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.     

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.     

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.     

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.     

Different mechanisms for benefit and risk of coronary heart disease and stroke in early postmenopausal women: a hypothetical explanation

In younger postmenopausal women, estrogen is thought to be protective against coronary heart disease. The mechanism for this effect is likely to be an inhibition of the development of atherosclerosis. However, in older postmenopausal women with established atherosclerosis, the initiation of estrogen therapy may cause coronary artery plaque instability and rupture, resulting in coronary thrombosis and myocardial infarction. Compared with these findings of coronary disease prevention in younger women, estrogen therapy has been linked to an increased risk of ischemic stroke in both younger and older postmenopausal women, although the risk is small and the event rate in younger women is considered to be rare. Here, we provide an argument that the mechanism for stroke risk in younger women is not based on atherosclerotic disease, as occurs in older women for both coronary disease and stroke, but is related to thrombosis. Susceptibility for stroke is increased in women, and various factors leading to thrombosis may explain this risk. This notion is supported by data that estrogen regimens that decrease the risk of venous thrombosis (lower oral doses and transdermal therapy) may not be associated with an increase in ischemic stroke risk.     

Luteal phase estrogen is decreased in regularly menstruating older women compared with a reference population of younger women

OBJECTIVE: To compare daily reproductive hormone secretion in regularly menstruating older versus younger women. DESIGN: This was a prospective cohort study. RESULTS: Daily morning urine samples were obtained from 106 women, 28 of whom were aged between 20 and 34 years (mean: 27.8+/-3.7 y) and 78 of whom were aged between 35 and 50 years (mean: 40.3+/-3.7 y). Lower luteal estrone-3-glucuronide levels were seen in the older versus the younger group (82.7 vs 93.5 ng/ml, P=0.035). The pregnanediol-3-glucuronide levels in the older group were lower than those in the younger group throughout the entire cycle. The median length of the follicular phase was shorter in the older versus younger women (13 vs 14.5 d, P=0.005). There was no significant difference in the median luteal phase lengths between groups. CONCLUSIONS: We report the new finding that regularly menstruating older women not only have lower pregnanediol-3-glucuronide levels but also have a significant reduction in luteal phase estrone-3-glucuronide compared with a contemporaneous cohort of younger women. This combined deficit may play a key role during the luteal-follicular transition, potentially affecting follicle recruitment and decreasing fecundity in the subsequent cycle.     

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.     

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.     

New evidence regarding hormone replacement therapies is urgently required transdermal postmenopausal hormone therapy differs from oral hormone therapy in risks and benefits

Controversies about the safety of different postmenopausal hormone therapies (HTs) started 30 years ago and reached a peak in 2003 after the publication of the results from the Women Health Initiative (WHI) trial and the Million Women Study (MWS) [Writing group for the women's health initiative investigations. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002;288:321-33; Million women study collaborators. Breast cancer and hormone-replacement therapy in the million women study. Lancet 2003;362:419-27]. The single HT formulation used in the WHI trial for non hysterectomized women-an association of oral conjugated equine estrogens (CEE-0.625 mg/day) and a synthetic progestin, medroxyprogesterone acetate (MPA-2.5 mg/day)-increases the risks of venous thromboembolism, cardiovascular disease, stroke and breast cancer. The MWS, an observational study, showed an increased breast cancer risk in users of estrogens combined with either medroxyprogesterone acetate (MPA), norethisterone, or norgestrel. It is unclear and questionable to what extent these results might be extrapolated to other HRT regimens, that differ in their doses, compositions and administration routes, and that were not assessed in the WHI trial and the MWS. Significant results were achieved with the publication of the WHI estrogen-only arm study [Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004;291:1701-1712] in which hormone therapy was reserved to women who had carried out hysterectomy. What emerged from this study will allow us to have some important argument to develop.     

HRT as secondary prevention of cardiovascular disease

Objective: To review the evidence of the efficacy of postmenopausal hormone replacement therapy (HRT) in secondary prevention of coronary artery disease or stroke. Results: Although a number of rather large and prolonged non-randomized observational studies have produced convincing and consistent evidence of the efficacy of HRT in the prevention of recurrence of cardiac events, the first randomized, placebo controlled trial (RCT) on heart disease and estrogen replacement study (HERS) reported no benefit of conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA) in secondary prevention of cardiac events in women with established coronary artery disease. This was supported by RCT reporting no effect of CEE or CEE + MPA on the progress of coronary sclerosis. Similarly, some nonrandomized observational studies have evaluated the risk of recurrent stroke in regard to the use of HRT, and the data are conflicting reporting a reduced or increased risk of recurrence for HRT users. One RCT has shown that low-dose estrogen treatment can only slow down the progression of carotid arteriosclerosis in high-risk postmenopausal women, whereas two other RCTs have shown no benefit (or risk) of using HRT for secondary prevention of ischemic stroke or progression of carotid atherosclerosis. Conclusion: The evidence accumutaed so far shows that HRT has no place in secondary prevention of coronary or carotic artery disease. Its use in these patients must be based on solid nonvascular indications and expected benefits from these causes.     

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.     

Cardiovascular risk factors in a cohort of Danish women born in 1936 prior to use of hormone therapy

OBJECTIVE: Many observational studies suggest hormone therapy protects against coronary heart disease in contrast to findings from large randomised clinical trials and an observational Danish study. A potential bias in the observational literature concerning the cardiovascular risk and benefits associated with use of hormone therapy is the so-called 'healthy user' phenomenon, i.e. self-selection to HT use is associated with healthier cardiovascular risk profile. This study investigates whether a random sample of Danish women using HT was characterised by a favourable cardiovascular risk profile prior to menopause. METHODS: A sample of 621 women born in 1936 living in Copenhagen County was included in a prospective population-based study initiated in 1976 with follow-ups in 1981, 1987 and 1996. Investigations comprised questionnaires and physical examinations. RESULTS: At 51 and 60 years, respectively, one-third and one-half had ever used HT. At 40 years women who subsequently use HT had lower body mass index, lower self-rated health and lower fasting glucose, but no differences according to blood pressure, cholesterol, triglyceride, physical activity, smoking habits or alcohol consumption. CONCLUSION: In a cohort of Danish women from the general population ever users of HT could not be characterised as unambiguous 'healthy users'.     

HRT and the primary prevention of cardiovascular disease

Observational studies have consistently shown a benefit of hormone replacement therapy (HRT) on coronary heart disease (CHD), but some randomised studies have not shown any significant effect. Thus questions still remains as to whether HRT is beneficial for CHD, and in whom this benefit might be achieved. The biological effects of oestrogen on the cardiovascular system have been extensively studied, and beneficial effects on metabolic CHD risk factors, as well as on arterial function and on surrogate clinical markers of CHD, have been demonstrated. Thus it seems implausible that HRT should not benefit CHD in postmenopausal women. Most randomised trials using clinical outcomes have studied just one dose of one HRT regimen, a dose inappropriately high with the average starting age of the participants being in their mid-60s. The observational population studies largely comprise women starting on HRT at appropriate dose around the age of menopause, i.e. early 50s. In fact, it was the older women in the randomised trials that failed to show benefit, whereas there was a trend to benefit in the younger ones for whom the starting dose of HRT was appropriate. Furthermore, a pilot study of lower dose HRT in older women did not show any cardiovascular harm. Inappropriately high doses of oestrogen could cause cardiovascular harm due to transient disturbances in thrombogenesis and vascular remodelling. Whilst the greatest CHD benefit may be seen by starting HRT in the early postmenopause, this does not exclude benefit in older women given appropriate low dose therapy.     

Hormone replacement therapy and risk for coronary heart disease. Data from the CORA-study--a case-control study on women with incident coronary heart disease

BACKGROUND: Hormone replacement therapy (HRT) has been suggested to prevent cardiovascular disease, while some intervention studies have shed doubt on this concept. Thus, uncertainty remains whether current HRT use is beneficial as to cardiovascular disease or may even be harmful. OBJECTIVES: This research investigates the association of hormone replacement therapy, risk factors and lifestyle characteristics with the manifestation of coronary heart disease in current HRT users versus never users. DESIGN: The coronary risk factors for atherosclerosis in women study (CORA-study) provide clinical and biochemical parameters and data on lifestyle in 200 consecutive pre- and postmenopausal women with incident coronary heart disease compared to 255 age-matched population-based controls, of which 87.9% were postmenopausal. RESULTS: Significantly more controls than cases used currently HRT for a median of 9.5 years (32.9% versus 20.2%), while 50.0% of cases and 42.5% of controls had never used HRT (p<0.02). Compared to women who never used HRT, current users ate less meat and sausage, had a significantly lower BMI and waist-to-hip ratio and a lower prevalence of hypertension, insulin resistance and diabetes. However, current users among cases were often smokers and smoked significantly more cigarettes than never users. In a multivariate analysis the risk of current HRT users for coronary artery disease was 57% lower than the risk of never users (odds ratio 0.428, CI 0.206-0.860, p<0.02). Adjustment for conventional and dietary risk factors revealed neither current HRT use, nor HRT use combined with smoking as independent risk factors. CONCLUSIONS: These data from the CORA-study are not compatible with an adverse impact of hormone replacement therapy on cardiovascular disease, rather support the notion of beneficial effects of HRT on weight, central adiposity, insulin sensitivity and blood pressure. Yet, the data do not support the presumption of a general healthy user effect in women on HRT either. Rather, in some women adverse lifestyle habits, especially intense smoking, appear to counteract possible beneficial effects of HRT.     

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.