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.     

Hormone therapy initiation after the Women's Health Initiative

OBJECTIVES: To describe hormone therapy (HT) initiation after the 2002 publication of the Women's Health Initiative. DESIGN: Observational cohort (1999-2003) of women ages 40 to 79 years, five health plans, used HT in July 2002 and subsequently discontinued or never used before August 2002. RESULTS: Of discontinuers, 15.8% (3,203 of 20,205) reinitiated HT. Reinitiation was higher among estrogen users (23.8%) versus estrogen with progestin users (11.3%), and lower among those with diabetes (relative risk [RR]=0.68, 95% CI: 0.61-0.76), cardiovascular disease (RR=0.87, 95% CI: 0.83-0.92), and hyperlipidemia (RR=0.83, 95% CI: 0.79-0.88). Only 2.3% (2,072 of 90,261) of never users initiated (August 2002 to December 2003). First-time initiation was associated with cardiovascular disease (RR=1.17, 95% CI: 1.10-1.25) and hyperlipidemia (RR=1.24, 95% CI: 1.17-1.33) and was less common among those with diabetes (RR=0.70, 95% CI: 0.63-0.79). CONCLUSIONS: After the Women's Health Initiative, a minority of women reinitiated or became first-time initiators of HT. Women with cardiovascular disease, diabetes, and hyperlipidemia were less likely to reinitiate; women with cardiovascular disease and hyperlipidemia were more likely to be first-time initiators.     

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.     

Results from the Estonian postmenopausal hormone therapy trial [ISRCTN35338757

OBJECTIVES: At present the Women's Health Initiative trial is the only reported randomised controlled trial studying the effects of hormone therapy among healthy postmenopausal women. The Women's Health Initiative reports have been criticized for lacking in generalisability, due to the characteristics of the trial population. We aimed to compare the health effects of oral continuous combined hormone therapy with a placebo and non-treatment among healthy Estonian women. METHODS: Eligible women were randomised into a blind group of hormone therapy versus placebo and into a non-blind group of open label hormone therapy versus non-treatment. One thousand seven hundred and seventy-eight postmenopausal women aged 50-64 at the time of sampling were recruited in 1999-2001 at three clinical centers in Estonia. Participants received conjugated equine oestrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5mg/d, or conjugated equine oestrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 5mg/d, if less than 3 years had passed since menopause at recruitment, or matched placebo or non-treatment. Trial treatment was stopped gradually from 1 January 2004 to 31 May 2004. RESULTS: After a follow-up period from 2.0 to 5.0 years the combined hazard ratio, stratified by blinding and adjusted for age at recruitment and former oral contraceptive use was 1.12 (95% confidence interval [CI]: 0.90-1.40) for coronary heart disease, 1.24 (95% CI: 0.85-1.82) for cerebrovascular disease, 1.36 (95% CI: 0.73-2.52) for total cancer, and 0.61 (95% CI: 0.42 to 0.89) for bone fractures. CONCLUSIONS: The results from the Estonian Postmenopausal Hormone Therapy randomised trial are consistent with the Women's Health Initiative findings.     

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.     

Postmenopausal hormone therapy: new questions and the case for new clinical trials

Observational studies suggest that postmenopausal hormone therapy (HT) prevents coronary heart disease, whereas randomized clinical trials have not confirmed a cardioprotective effect. Although observational studies may have overestimated the coronary benefit conferred by postmenopausal hormone use, there are other plausible explanations for the apparent discrepancy between previous results and the less favorable findings from clinical trials such as the large Women's Health Initiative. There is now a critical mass of data to support the hypothesis that age or time since menopause may importantly influence the benefit-risk ratio associated with HT, especially with respect to cardiovascular outcomes, and that the method of administration, dose, and formulation of exogenous hormones may also be relevant. Although the weight of the evidence indicates that older women and those with subclinical or overt coronary heart disease should not take HT, estrogen remains the most effective treatment currently available for vasomotor symptoms, and its effects on the development of coronary disease in newly postmenopausal women remain unclear. Moreover, effects of HT on quality of life and cognitive function in recently postmenopausal women merit further study. These unresolved clinical issues provide the rationale for the design of the Kronos Early Estrogen Prevention Study, a 5-year randomized trial that will evaluate the effectiveness of low-dose oral estrogen and transdermal estradiol in preventing progression of atherosclerosis in recently postmenopausal women.     

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.     

Effects of specific post-menopausal hormone therapies on bone mineral density in post-menopausal women: a meta-analysis

BACKGROUND: Long-term post-menopausal hormone therapy (pHT) was often regarded as first-line therapy to prevent fractures in post-menopausal women, a recommendation under scrutiny given the benefit-risk profile of the Women's Health Initiative results of the estrogen-progestin combination. Apart from controlled clinical studies providing data with fractures as an end point, measures of lumbar and hip bone mineral density (BMD) may be used to assess bone-related effects of pHT. The objective of this study was to conduct a systematic review of 2-year trials, published between 1990 and December 2002, and assessing changes in BMD by any estrogen including ethinyl estradiol, any estrogen plus any progestin, or tibolone. METHODS: We searched MEDLINE, EMBASE and systematic reviews. Thirty-nine randomized, prospective, controlled 2-year trials were analysed in pre-specified groups according to the profile of the compounds. RESULTS: Virtually all pHT regimens at least maintain BMD at the lumbar spine and the hip compared with baseline; there is no apparent difference between the various estrogenic compounds. Tibolone, a synthetic progestin, appears to be as effective as any estrogen. Most trials were conducted in early post-menopausal women, fewer in women with hysterectomy and/or bilateral oophorectomy. CONCLUSIONS: The size of impact on BMD does not appear to differ between tibolone and any estrogen compound studied.     

Hormone use and patient concerns after the findings of the Women's Health Initiative

OBJECTIVE: To assess behaviors and concerns related to hormone therapy after the findings of the Women's Health Initiative (WHI). DESIGN: A survey was mailed to a random sample of 1,200 women identified through the pharmacy database as taking one of two estrogen + progestogen therapies (EPT) during the 6-month period before the publication of WHI findings. Questions included hormone use history, changes in usage, an assessment of symptoms, symptom changes, health behavior changes, use of alternative therapies, and demographics. RESULTS: The response rate was 70%, with women in their 60s and those receiving hormone therapy for 5 or more years were more likely to respond (P < 0.05). The majority had started hormones for symptom relief (69%) and expected to continue use. Many reported discontinuation (63%) or modifying their medication (18%). Half of these women stopped then restarted, the other half changed products. Women in their 50s were more likely to remain on hormones than older women (P < 0.01), and those taking ethinyl estradiol and norethindrone acetate were more likely to remain on their medication than those on conjugated estrogens (43% vs 29%, P < 0.01). Little change was reported in exercise and 19% increased their calcium intake. Patient concerns fell into five major categories: long-term effects, symptom control, breast cancer risk, bone health, and cognitive function. CONCLUSIONS: Women seem to be heeding the warnings about hormones but remain concerned about the potential long-term sequelae and symptom control. More research is needed to identify safer approaches to symptom relief and to address the concerns expressed.     

Estrogen and cognitive aging in women

Although several randomized controlled trials of surgically menopausal women have provided evidence that estrogen protects aspects of memory, many cross-sectional and longitudinal studies, including those from the Women's Health Initiative Memory Study, have failed to confirm these findings. One critical difference between studies that found a protective effect of estrogen on memory and those that did not is that, in the former studies, treatment with estrogen began at the time of menopause and in the latter studies, it was first administered many years after the menopause had occurred. Recent evidence from rodent, nonhuman primate, and human studies consistently suggests that the timing of the initiation of estrogen treatment with regard to the menopause may be critical to our understanding of the estrogenic effect on memory. Results of these animal and human studies indicate that the initiation of estrogen treatment at the time of menopause, or soon after ovariectomy, provides a window of opportunity for the protection of memory in females whereas the administration of the hormone following a considerable delay in time after ovariectomy or following a natural menopause has little or no beneficial effect on cognition.     

Progestins in HRT: Sufferance or desire?

While the benefits of progestins in hormonal replacement therapy are well recognized as far as endometrial protection is concerned the data on breast tissue and the cardiovascular system are contentious. Following the Women's Health Initiative study, the Million Women Study and The Women's International Study of Long-duration (O)estrogen after Menopause the question can be raised: When dealing with optimal hormonal therapy after the menopause, is the progestin component accepted here on sufferance or is it desired? The answer is partly made up by the fact that the recent epidemiological data may have been not only wrongly translated in relation to the clinical settings, but also to the whole class of therapies. The various progestins available for hormonal therapy exert different partial effects at cellular level according to the biochemical composition. Due to the structural differences the progestins result in a variety of tissue transforming changes as well as metabolic and hemostatic changes. Since no single test or algorithm presently serves as golden standard for all desired hormonal effects the least changes or no changes from the premenopausal physiology may often be advantageous. In our opinion targeting this goal includes a sustained desire for an estrogen/progestin combination as optimal future hormone therapy. Moreover the strategy not only includes evaluation of the specific steroidal formula, but also a titration of the dose and choosing the optimal route of administration. With special reference to cardiovascular disease this review therefore makes a plea for differentiating between the array of chemically and functionally distinct progestins used therapeutically after the menopause in combination 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.     

Hormone therapy and cognitive function: Is there a critical period for benefit?

The large majority of women receiving hormone therapy initiate therapy early in life for the treatment of menopausal symptoms. However, the Women's Health Initiative Memory Study, the only randomized clinical trial to date on hormone therapy and dementia, was carried out in women age 65 and older. That trial provided important insights into the detrimental effects of hormone therapy on dementia in women initiating later in life. The generalizability of those findings to the typical hormone therapy user who initiates earlier in life is unknown. To address this important issue, this review focuses on observational trials of hormone therapy and dementia risk, randomized clinical trials of hormone therapy and cognitive function, and basic science studies. These lines of research provide suggestive, but not definitive, evidence that early initiation of hormone therapy may provide cognitive benefits, particularly to verbal memory and other hippocampally mediated functions. Other forms of hormone therapy, other cognitive domains, and cyclic hormone regimens may not conform to this "critical period hypothesis." Further research is needed to test the validity and limits of this hypothesis.     

Breast cancer incidence in postmenopausal women using testosterone in addition to usual hormone therapy

OBJECTIVE: There is now convincing evidence that usual hormone therapy for ovarian failure increases the risk for breast cancer. We have previously shown that ovarian androgens normally protect mammary epithelial cells from excessive estrogenic stimulation, and therefore we hypothesized that the addition of testosterone to usual hormone therapy might protect women from breast cancer. DESIGN: This was a retrospective, observational study that followed 508 postmenopausal women receiving testosterone in addition to usual hormone therapy in South Australia. Breast cancer status was ascertained by mammography at the initiation of testosterone treatment and biannually thereafter. The average age at the start of follow-up was 56.4 years, and the mean duration of follow-up was 5.8 years. Breast cancer incidence in this group was compared with that of untreated women and women using usual hormone therapy reported in the medical literature and to age-specific local population rates. RESULTS: There were seven cases of invasive breast cancer in this population of testosterone users, for an incidence of 238 per 100,000 woman-years. The rate for estrogen/progestin and testosterone users was 293 per 100,000 woman-years--substantially less than women receiving estrogen/pro-gestin in the Women's Health Initiative study (380 per 100,000 woman-years) or in the "Million Women" Study (521 per 100,000 woman-years). The breast cancer rate in our testosterone users was closest to that reported for hormone therapy never-users in the latter study (283 per 100,000 woman-years), and their age-standardized rate was the same as for the general population in South Australia. CONCLUSIONS: These observations suggest that the addition of testosterone to conventional hormone therapy for postmenopausal women does not increase and may indeed reduce the hormone therapy-associated breast cancer risk-thereby returning the incidence to the normal rates observed in the general, untreated population.     

Changing use of hormone therapy among minority women since the Women's Health Initiative

OBJECTIVE: There has been a significant shift in the use of hormone therapy (HT) among nonminority women since the publication of results of the Women's Health Initiative (WHI). Little is known about how the WHI results affected minority populations. This survey measured patterns of HT use among inner city women after publication of the WHI results, identified factors involved in the decision to continue or discontinue HT, and characterized the symptom burden and the experience of women who attempted to discontinue HT. DESIGN: We conducted a cross-sectional survey of 101 English- and Spanish-speaking women in an inner city general internal medicine clinic from August 2003 to April 2004. All women had been taking HT at the time of the publication of the WHI results. The survey included questions on patient-reported experience with HT, symptoms of menopause, and use of alternative treatments. RESULTS: Overall, 101 of 142 (71%) eligible women agreed to participate. The mean age of participants was 60 years; 43% were African American and 46% were Hispanic. The mean duration of HT use was 9.6 years. Three quarters (74%) had heard about the WHI findings, and 87% had attempted to stop taking HT after their publication. The most common reason for attempting to stop HT was concern about an increased risk of cancer or a general increase in risk to health. Of those who stopped HT, the vast majority (85%) reported vasomotor symptoms, and 26% restarted HT, mostly to treat those symptoms. CONCLUSIONS: Nearly all minority women in this small sample attempted to stop HT use after the results of the WHI were published. Restarting HT for treatment of symptoms was common.