Commentary on the Women's Health Initiative

The Women's Health Initiative (WHI), established by the National Institutes of Health in 1991, is a long-term national health study that focuses on strategies for preventing heart disease, breast and colorectal cancer and osteoporosis in postmenopausal women. These chronic diseases are the major causes of death, disability and frailty in older women of all races and socioeconomic backgrounds. The WHI a 15-year multi-million dollar endeavor, and one of the largest U.S. prevention studies of its kind. The study involves over 161,000 women aged 50-79, and is one of the most definitive, far reaching clinical trials of women's health ever undertaken in the U.S. The WHI Clinical Trial and Observational Study will attempt to address many of the inequities in women's health research and provide practical information to women and their physicians about hormone replacement therapy, dietary patterns and calcium/vitamin D supplements, and their effects on the prevention of heart disease, cancer and osteoporosis. Emerging information from the NIH Women's Health Initiative and other studies of women's health begun in the 1990's should be changing the landscape of options for older women in the years to come.     

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.     

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.     

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 Women’s Health Initiative Conundrum

Summary The WHI has been designed to evaluate the metabolic risks and benefits of Estrogen/Progestagen Therapy (HT) or Estrogen Therapy (ET) in women in their later postmenopause. It has not been designed to study the effect of HT or ET on symptomatic peri- and early postmenopausal women. Furthermore, the selection criteria used in the WHI are not congruent with the profiles of women treated in daily medicine by HT/ET: women starting HT/ET in clinical routine are younger, less obese and healthier than the WHI population. Therefore, the results and the risk-benefit-conclusions of the WHI cannot be applied to normal symptomatic peri- and immediately postmenopausal women, and even less to women with early (40–50 years) or premature (40yrs.) menopause.     

The woman patient after WHI

An epidemic of fear and distrust has infected women (and physicians) after publication of the Women's Health Initiative (WHI). The overinflated negative data emerging from the oestroprogestinic arm of WHI have frightened women and gave rise to the most difficult emotions to cope with. Keywords such as cancer, death and hormones combined together, have potentiated an avoidant attitude towards hormonal therapy (HT) driven more emotionally than rationally. This negative aura has not been dissipated by the positive data from the oestrogen-only arm of WHI. This paper will discuss: women's different emotional reactions to and coping strategies for HT-related fear after WHI; the communication skills physicians should use in focusing on positive messages emerging from WHI; predictors of current HT use; the meaning of the higher use of HT in postmenopausal highly-educated women and women gynaecologists; the importance of increasing healthy life-styles as a taking of responsibility towards aging by every woman; shifting from passivity to active sharing of the decision making process with the caring physician; and the use of an individually tailored HT, when appropriate, as part of an active strategy in the pursuit of a longer health expectancy.     

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.     

Recency and duration of postmenopausal hormone therapy: effects on bone mineral density and fracture risk in the National Osteoporosis Risk Assessment (NORA) study

OBJECTIVES: Results from the Women's Health Initiative showed that postmenopausal hormone replacement therapy (HRT) prevents fractures but has an overall unfavorable risk:benefit ratio, leading to the recommendation that HRT be used only for women with troublesome menopause symptoms, and for as short a time as possible. This recommendation has important implications for the timing and duration of HRT and the prevention of osteoporosis. The large number of women participating in the National Osteoporosis Risk Assessment (NORA) program provided the opportunity to evaluate bone mineral density (BMD) and 1-year fracture risk in analyses stratified by duration and recency of HRT. DESIGN: Participants were 170,852 postmenopausal women aged 50 to 104, without known osteoporosis, who were recruited from primary physicians offices across the US. BMD was measured at one of four peripheral sites, and the 1-year risk of osteoporotic fracture was assessed by questionnaire. RESULTS: At baseline, current HRT users had the highest T-scores at every age. Among current hormone users, women who had used HRT longest had the highest BMD levels. Women who had stopped HRT more than 5 years previously, regardless of duration of use, had T-scores similar to never-users. Current but not past hormone use at baseline was associated with a 25% to 29% lower risk of osteoporotic fracture (P < 0.0001) in 1 year, compared with nonusers. These findings were independent of age, ethnicity, body mass index, lifestyle, years postmenopausal, and site of BMD measurement. CONCLUSIONS: We conclude that postmenopausal BMD and fracture are closely associated with current, but not prior, HRT use. Use of HRT for 5 years or less, as proposed for treatment of symptomatic women during menopause transition, is unlikely to preserve bone or significantly reduce fracture risk in later years.     

The women's health initiative: a potential resource for future studies of autoimmune diseases

The women's health initiative observational and clinical trials cohort is one of the largest and most carefully characterized group of postmenopausal women who have undergone long-term follow-up. Although outcome assessment has focused on the outcomes of CVD, cancer, and fractures, a wealth of data have been collected, which could form the basis for researchers interested in autoimmune diseases to begin important studies. Baseline and follow-up blood samples and DNA samples are available upon application to the study's Design and Analysis Committee and publications can be planned based on the current dataset upon application to the Publications and Presentations Committee. In both of these cases, one of the principal investigators from the 40 clinical centers or the Central Coordinating Center would need to be involved as a collaborator. Upon obtaining appropriate IRB approval, it could be possible to recontact women to collect additional information to verify outcomes or obtain further follow-up data. In addition to the WHI, the National Institutes of Health have funded a number of other large cohort studies that could be of use for researchers of autoimmune diseases. These include several longitudinal studies of diabetes funded by the NIDDK and several other large cardiovascular cohorts funded by the National Heart, Blood and Lung institute (e.g. ARIC, CARDIA and CHS. In addition, the national Cancer Institute has funded studies of large cohorts of Whites, Blacks, Hispanics, and American Indians in the United States. In all these studies, individuals have undergone baseline assessment for environmental and lifestyle risk factors and are being followed for long-term health outcomes. Given the time and expense devoted to the Women's Health initiative and these other studies, it would be of great value if researchers interested in a wide variety of chronic diseases would make use of these rich sources of data.     

Updating the EMAS 2004/2005 clinical recommendations on postmenopausal therapy following the recent publications: WHI and Nurses' Health Study

This new statement from EMAS presents the findings reported in recent publications from both WHI and the Nurses' Health Study to consider if these findings require the EMAS position to be modified. In general the reports do not necessitate a revision of the current EMAS advice but do provide further insight into the ongoing controversy around the possibility that estrogen (E) or estrogen-progestogen (E-P) use in younger postmenopausal women may supply cardiovascular benefit in the younger group.     

WHI risks: Any relevance to menopause management?

Two randomised controlled trials of hormone therapy (HT) were conducted within the US Women's Health Initiative. Both were chronic disease prevention trials, undertaken to determine whether HT reduced cardiovascular risk and increased breast cancer risk. Because the majority of subjects in both trials were asymptomatic and many years postmenopausal, and because substantial numbers had received HT prior to recruitment to the trials, care must be taken in drawing conclusions that the observed risks are applicable to women for whom HT is conventionally prescribed. Each of the reported risks must be examined critically to determine its likely applicability to symptomatic women treated for two to three years to relieve symptoms, but sometimes for substantially longer periods. Further, the risks reported in each of the two trials must be considered separately. Concerning cardiovascular disease, many subjects in the trials were at increased baseline risk because of their age, body mass index, smoking status, blood pressure and years since menopause, in contrast to the usual situation for symptomatic perimenopausal women. Therefore the reported overall cardiovascular risks in WHI, in both treatment arms, should be regarded as irrelevant to menopause management. In contrast, breast cancer risk is relevant, providing that proper note is taken of the fact that there was no increased risk after five years of combined hormone therapy in non-prior HT users and there was a tendency to a decreased risk in oestrogen only treated individuals. Other risks are analysed similarly.     

The North American Menopause Society 1998 Menopause Survey. Part I: Postmenopausal women's perceptions about menopause and midlife.

OBJECTIVE: To collect information relevant to the mission of The North American Menopause Society (NAMS)--i.e., increasing understanding of menopause--by assessing perceptions held by postmenopausal women in the United States aged 50 to 65 years regarding their menopause transition and early postmenopausal years. DESIGN: During the period from June to July 1998, The Gallup Organization conducted 752 telephone interviews with a randomly selected sample of postmenopausal women aged 50 to 65 years from across the United States, based on questions developed by NAMS. In Part I of this survey, women were asked about their personal experiences with menopause, their health-related lifestyle changes since premenopause, their frequency of discussing menopause, and their rating of preparedness for menopause. Part II of this survey, including use of hormone replacement therapy as well as use of healthcare services, will be reported in a future communication from NAMS. RESULTS: The majority (51%) of the postmenopausal women surveyed reported being happiest and most fulfilled between the ages of 50 to 65 years, compared with when they were in their 20s (10%), 30s (17%), or 40s (16%). Many areas of their lives had improved since menopause, including family/home life, sense of personal fulfillment, ability to focus on hobbies or other interests, relationship with spouse/partner, and friendships. A majority (51%) said their sexual relationships had remained unchanged. Approximately three-quarters of women surveyed reported making some type of health-related lifestyle change, such as stopping smoking, at menopause/midlife. Women who had undergone hysterectomy expressed more improvement than women with an intact uterus, especially in the areas of sexual relationships, spouse/partner relationships, personal fulfillment, and physical health; data are not available regarding the health state of these women before surgery or whether they experienced surgical menopause, but this improvement did not appear to be the result of hormone replacement therapy. Women tended to look to women from their own generation for menopause-related information and believed that they have prepared the younger generation for menopause better than they were prepared by their mothers' generation. Those surveyed advised younger women to engage in healthful activities and become knowledgeable so that they could make informed health decisions. CONCLUSIONS: Although the postmenopausal women surveyed had differing views of menopause as well as their perceptions of postmenopause compared with premenopause, the majority viewed menopause and midlife as the beginning of many positive changes in their lives and health. Hysterectomy was a factor associated with improved sexual relationships, spouse/partner relationships, sense of personal fulfillment, and physical health.