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.     

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.     

Breast cancer risk in the WHI study: the problem of obesity

In the climacteric, about 40% of the women have occult breast tumors the growth of which may be stimulated by hormones. Many genetic, reproductive and lifestyle factors may influence the incidence of breast cancer. Epidemiological data suggest that the increase in the relative risk (RR) of breast cancer induced by hormone replacement therapy (HRT) is comparable with that associated with early menarche, late menopause, late first birth, alcohol consumption, etc. One of the most important risk factors is obesity which exceeds the effect of HRT by far, and in overweight postmenopausal women the elevated risk of breast cancer is not further increased by HRT. As in the WHI study the majority of women was overweight or obese, this trial was unsuitable for the investigation of breast cancer risk. In the women treated with an estrogen/progestin combination, the RR of breast cancer rose only in those women who have been treated with hormones prior to the study, suggesting a selection bias. In the women not pretreated with hormones, it was not elevated. In the estrogen-only arm of the WHI study, there was no increase but a steady decrease in the RR of breast cancer during 6.8 years of estrogen therapy. This result was unexpected, as estrogens are known to facilitate the development and growth of breast tumors, and the effect is enhanced by the addition of progestins. Obese women are at high risk to develop a metabolic syndrome including insulin resistance and hyperinsulinemia. In postmenopausal women, elevated insulin levels are not only associated with an increased risk for cardiovascular disease, but also for breast cancer. This might explain the effects observed in both arms of the WHI study: HRT with relative low doses of estrogens may improve insulin resistance and, hence, reduce the elevated breast cancer risk in obese patients, whereas this beneficial estrogen effect may be antagonized by progestins. The principal options for the reduction of breast cancer risk in postmenopausal women are the prevention of overweight and obesity to avoid the development of hyperinsulinemia, the medical treatment of insulin resistance, the use of low doses of estrogens and the reduction of exposure to progestins. The latter might include long-cycles with the sequential use of appropriate progestins every 3 months for 14 days. There are large inter-individual variations in the proliferative response to estrogens of the endometrium. Control by vaginalsonography and progestin challenge tests may help to identify those women who may be candidates for low-dose estrogen-only therapy.     

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.     

The relationship between mammographic density and duration of hormone therapy: effects of estrogen and estrogen-progestin

BACKGROUND: The purpose of this study was to examine the effects of duration of hormone therapy (HT) and treatment regimens on mammographic density. METHODS: A retrospective study was carried out of of 467 post-menopausal women who received estrogen or estrogen-progestin and had regular mammographic density determination by the Breast Imaging Reporting and Data System between 1994 and 2001. RESULTS: The fraction of women using HT who had an increase in mammographic density became more important over time. Further analysis of the effects of regimens after 4 years of HT shows that the increase in mean density was much greater in women receiving combined HT than in those receiving estrogen alone. The incidence of increased mammographic density showed significantly progressive increases over the duration of combined HT from 7.5 to 22.4%. CONCLUSIONS: Although most women using HT maintained breast density at pre-treatment levels, there is a note of caution for women using long-term HT, especially those using combined estrogen-progestin.     

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.     

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.     

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.     

Breast cancer risk with postmenopausal hormonal treatment

This review was designed to determine from the best evidence whether there is an association between postmenopausal hormonal treatment and breast cancer risk. Also, if there is an association, does it vary according to duration and cessation of use, type of regimen, type of hormonal product or route of administration; whether there is a differential effect on risk of lobular and ductal cancer; and whether hormone treatment is associated with breast cancers that have better prognostic factors? Data sources for the review included Medline, the Cochrane Database of Systematic Reviews (Cochrane Library, 2005) and reference lists in the identified citations. Eligible citations addressed invasive breast cancer risk among postmenopausal women and involved use of the estrogen products with or without progestin that are used as treatment for menopausal symptoms. Abstracted data were demographic groupings, categories of hormone use, categories of breast cancer, two-by-two tables of exposure and outcome and adjusted odds ratios, relative risks (RRs) or hazard rates. Average estimates of risk were weighted by the inverse variance method, or if heterogeneous, using a random effects model. The average risk of invasive breast cancer with estrogen use was 0.79 [95% confidence interval (95% CI) = 0.61-1.02] in four randomized trials involving 12 643 women. The average breast cancer risk with estrogen-progestin use was 1.24 (95% CI = 1.03-1.50) in four randomized trials involving 19 756 women. The average risks reported in recent epidemiological studies were higher: 1.18 (95% CI = 1.01-1.38) with current use of estrogen alone and 1.70 (95% CI = 1.36-2.17) with current use of estrogen-progestin. The association of breast cancer with current use was stronger than the association with ever use, which includes past use. For past use, the increased breast cancer risk diminished soon after discontinuing hormones and normalized within 5 years. Reasonably adequate data do not show that breast cancer risk varies significantly with different types of estrogen or progestin preparations, lower dosages or different routes of administration, although there is a small difference between sequential and continuous progestin regimens. Epidemiological studies indicate that estrogen-progestin use increases risk of lobular more than ductal breast cancer, but the number of studies and cases of lobular cancer remains limited. Among important prognostic factors, the stage and grade in breast cancers associated with hormone use [corrected] do not differ significantly from those in non-users, but breast cancers in estrogen-progestin users are significantly more likely to be estrogen receptor (ER) positive. In conclusion, valid evidence from randomized controlled trials (RCTs) indicates that breast cancer risk is increased with estrogen-progestin use more than with estrogen alone. Epidemiological evidence involving more than 1.5 million women agrees broadly with the trial findings. Although new studies are unlikely to alter the key findings about overall breast cancer risk, research is needed, however, to determine the role of progestin, evaluate the risk of lobular cancer and delineate effects of hormone use on receptor presence, prognosis and mortality in breast cancer.     

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.     

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.     

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?     

Breast cancer risk associated with being treated for infertility: results from the French E3N cohort study

BACKGROUND: The use of fertility drugs (FDs) is steadily increasing in Western countries and concern has been raised as to the possible impact of fertility treatments on breast cancer risk. METHODS: We analysed this association in the French E3N study. In this prospective cohort, data on treatment against infertility, duration and time of administration were collected at entry through self-administered questionnaires. Cox regression analysis was used to estimate adjusted relative risks (RRs). RESULTS: Among the 92 555 women from the study population, 6602 women were treated for infertility. During the 10 year follow-up period, 2571 cases of primary invasive breast cancer were diagnosed (183 in treated women). Our study showed no overall significant association between breast cancer risk and treatment for infertility (RR = 0.95, confidence interval 0.82-1.11), after surgery or FDs, and whatever the type, the duration of use and the age at first use of FDs. However, infertility treatment was associated with an increased risk, of borderline significance, of breast cancer among women with a family history of breast cancer. This last result had limited statistical power. CONCLUSIONS: Our study provides evidence that treatment for infertility does not influence breast cancer risk overall. An interaction with a familial history of breast cancer is possible but should be investigated further.     

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.     

Tumour incidence in Swedish women who gave birth following IVF treatment

BACKGROUND: Possible effects on maternal tumour incidence of a full-term pregnancy following IVF treatment with indicated supraphysiologic steroid and peptide hormonal levels in pregnancy remain uncertain. METHODS: National registries were used to compare incidence of non-invasive and invasive tumour disease in Swedish women with live birth following IVF treatment with women with live birth without IVF. RESULTS: The study had a mean follow-up period of 6.2 years in the IVF group and 7.8 years in the non-IVF group, and the mean gestation period (s.d.) for IVF and non-IVF group was 271.0 (21.1) days and 278.5 (14.1) days, respectively. In a multivariate Poisson regression analysis, adjusted rate ratios of 0.70 (0.52-0.92) and 0.93 (0.58-1.43) among IVF women were found for the risk of carcinoma in situ (CIS) of the cervix and breast cancer, respectively. When date of conception plus 1 and 3 years were used as start of follow-up, the rate ratios of CIS of the cervix increased to 0.77 (0.57-1.03) and 0.86 (0.60-1.19), respectively, and the corresponding figures for breast cancer decreased to 0.91 (0.58-1.42) and 0.74 (0.40-1.26). CONCLUSION: Following a relatively short follow-up period, there is little if any increased risk of premenopausal cancer development in women who gave birth after IVF treatment. The women who gave birth after IVF treatment had a decreased incidence of CIS of the cervix and breast cancer, but only the former was statistically significant. However, further studies are necessary to include longer follow-up times.