HRT users was reported recently by the Women's Health Initiative (WHI) study. The objective of this study was to assess, using a systematic review of current literature, whether the data of the WHI study are in contradiction to observational data. METHODS: We selected 25 studies, for which we evaluated the methodology, the characteristics of the studied populations, confounding breast cancer risk factors and prognostic indicators. RESULTS: The WHI study, showing a worsening of some prognostic parameters, is in contradiction to most published observational studies. Most observational studies are retrospective, not well matched and did not consider most confounding factors. Their methodology and selection criteria varied considerably and the number of patients was often small. No differences in the distributions of histology, grade or steroid receptors were observed in the WHI trial, while this was the case in some of the observational studies. Other parameters (S phase, protein Neu, Bcl-2 gene, protein p53 and E-cadherin, cathepsin D) were not reported in the WHI trial. CONCLUSIONS: In view of these data, the current clinical message to patients should be changed: one can no longer declare that breast cancers developed while using HRT are of better prognosis.     

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.     

Issues to debate on the Women's Health Initiative: failure of estrogen plus progestin therapy for prevention of breast cancer risk

Several studies on hormone replacement therapy (HRT) in the USA have been published. They revealed that the risk of breast cancer is increased with HRT more than with estrogen alone (ERT). A progestin has been given with each dose of ERT, as was the case in the Women's Health Initiative (WHI) study. The results of studies in Europe show similar trends. The increased risk of breast cancer in the WHI study was significantly higher only in women who had used HRT for several years before entering the study. The study was non-blind in 3444 cases, i.e. 40.5% of women in the estrogen plus progestin group and 6.8% in controls. If the women in the HRT group had more mammographic examinations it could change the validity of the results of the study. Estradiol-containing drugs have now been added to the list of carcinogens and the packages of these drugs have warning labels. The results of the WHI study do not support this labelling. The results of the WHI study show that the administration of HRT increases the risks of stroke and pulmonary embolism. It is reasonable to think that in the case of bleeding, at least at weekends in nursing homes (when staff levels may be low) patients were immobilized in their beds. Immobilization among women on HRT could have been more dangerous than the HRT itself. Progestins need to be delivered to the endometrium in a manner that will have the least effect on the breast. Systemic administration can be replaced by releasing progestin locally in the uterine cavity. Endometrial protection with a levonorgestrel-releasing intra-uterine system (IUS) is well tolerated. The high hepatic concentrations of estrogens given orally could be avoided by transdermal administration. New studies should be planned to reflect the situation in clinical practice. The time to start HRT in healthy menopausal women is between the ages of 45 to 55 years.     

Issues to debate on the Women's Health Initiative (WHI) study. Epidemiology or randomized clinical trials--time out for hormone replacement therapy studies?

Over the last 40 years, there has been increasing epidemiological evidence that post-menopausal treatment with sex steroids in physiological doses may reduce the relative risk of cardiovascular disease (CVD). These findings have been supported by biological studies showing favourable changes in cardiovascular risk factors with estrogen supplementation. The impact of the so-called 'healthy user' bias has been eagerly debated, and the results of the first and only randomized long-term clinical trial of HRT for primary prevention have therefore been long awaited. The dramatic decision to halt the Women's Health Initiative (WHI) study before completion came unexpectedly as the consequence of not only an increased risk of breast cancer but also increased occurrence of cardiovascular events with HRT. Due to the superior design of the study, the results from the WHI study have had an enormous impact on the clinical recommendations of HRT to post-menopausal women, concurrent with a degradation of evidence from observational studies. It is not very likely that other long-term randomized clinical trials (RCTs) will be completed and epidemiology has certainly been disreputed-so is this 'time out' for HRT studies?     

HRT, osteoporosis and regulatory authorities Quis custodiet ipsos custodes?

HRT has been widely used for the relief of menopausal symptoms and the prevention and treatment of post-menopausal osteoporosis. However, following the publication of the Women's Health Initiative (WHI) and the Million Women Study (MWS), regulatory authorities issued an urgent safety restriction on HRT use in preventing post-menopausal osteoporosis, recommending that it now be considered a second-line treatment. Are such recommendations justified? Treatments for osteoporosis, in women with increased future risk for fractures but who have not yet developed the disease, should prevent all types of osteoporotic fractures. Of the available therapies, none other than HRT has been clearly demonstrated to prevent hip fractures in such women. Thus, HRT should be recommended as first-line treatment for osteoporosis prevention. Potential risks of HRT, such as increased development of breast cancer and increased thromboembolism, have long been known. The WHI showed risks in less than 0.3% of women studied, and the MWS appears to have overestimated the risk of breast cancer. Thus, no new safety issues have been identified, and the regulatory authorities may have misinterpreted the data from these recent studies. When given for the correct indications, HRT is of major benefit to many women.     

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.     

Motives for initiation,temporary discontinuation,and permanent discontinuation of hormone replacement therapy use among Norwegian women

Objective

The use of hormone replacement therapy (HRT) declined strongly in many countries after publication of the WHI-study. The purpose of the present study was to investigate HRT usage patterns and motives for initiation, temporary discontinuation, and permanent discontinuation of HRT use among Norwegian women.

Methods

A questionnaire study about use and attitudes towards HRT was carried out in 2005. Women 45–64 years old were invited to the study (n = 2325, response rate 47%).

Results

Women initiated HRT use mainly due to climacteric complaints (74%), while prophylactic motives were less frequently reported (27%). The most often reported benefits of HRT use were reduced climacterical symptoms, especially hot flushes/sweating (83%), and improved quality of life (59%). The major proportion of ever-users (57%) had at some point temporarily discontinued HRT use. The motive for temporary discontinuation of HRT use most frequently reported was to see if climacterical symptoms had ceased (58%). Permanent discontinuation of HRT use was most often motivated by anxiety to side effects (55%). In multivariable analyses, women using HRT prophylactically were less likely to temporarily discontinue use. Women with a positive attitude towards HRT were the most unlikely ones to permanently discontinue HRT use.

Conclusions

Temporary discontinuation of HRT use was common among Norwegian women. The majority of HRT users reported a reduction in climacteric complaints after initiation of HRT use but many women were afraid of side effects.     

Determinants of hormone replacement therapy duration among postmenopausal women with intact uteri

OBJECTIVE: To investigate factors associated with hormone replacement therapy (HRT) duration among postmenopausal women with intact uteri. DESIGN: A Cox proportional hazard model on time to HRT discontinuation is estimated for 2,632 postmenopausal HRT users with intact uteri who began a new episode of treatment between January 1990 and December 1994 in Saskatchewan, Canada. RESULTS: Major contraindicating medical events were highly associated with HRT discontinuation among postmenopausal women. Women who were diagnosed with uterine cancer while taking HRT were almost four times as likely to discontinue HRT, and women who were diagnosed with breast cancer while taking HRT were nearly five times as likely to discontinue HRT. Other statistically significant factors associated with the duration of HRT episodes include administration mode and the ability to try different types and strengths of HRT. Women initiating HRT with a transdermal patch were 50% more likely to discontinue it. Women who were willing and able to experiment with different HRT reduced their likelihood of discontinuing by one-half to three-fourths. CONCLUSIONS: Although some of the factors associated with the hazard of HRT discontinuation among postmenopausal women who are taking the treatment for preventive benefits are immutable, clinicians may influence HRT continuation rates through initial drug choice or modifications in drug type or regimen over the course of therapy.     

Influences of hormone replacement therapy on postmenopausal women's health perceptions

OBJECTIVE: To assess the beliefs of climacteric women regarding their health, menopause, and hormone replacement therapy (HRT). DESIGN: Medical students asked to interview 526 healthy women, ranging from 40 to 64 years of age, between January and February of 2002. Of that number, 26 (4.9%) declined to participate in the interview. Thus, 500 women were interviewed about their beliefs and perceptions regarding their quality of life and health risks, as well as their opinions on menopause and HRT. RESULTS: The mean age of the sample was 53.3 +/- 6.2 years; 83.4% were postmenopausal, and 18.8% were HRT users. Of the women interviewed, 38.6% believed that their health was good. Although 78.8% thought that cancer is the main cause of death, 64% of them considered themselves to be at high risk for cardiovascular disease and osteoporosis. Most (64%) believed that menopause deteriorates the quality of life and that it increases cardiovascular risk (52.4%) and osteoporosis (72.0%). The HRT users perceived that they had better health status (48.9% v 36.2%, P < 0.02) and smaller cardiovascular risk (54.3% v 66.3%, P < 0.04) than did the nonusers; however, they ignored the preventive effect of estrogens in osteoporosis. CONCLUSIONS: Women believe that menopause deteriorates their health. The HRT users perceived themselves to be healthier and to have a smaller risk for cardiovascular disease.     

Comparison of soft tissue body composition in postmenopausal women with or without hormone replacement therapy considering the influence of reproductive history and lifestyle

OBJECTIVES: To examine long-term effects of at least 5 years' conventional hormone replacement therapy (HRT), reproductive history and lifestyle on fat mass and muscle mass in postmenopausal women. RESEARCH DESIGN AND METHODS: A cross-sectional retrospective approach was used, including 64 healthy women (56-69 years, mean age 63.4 years). Hormone users were compared with age-matched non-users with respect to (a) type of HRT used (oestrogen vs oestrogen plus gestagen vs no hormones), (b) categories of oestrogens used (oestradiol-based oestrogens vs conjugated equine oestrogens vs no oestrogens) and (c) categories of gestagens used (testosterone derivatives vs progesterone derivatives vs no gestagens). Data on hormone use, reproductive history (age at menarche, age at menopause, number of years postmenopausal, number of children) and lifestyle (physical activity level, alcohol consumption, smoking habits) were collected by questionnaires. Body composition was analysed by multiple-frequency bioelectrical impedance analysis, estimating fat mass, fat-free mass and body cell mass as absolute values (FM, FFM, BCM, respectively) and percentages of body weight (%FM, %FFM, %BCM). RESULTS: Analysis of covariance, adjusting body composition variables for body mass index, showed that (a) unopposed oestrogen users, oestrogen plus gestagen users and non-users did not differ significantly in body composition variables, (b) users of oestradiol-based oestrogens had significantly more BCM than oestrogen abstainers (p < 0.05), (c) users of testosterone-based gestagens had more BCM than gestagen abstainers (p = 0.05). Stepwise multiple regression analyses, including HRT-related, reproductive and lifestyle variables, indicated that the duration of HRT (p < 0.05) and physical activity level (p = 0.01) were significant positive predictors of %BCM, whereas the number of children significantly positively predicted FM and %FM (each p < 0.05). No significant associations between fat-free mass and HRT were found. CONCLUSIONS: The results suggest that conventional doses of oestrogens and gestagens used in HRT might be a factor in preserving muscle mass after long-term administration. It is recommended that BCM is used instead of FFM as an indicator of muscle mass. Studies relating muscle mass to HRT in postmenopausal women should consider physical activity as a possible confounding variable.