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.     

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.     

Women's awareness and knowledge of hormone therapy post-Women's Health Initiative

OBJECTIVE: Findings from the Women's Health Initiative (WHI) failed to confirm previous expectations about the net benefits of menopausal hormone therapy and have resulted in reduced use of these medications. The aim of this study was to evaluate women's awareness and knowledge concerning the risks and benefits of hormone therapy. DESIGN: A nationally representative survey was completed for a sample of 781 women (ages 40-60 y, mean 49 y) drawn from the Knowledge Networks Internet panel 24 months after publication of the first WHI findings, in June 2004. Responses were weighted to reflect the demographics of the US population. The main outcome measures were awareness of WHI and knowledge of its findings. An aggregate score was constructed to assess women's knowledge of the impact of hormone therapy on seven key disease outcomes. Logistic regression determined the independent predictors of (1) WHI awareness and (2) a positive aggregate knowledge score, reflecting appropriate responses about risks and benefits. RESULTS: Only 29% of women were aware of the WHI results. Only 40% of women had a positive aggregate knowledge score. Aside from awareness of WHI and independent of other factors, knowledge scores were lower for African American women (odds ratio, 0.4; 95% CI: 0.2-0.6) and among women with less education (odds ratio, 0.5; 95% CI: 0.3-0.9). Knowledge was greatest for breast cancer and osteoporosis outcomes and most limited for colorectal cancer and memory loss. CONCLUSION: Surveyed women had limited awareness and knowledge of the WHI results, suggesting limited diffusion. Targeting younger, less educated, and African American women is warranted.     

Low-dose estrogen therapy for prevention of osteoporosis: working our way back to monotherapy

The risks of low bone mineral density, osteoporosis and fractures, are major concerns in postmenopausal women. Although postmenopausal hormone therapy is effective for reducing these risks, safety issues have been raised by the results of studies such as the Women's Health Initiative. Although there are scientifically valid reasons to be wary of the general applicability of the Women's Health Initiative findings, the study has underscored the continuing need for research into new forms of menopausal hormone therapy. Low-dose transdermal estrogen monotherapy can preserve bone density while relieving vasomotor symptoms. Transdermal administration may offer advantages, including lack of first-pass liver metabolism, which permits the use of lower doses and avoids a negative impact on the lipid profile. Moreover, a recently published 2-year study of ultra-low-dose transdermal estrogen monotherapy in an older population similar to that of the WHI reported significant increases in bone mineral density, accompanied by significant reductions in markers of bone turnover, with no increased risk of endometrial hyperplasia or other side effects. Additional studies are warranted to shed further light on the possible benefits of low-dose estrogen monotherapy for the prevention of bone loss in postmenopausal women.     

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.     

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.     

Menopause in crisis post-Women's Health Initiative? A view based on personal clinical experience

Menopausal women should not consider that hormonal treatment is an obligatory long-term commitment. Estrogen-based treatments are extremely effective for vasomotor symptom relief and for vaginal atrophy. HRT also is one of several effective methods for the primary prevention of osteoporosis. If trials were done early after the menopause when the endothelium is likely still to be intact, estrogen-based treatment might be shown to prevent coronary heart disease. However, greater efficacy is to be expected from smoking cessation, proper nutrition, exercise, moderate alcohol consumption, statins, beta-blockers and angiotensin-converting enzyme inhibitors. The treatment options for a menopausal woman should include non-drug-related strategies, non-hormonal pharmaceutical therapies as well as hormonal treatments. The first objective of this contribution is to call to the attention of practising physicians the fact that the Women's Health Initiative (WHI) and Heart and Estrogen/Progestin Replacement Study (HERS) studies involved women much older than the early postmenopausal age groups for whom HRT is prescribed because of symptoms. The second objective is to emphasize that the attending physicians must not only treat the symptomatic women but also prevent the occurrence of diseases more prevalent after 60 years of age. Hormones can safely be used for the former, when not contraindicated, whereas for the latter non-pharmacological interventions and non-hormonal medications are preferable.     

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.     

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?     

Estrogen affects post-menopausal women differently than estrogen plus progestin replacement therapy

BACKGROUND: In the Women's Health Initiative Randomized Controlled Trial (WHI RCT), estrogen-only treatment compared with combined estrogen-progestin treatment resulted in less coronary artery disease, no increase in breast cancer and no reduction in colorectal cancer. Since we previously reasonably replicated the combined estrogen-progestin WHI RCT using the UK General Practice Research Database (GPRD), estrogen-only treatment was investigated using a similar methodology. METHODS: This GPRD study simulated the estrogen-only WHI RCT of women who had undergone a hysterectomy except for randomization. The primary analysis examined 11 572 unexposed and 6890 Exposed women (aged 55-79) treated with conjugated equine estrogen and was compared with the combined estrogen-progestin GPRD study. RESULTS: At baseline, women with a hysterectomy exhibited more cardiovascular disease than those with an intact uterus. In the estrogen-only GPRD study, adjusted hazard ratios (HRs) were 0.50 (0.38-0.67) for myocardial infarction (MI), 1.13 (0.91-1.41) for breast cancer, and 1.18 (0.72-1.92) for colorectal cancer. Compared to the HRs in the estrogen-progestin GPRD study, the estrogen-only results are significantly lower for MI and breast cancer and higher for colon cancer, a pattern similar to the WHI RCT study comparisons. CONCLUSIONS: This study confirms that post-menopausal women in the overall population respond differently to estrogen-only treatment compared with estrogen-progestin treatment, due to different hormone regimens and/or increased cardiovascular disease in hysterectomized women.     

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.     

Influences on older women's adherence to a low-fat diet in the Women's Health Initiative

OBJECTIVE: Most studies of dietary change during aging have focused on maintaining adequate intake by impaired elderly, and little is known about factors affecting dietary change for preventive purposes in older individuals. The purpose of this exploratory study was to determine the major behavioral influences on older women's adherence to a dietary fat reduction intervention. METHOD: A diverse sample of 92 women aged 55 to 80 was recruited from two East Coast sites of the Women's Health Initiative. All the women were participating in the dietary modification arm of WHI, had received the same dietary instruction, and were in the maintenance phase of the intervention. The women were classified by nutritionists as adherent or nonadherent to a diet limiting fat intake to <20% of total calories. Focus groups and telephone interviews were conducted, and textual data were coded and sorted using content analysis techniques within the four categories of the Stimuli-Organismic Factors-Response Repertoire-Consequences (SORC) behavioral model. Frequencies of responses within categories were tabulated and compared qualitatively. RESULTS: Adherent women were more likely to report assertiveness, a lifelong commitment to reduced dietary fat, satisfaction with their lifestyle changes, and having applicable knowledge and skills. Nonadherent women reported more difficulty resisting negative emotions and prior food preferences and habits; they were also more concerned about negative responses from others. CONCLUSIONS: Enhancing adherence of older women to a dietary fat reduction program will require shifting priorities away from conforming to social pressure and using high-fat foods for personal satisfaction and moving toward enhancing motivation and commitment to long-term 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.     

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.     

Estrogen-containing hormone therapy and Alzheimer's disease risk: understanding discrepant inferences from observational and experimental research

Estrogen has the potential to influence brain processes implicated in Alzheimer's disease pathogenesis. With the loss of ovarian estrogen production after menopause, estrogen-containing hormone therapy might be expected to influence the risk of Alzheimer's disease. Observational data link use of hormone therapy to reductions in Alzheimer risk, but experimental evidence from the Women's Health Initiative Memory Study trial demonstrates that oral estrogen, with or without a progestin, increases the incidence of dementia for postmenopausal women age 65 years or older. Mechanisms of harm in this setting are unknown. Bias and unrecognized confounding in observational research are leading candidates for discrepant results between observational studies and the Women's Health Initiative Memory Study trial. Studies are also distinguished by differences in outcome measures, hormone therapy formulations, prevalence of menopausal symptoms among study participants, and participant age. Finally, Women's Health Initiative Memory Study findings may not generalize to estrogen use by relatively young women during the menopausal transition or early postmenopause, a class of women who were ineligible for the Women's Health Initiative Memory Study trial. In observational studies, hormone therapy exposure often included use by younger women for menopausal vasomotor symptoms. Although there is no clinical trial evidence that hormone therapy at any age protects against Alzheimer's disease, it remains to be determined whether the age at which hormone exposure occurs or the timing of hormone therapy initiation in relation to the menopause (the critical window hypothesis) modifies treatment outcomes on dementia risk.     

Lessons to be learned from animal studies on hormones and the breast

The relation of hormone use by postmenopausal women to breast cancer risk has been controversial and unclear. A recent large randomized trial, the Women's Health Initiative (WHI) and a large observational study (Million Women Study) provided somewhat conflicting answers. The WHI found an increased incidence of breast cancer among women given hormone therapy (conjugated equine estrogen plus medroxyprogesterone acetate) but no increase in those given estrogen only therapy (conjugated equine estrogen alone). Whereas, the Million Women Study found an increased breast cancer risk among the estrogen plus progestin and the estrogen only users. This review brings comparative perspective to the issue of the effects of estrogen plus progestin versus estrogen only effects on breast cancer and is focused particularly on nonhuman primates. Although data from rodents is mixed, studies of monkeys suggest that estrogen only treatment has little or no effect on breast cell proliferation, and by inference, on breast cancer risk. On the other hand, data from both mouse and monkey studies strongly support the conclusion that the co-administration of a progestogen with an estrogen markedly increases breast cell proliferation and the potential for breast cancer promotion.     

Attitudes towards and level of information on perimenopausal and postmenopausal hormone replacement therapy among Norwegian women

In order to investigate women's attitudes towards and level of information on perimenopausal and postmenopausal hormone replacement therapy (HRT) 1019 women over 17 years of age constituting a representative sample of the Norwegian female population were interviewed in 1990 as part of a monthly national opinion poll (response rate 96.5%). Women's magazines proved to be the most important source of information on hormone therapy. Only in the over-45 age group were doctors mentioned frequently as information sources. A high self-assessed information level was associated with a positive attitude towards hormone therapy. Those who had obtained information from a doctor were more positive than those who had not. More than half of those who expressed an opinion believed that hormone therapy increased the risk of heart infarction, stroke, breast cancer and cancer in general. There was a strong association between a negative attitude, towards using hormones and belief in an increased risk of serious disease. The women were more positive towards the use of HRT for the prevention of osteoporosis and for postmenopausal urogenital complaints than for the alleviation of climacteric symptoms.