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Summary

This NIA-sponsored workshop was aimed at understanding the impact of the menopausal transition on mood symptoms and cognitive disorders during the menopausal transition and identifying research priorities for further investigation. Longitudinal studies provide insights into the frequency of these problems in representative samples of midlife women. The majority of women do not experience serious depressive symptoms during the transition, but a subgroup of women is at increased risk. Slight changes in memory function and processing speed are evident during the transition, and physiological factors associated with hot flashes may contribute to memory problems. Clinical trial evidence indicates that estradiol therapy can be effective in treating perimenopausal depression. There is some limited evidence of a cognitive benefit with estrogen alone therapy in younger postmenopausal women, and stronger evidence that certain forms of combination hormone therapy produce modest deficits in verbal memory in younger and older women. Identifying a cognitively neutral or beneficial combination therapy for the treatment of menopausal symptoms in naturally menopausal women is an important goal for future research. Pharmacological challenge studies bridge the basic science and clinical literatures to provide insights into the extent to which changes in endogenous and exogenous hormones and other neurotransmitter systems contribute to cognitive and mood problems. Routine evaluation of depressive symptoms in perimenopausal women is warranted by the literature. Quick and valid screening tools for assessing depression in the clinic are available on-line and free of charge.

Objective

To review the relation in midlife and beyond between estrogen exposures and episodic memory in women.

Background

Episodic memory performance declines with usual aging, and impairments in episodic memory often portend the development of Alzheimer's disease. In the laboratory, estradiol influences hippocampal function and animal learning. However, it is controversial whether estrogens affect memory after a woman's reproductive years.

Method

Focused literature review, including a summary of a systematic search of clinical trials of estrogens in which outcomes included an objective measure of episodic memory.

Results

The natural menopause transition is not associated with objective changes in episodic memory. Strong clinical trial evidence indicates that initiating estrogen-containing hormone therapy after about age 60 years does not benefit episodic memory. Clinical trial findings in middle-age women before age 60 are limited by smaller sample sizes and shorter treatment durations, but these also do not indicate substantial memory effects. Limited short-term evidence, however, suggests that estrogens may improve verbal memory after surgical menopause. Although hormone therapy initiation in old age increases dementia risk, observational studies raise the question of an early critical window during which midlife estrogen therapy reduces late-life Alzheimer's disease. However, almost no data address whether midlife estrogen therapy affects episodic memory in old age.

Conclusions

Episodic memory is not substantially impacted by the natural menopause transition or improved by use of estrogen-containing hormone therapy after age 60. Further research is needed to determine whether outcomes differ after surgical menopause or whether episodic memory later in life is modified by midlife estrogenic exposures.

A plethora of in vitro and in vivo studies have supported the neuroprotective role of estrogens and their impact on the neurotransmitter systems implicated in cognition. Recent hormonal replacement therapy trials in non-demented post-menopausal women suggest a temporary positive effect (notably on verbal memory), and four meta-analyses converge to suggest a possible protective effect in relation to Alzheimer’s disease (reducing risk by 29 to 44%). However, data from the only large randomized controlled trial published to date, the Women’s Health Initiative Memory Study, did not confirm these observations and have even suggested an increase in dementia risk for women using hormonal replacement therapy compared to controls. Apart from methodological differences, one key short-coming of this trial has probably been the focus on late-onset (postmenopausal) hormonal changes, i.e. at a time when the neurodegenerative process has already begun and without taking into account individual lifetime exposure to hormone variability. Multifactorial models based on an exhaustive view of all hormonal events throughout the reproductive life (rather than on a specific exposure to a given steroid) together with other risk factors (notably genetic risk factors related to estrogen receptor polymorphisms) should be explored to clarify the role of hormonal risk factors, or protective factors for cognitive dysfunction and dementia.

Context

Women seem to be more vulnerable to dementia, particularly Alzheimer’s disease (AD), than men. There is controversy among studies correlating estrogen deficit to cognitive impairment. Because of the sudden drop of estrogens in menopause, this hormonal deficit could represent one of the risk factors for the larger incidence and prevalence of AD in post-menopausal women.

Rationale

We therefore wanted to find out if post-menopausal women with dementia, or even in a prior stage, mild cognitive impairment (MCI), would have a more significant deficit of estrogens than post-menopausal women without dementia, or any other type of cognitive problem.

Objectives

The aim of this study was to detect possible differences of the sex hormone levels among post-menopausal women, simultaneously affected by MCI or dementia, in comparison with a control group without cognitive impairment.

Design, setting, and participants

A small, multicenter, prospective study was performed on 82 post-menopausal women (41 cases, 41 controls), aged 45–81 years, to investigate their sex hormone balance. The diagnosis of dementia was made according to ICD 9 or 10 and DSM III-R or IV appropriate to the time interval. The diagnosis of probable AD followed the NINCDS-ADRDA criteria. MCI met the Paquid-study criteria. Blood was analyzed in qualified centers for LH, FSH, and 17-β-estradiol. All women went through a thorough psychiatric examination and those with a suspected hormonal impairment were examined by a gynecologist.

Results

15 cases (36.6%) had impaired hormonal function, compared with 8 controls (19.5%). Of the 15 cases with hormonal impairment, 9 had MCI.

Conclusions

These preliminary data stress a considerable difference between the sex hormone status of these two populations, showing a tendency towards a more accentuated estrogen deficit linked to cognitive deficit. Enlarging the sample and following the evolution could bring more interesting data.

Largely on the basis of the first publication of findings of net harm with menopausal hormone treatment in the Women’s Health Initiative (WHI) hormone trials, current Food and Drug Administration recommendations limit menopausal hormone treatment to the “… shortest duration consistent with treatment goals …,” with goals generally taken to mean relief of menopausal symptoms and maximal duration as approximately 5 years. The WHI finding of net harm was due largely to the absence of beneficial effects on coronary heart disease incidence rates. Published analyses of WHI data by age or time since menopause find that excess coronary heart disease risk with menopausal hormone treatment is confined to more remotely menopausal or older women, with younger women showing nonsignificant trends toward benefit (the “timing hypothesis”). Moreover, a recently published reexamination of data from the WHI Estrogen plus Progestin trial suggests that reduced coronary heart disease risk may appear only after 5 to 6 years of treatment. Consistent with this finding, risk ratios for coronary heart disease were calculated as 1.08 (95% confidence interval, 0.86–1.36) in years 1 to 6 and as 0.46 (confidence interval, 0.28–0.78) in years 7 to 8+ in the WHI Estrogen Alone trial. Previous studies also support the beneficial effects of menopausal hormone treatment after prolonged exposure. Thus, current analyses do not support a generalized recommendation for short duration of menopausal hormone treatment. Rather, they suggest that current Food and Drug Administration practice guidelines should be reconsidered to allow individualized care based on risk:benefit considerations. New research is urgently needed evaluating influences of timing, duration, dose, route of administration, and agents on menopausal hormone treatment-related risks and benefits to better understand how to optimize recommendations for individual patients.

The question of whether ovarian hormone therapy can prevent or reduce age-related memory decline in menopausal women has been the subject of much recent debate. Although numerous studies have demonstrated a beneficial effect of estrogen and/or progestin therapy for certain types of memory in menopausal women, recent clinical trials suggest that such therapy actually increases the risk of cognitive decline and dementia. Because rodent models have been frequently used to examine the effects of age and/or ovarian hormone deficiency on mnemonic function, rodent models of age-related hormone and memory decline may be useful in helping to resolve this issue. This review will focus on evidence suggesting that estradiol modulates memory, particularly hippocampal-dependent memory, in young and aging female rats and mice. Various factors affecting the mnemonic response to estradiol in aging females will be highlighted to illustrate the complications inherent to studies of estrogen therapy in aging females. Avenues for future development of estradiol-based therapies will also be discussed, and it is argued that an approach to drug development based on identifying the molecular mechanisms underlying estrogenic modulation of memory may lead to promising future treatments for reducing age-related mnemonic decline.

The influence of hormone treatment on brain and cognition in postmenopausal women has been a controversial topic. Contradictory patterns of results have prompted speculation that a critical period, or a limited window of opportunity, exists for hormone treatment to protect against cognitive and neural decline in older women. Consistent with this hypothesis, studies in both humans and rodents indicate that the latency between the time of menopause and the initiation of hormone treatment is an important factor in determining whether hormone treatment will prevent or exacerbate cognitive impairment. In this cross-sectional study of 102 postmenopausal women, we examined whether hippocampal, amygdala, or caudate nucleus volumes and spatial memory performance were related to the interval between menopause and the initiation of hormone treatment. Consistent with a critical period hypothesis, we found that shorter intervals between menopause and the initiation of hormone treatment, as determined by self-report, were associated with larger hippocampal volumes compared with longer intervals between menopause and treatment initiation. Initiation of hormone treatment at the time of menopause was also associated with larger hippocampal volumes when compared to peers who had never used hormone treatment. Furthermore, these effects were independent from potentially confounding factors such as age, years of education, the duration of hormone treatment, current or past use of hormone therapy, the type of therapy, and the age at menopause. Larger hippocampal volumes in women who initiated hormone treatment at the time of menopause failed to translate to improved spatial memory performance. There was no relationship between the timing of hormone initiation, spatial memory performance, and amygdala or caudate nucleus volume. Our results provide support for the idea that there is a limited window of opportunity at the time of menopause for hormone treatment to influence hippocampal volume, yet the degree to which these effects translate to improved memory performance is uncertain.

Health Issue

The average age of natural menopause in Western societies is estimated to be 51 years; women in Canada can therefore expect to live, on average, a third of their lives in post-menopausal years. During these years women are at increased risk of chronic diseases such as osteoporosis and cardiovascular disease.

Key Findings

Clinical and epidemiological data on women in perimenopause are limited. There are no adequate Canadian data on symptom severity and prevalence among perimenopausal and postmenopausal women. Scientific evidence is lacking to support or refute claims that commonly used botanical products can offer therapeutic relief of menopausal symptoms.

Recent data from the Women's Health Initiative suggest that combined estrogen plus therapy increases the risk of stroke, coronary artery disease and breast cancer. Hormone therapy is no longer recommended for the prevention of chronic diseases for asymptomatic women. Stroke is an important issue for perimenopausal and postmenopausal women and sex differences may exist in the progestin treatment of stroke. Osteoporosis affects an estimated one in six women over the age of 50.

Data Gaps and Recommendations

There is a need to conduct clinical and epidemiological research aimed at better understanding the menopausal transition and defining its clinical phases. Investigations aimed at alternative combinations and doses of hormone therapy and non-pharmaceutical alternatives in light of known risks and benefits are also necessary. Health care practitioners and women need to be educated on the risks and effective treatment related to cardiovascular disease so they can present for treatment more quickly and receive the most effective therapies.

Research increasingly suggests that changes in estrogen levels during aging may increase risk for Alzheimer disease, the most common type of dementia. This update reviews the newest information about estrogen and cognitive aging, including information regarding the role of bioavailable estrogen in older women and men, use of selective estrogen receptor modulators (SERMs) to improve cognition, and studies of genetic risk factors to elucidate the effects of endogenous estrogen on aging and cognition. Future trials are needed to determine whether alternate timing, dosage, formulation, or method of administration of hormone replacement can reduce risk of dementia.

We now appreciate that estrogen is a pleiotropic gonadal steroid that exerts profound effects on the plasticity and cell survival of the adult brain. Over the past century, the life span of women has increased, but the age of the menopause remains constant. This means that women may now live over one third of their lives in a hypoestrogenic, postmenopausal state. The impact of prolonged hypoestrogenicity on the brain is now a critical health concern as we realize that these women may suffer an increased risk of cognitive dysfunction and neurodegeneration due to a variety of diseases. Accumulating evidence from both clinical and basic science studies indicates that estrogen exerts critical protective actions against neurodegenerative conditions such as Alzheimer's disease and stroke. Here, we review the discoveries that comprise our current understanding of estrogen action against neurodegeneration. These findings carry far-reaching possibilities for improving the quality of life in our aging population.

Introduction

Menopause is associated with midlife, a time when many women begin to experience the signs and symptoms of aging, such as increases in blood pressure, changes in lipid profiles, loss of bone mass density, and diminished memory and cognition. Given the result of the Women’s Health Initiative, many women no longer consider hormone therapy the first option for promoting healthy aging. Instead they are turning to botanical and dietary supplement (BDS) products in place of hormone therapy. This paper reviews the evidence available for use of isoflavones from soy and red clover, for the treatment or prevention of these health issues.

Methods

The MEDLINE and EMBASE databases was searched for articles relating to soy or red clover supplement use for prevention and/or treatment of heart disease, hyperlipidemia, osteoporosis, mood disorders and cognitive abilities. Studies were included if they were randomized, controlled trials and included peri- or postmenopausal women.

Results

Isoflavone products appear to be the most useful for improving lipid profiles; however, the evidence suggests that isoflavone extracts from soy are less effective than products containing soy protein or red clover isoflavones. Soy protein appears to reduce total cholesterol levels and LDL cholesterol, while red clover reduces triglycerides and increases HDL cholesterol. The data was somewhat less convincing, although promising, for increasing bone mass density and improving cognitive abilities.

Conclusions

Research suggests that isoflavone found in soy foods and red clover appear to have a small but positive health effect on plasma lipid concentrations, bone mass density, cognitive abilities. Given the lack of serious safety concerns in the short term, it would appear that including soy and red clover in the diet of postmenopausal women, not withstanding a soy allergy, would be beneficial.

The Women’s Health Initiative trial found a modestly increased risk of invasive breast cancer with daily 0.625-mg conjugated equine estrogens plus 2.5-mg medroxyprogesterone acetate, with most evidence among women who had previously received postmenopausal hormone therapy. In comparison, observational studies mostly report a larger risk increase. To explain these patterns, the authors examined the effects of this regimen in relation to both prior hormone therapy and time from menopause to first use of postmenopausal hormone therapy (“gap time”) in the Women’s Health Initiative trial and in a corresponding subset of the Women’s Health Initiative observational study. Postmenopausal women with a uterus enrolled at 40 US clinical centers during 1993–1998. The authors found that hazard ratios agreed between the two cohorts at a specified gap time and time from hormone therapy initiation. Combined trial and observational study data support an adverse effect on breast cancer risk. Women who initiate use soon after menopause, and continue for many years, appear to be at particularly high risk. For example, for a woman who starts soon after menopause and adheres to this regimen, estimated hazard ratios are 1.64 (95% confidence interval: 1.00, 2.68) over a 5-year period of use and 2.19 (95% confidence interval: 1.56, 3.08) over a 10-year period of use.

Many postmenopausal women question whether to start or continue hormone therapy because of recent clinical trial negative results. However, evidence from other studies of postmenopausal women, and from studies in menopausal monkeys, indicate that estrogen has neurocognitive protective effects, particularly when therapy is initiated close to the time of menopause before neural systems become increasingly compromised with age. In this review, we present studies of menopausal women and female monkeys that support the concept that estrogen therapies protect both cognitive function and neurobiological processes.

Interest in the years of reproductive changes for women with epilepsy (WWE), specifically perimenopause, menopause and postmenopause has been emerging in the epilepsy community. This article discusses evidence for changes in seizure frequency during perimenopause and postmenopause. Further, a catamenial epilepsy pattern during the reproductive years may be a hallmark for the observed seizure frequency change during these years; that is, an increase at perimenopause but a decrease at menopause. This finding implies that a subset of WWE are particularly susceptible to endogenous reproductive hormonal changes. An adverse effect on seizure frequency with the use of hormone replacement therapy (HRT) during postmenopause for WWE was reported in questionnaires, and was later borne out in a clinical trial. The laboratory counterpart of this human trial, HRT in ovariectomized rodent seizure models, shows that estrogen and progesterone are neuroprotective and do not uniformly increase seizure frequency. Possible reasons for the discrepancy between “the lab and the clinic” are presented. Strategies for managing HRT in symptomatic postmenopausal WWE using estrogenic and progestogenic compounds that may be less likely to promote seizures are discussed.

Background

Premature menopause is a major concern of younger women undergoing adjuvant therapy for breast cancer. Hormone replacement therapy is contraindicated in women with a history of breast cancer. Non-hormonal medications show a range of bothersome side-effects. There is growing evidence that cognitive behavioral therapy (CBT) and physical exercise can have a positive impact on symptoms in naturally occurring menopause. The objective of this study is to investigate the efficacy of these interventions among women with breast cancer experiencing treatment-induced menopause.

Methods/design

In a randomized, controlled, multicenter trial, we are evaluating the effectiveness of CBT/relaxation, of physical exercise and of these two program elements combined, in reducing menopausal symptoms, improving sexual functioning, reducing emotional distress, and in improving the health-related quality of life of younger breast cancer patients who experience treatment-induced menopause. 325 breast cancer patients (aged < 50) are being recruited from hospitals in the Amsterdam region, and randomly allocated to one of the three treatment groups or a 'waiting list' control group. Self-administered questionnaires are completed by the patients at baseline, and at 12 weeks (T1) and 6 months (T2) post-study entry. Upon completion of the study, women assigned to the control group will be given the choice of undergoing either the CBT or physical exercise program.

Discussion

Cognitive behavioral therapy and physical exercise are potentially useful treatments among women with breast cancer undergoing treatment-induced, premature menopause. For these patients, hormonal and non-hormonal therapies are contraindicated or have a range of bothersome side-effects. Hence, research into these interventions is needed, before dissemination and implementation in the current health care system can take place.

Trial registration

The study is registered at the Netherlands Trial Register (NTR1165) and ClinicalTrials.gov (NCT00582244).

Objectives

To examine the association between hormone therapy (HT) and cognitive performance or dementia, focusing on the duration and type of treatment used, as well as the timing of initiation of HT in relation to the menopause.

Methods

Women 65 years and older were recruited in France as part of the Three City Study. At baseline and 2 and 4 year follow-up, women were administered a short cognitive test battery and a clinical diagnosis of dementia was made. Detailed information was also gathered relating to current and past HT use. Analysis was adjusted for a number of socio-demographic, behavioural, physical and mental health variables, as well as Apolipoprotein ε4 (Apoe-ε4).

Results

Among 3130 naturally postmenopausal women, current HT users performed significantly better than never users on verbal fluency, working memory and psychomotor speed. These associations varied according to the type of treatment and a longer duration of HT appeared to be more beneficial. However, initiation of HT close to the menopause was not associated with better cognition. HT did not significantly reduce dementia risk over 4 years but current treatment diminished the negative effect associated with Apoe-ε4.

Conclusions

Current HT was associated with better performance in certain cognitive domains but these associations are dependent on the duration and type of treatment used. We found no evidence that HT needs to be initiated close to the menopause to have a beneficial effect on cognitive function in later life. Current HT may decrease the risk of dementia associated with the Apoe-ε4 allele.

BACKGROUND

Clinical trials yield discrepant information about the impact of hormone therapy on verbal memory and executive function. This issue is clinically relevant because declines in verbal memory are the earliest predictor of Alzheimer's disease and declines in executive function are central to some theories of normal, age-related changes in cognition.

METHODS

We conducted a systematic review of randomized clinical trials of hormone therapy (i.e. oral, transdermal, i.m.) and verbal memory, distinguishing studies in younger (i.e. ≤65 years of age; n = 9) versus older (i.e. >65 years; n = 7) women and studies involving estrogen alone versus estrogen plus progestogen. Out of 32 placebo-controlled trials, 17 were included (13 had no verbal memory measures and 2 involved cholinergic manipulations). We also provide a narrative review of 25 studies of executive function (two trials), since there are insufficient clinical trial data for systematic review.

RESULTS

There is some evidence for a beneficial effect of estrogen alone on verbal memory in younger naturally post-menopausal women and more consistent evidence from small-n studies of surgically post-menopausal women. There is stronger evidence of a detrimental effect of conjugated equine estrogen plus medroxyprogesterone acetate on verbal memory in younger and older post-menopausal women. Observational studies and pharmacological models of menopause provide initial evidence of improvements in executive function with hormone therapy.

CONCLUSIONS

Future studies should include measures of executive function and should address pressing clinical questions; including what formulation of combination hormone therapy is cognitively neutral/beneficial, yet effective in treating hot flashes in the early post-menopause.

Objectives

Every year, millions of women begin the peri-menopause and may experience a number of symptoms related to this transition. Many women are reluctant to use exogenous hormone therapy for treatment of menopausal symptoms and are turning to botanical and dietary supplements (BDS) for relief. This paper reviews the literature on alternatives to plant estrogens for relief of menopausal symptoms.

Methods

The MEDLINE database was searched for clinical trials of non-estrogenic plant extracts for menopausal symptoms. To be included, studies had to include peri- or postmenopausal women as subjects. All clinical trials (randomized-controlled trials, open trials, and comparison group studies) were included for this review.

Results

Black Cohosh appears to be one of the most effective botanicals for relief of vasomotor symptoms, while St. John’s wort can improve mood disorders related to the menopausal transition. Many other botanicals have limited evidence to demonstrate safety and efficacy for relief of symptoms related to menopause.

Conclusions

A growing body of evidence suggests that some botanicals and dietary supplements could result in improved clinical outcomes. Health care providers should discuss these issues with their patients so they can assist them in managing these alternative therapies through an evidence-based approach.

Risk for Alzheimer’s disease (AD) is associated with age-related loss of sex steroid hormones in both women and men. In postmenopausal women, the precipitous depletion of estrogens and progestogens is hypothesized to increase susceptibility to AD pathogenesis, a concept largely supported by epidemiological evidence but refuted by some clinical findings. Experimental evidence suggests that estrogens have numerous neuroprotective actions relevant to prevention of AD, in particular promotion of neuron viability and reduction of β-amyloid accumulation, a critical factor in the initiation and progression of AD. Recent findings suggest neural responsiveness to estrogen can diminish with age, reducing neuroprotective actions of estrogen and, consequently, potentially limiting the utility of hormone therapies in aged women. In addition, estrogen neuroprotective actions are also modulated by progestogens. Specifically, continuous progestogen exposure is associated with inhibition of estrogen actions whereas cyclic delivery of progestogens may enhance neural benefits of estrogen. In recent years, emerging literature has begun to elucidate a parallel relationship of sex steroid hormones and AD risk in men. Normal age-related testosterone loss in men is associated with increased risk to several diseases including AD. Like estrogen, testosterone has been established as an endogenous neuroprotective factor that not only increases neuronal resilience against AD-related insults, but also reduces β- amyloid accumulation. Androgen neuroprotective effects are mediated both directly by activation of androgen pathways and indirectly by aromatization to estradiol and initiation of protective estrogen signaling mechanisms. The successful use of hormone therapies in aging men and women to delay, prevent, and or treat AD will require additional research to optimize key parameters of hormone therapy and may benefit from the continuing development of selective estrogen and androgen receptor modulators.

Over a decade of converging findings from clinical, observational and basic science research indicate that estrogen administration during the menopausal transition exerts beneficial effects on cognition and decreases a woman's risk of developing Alzheimer's disease (AD) later in life. This review article stresses the research focus of AD prevention, and introduces hormone therapy (HT) as a probable catalyst that may achieve this goal. Furthermore, this article outlines 3 mechanisms proposed to mediate estrogen's beneficial effects, discusses the controversy surrounding HT administration, and presents the most promising estrogen related research in AD prevention and treatment. Although controversial, cumulative evidence suggests that the potential of estrogen initiated during perimenopause to prevent AD needs to be systematically evaluated.

Objective

To review and summarize current evidence on the health consequences of premature menopause and early menopause.

Methods

We reviewed existing literature and combined graphically some results from the Mayo Clinic Cohort Study of Oophorectomy and Aging.

Results

Premature menopause or early menopause may be either spontaneous or induced. Women who experience premature menopause (before age 40 years) or early menopause (between ages 40 and 45 years) experience an increased risk of overall mortality, cardiovascular diseases, neurological diseases, psychiatric diseases, osteoporosis, and other sequelae. The risk of adverse outcomes increases with earlier age at the time of menopause. Some of the adverse outcomes may be prevented by estrogen treatment initiated after the onset of menopause. However, estrogen alone does not prevent all long-term consequences and other hormonal mechanisms are likely involved.

Conclusions

Regardless of the cause, women who experience hormonal menopause and estrogen deficiency before reaching the median age of natural menopause are at increased risk for morbidity and mortality. Estrogen treatment should be considered for these women, but may not eliminate all of the adverse outcomes.

Observational and epidemiological studies suggest that menopausal hormone therapy (MHT) reduces cardiovascular disease (CVD) risk. However, results from prospective trials showed neutral or adverse effects most likely due to differences in participant demographics, such as age, timing of initiation of treatment, and preexisting cardiovascular disease, which reflected in part the lack of basic science information on mechanisms of action of hormones on the vasculature at the time clinical trials were designed. The Kronos Early Estrogen Replacement Study (KEEPS) is a prospective, randomized, controlled trial designed, using findings from basic science studies, to test the hypothesis that MHT when initiated early in menopause reduces progression of atherosclerosis. KEEPS participants are younger, healthier, and within 3 years of menopause thus matching more closely demographics of women in prior observational and epidemiological studies than women in the Women’s Health Initiative hormone trials. KEEPS will provide information relevant to the critical timing hypothesis for MHT use in reducing risk for CVD.

Appropriate and safe use of hormone replacement therapy (HRT) in postmenopausal women is an evolving saga, triggered by the unexpected results from the first publication of the Women's Health Initiative (WHI) Trial in 2002. These results showed a slight but significantly increased risk of breast cancer, stroke, and dementia with standard HRT compared with placebo. A reanalysis of these results shows that use of HRT within the first few years after the onset of menopause may be associated with decreased risk of dementia and coronary artery disease. However, HRT in its commonly used form of conjugated equine estrogen and medroxyprogesterone acetate can increase seizure frequency in menopausal women with epilepsy; this outcome may be an adverse effect of these neuroactive steroids on the epileptic female brain, which is already in a hormonally deprived state. To explore this possibility, more information about the neurophysiologic activity of medroxyprogesterone acetate is needed and alternatives to this specific HRT regimen should be considered for women with epilepsy.

The onset of menopause marks a pivotal time in which the incidence of hypertension and cardiovascular disease begins to increase dramatically in women. Prior to menopause, the incidence of these diseases is significantly lower than in similarly aged men, but following menopause the rates rise rapidly until paralleling that in men. The loss of endogenous estrogen at menopause has traditionally been thought to be the primary factor involved in these changes and resulted in the widespread use of hormone replacement therapy (HRT) to reduce cardiovascular risk factors and decrease the affective symptoms of menopause. However, the adverse effects of HRT reported in recent large-scale trials (e.g., the Women’s Health Initiative) have greatly decreased the use of HRT by postmenopausal women.

Many women are seeking alternatives to HRT, including the use of dietary supplements that have a long history of use in traditional medicine, particularly in Asia. Examples of frequently used botanicals are soy, black cohosh, red clover, grape derivatives, St. John’s wort, Ginko biloba and Echinacea. While many of these botanicals appear to ameliorate some postmenopausal symptoms (i.e., bone loss, hot flushes/flashes and night sweats), none of the tested botanicals has proven as effective as HRT in decreasing the affective disorders of menopause. Further, despite the increasing usage of botanical supplements, their efficacy and safety have not been well documented by critical research studies. This review summarizes recent findings related to the utility of botanicals for menopause-related cardiovascular and metabolic disorders, specifically hypertension, diabetes, progressive cognitive decline and hyperlipidemia. While great caution should be exercised in the translation of animal findings to the human, these studies, along with those of others, suggest that some commonly used botanical supplements may be useful adjuvants for providing protection to women (and men) against cardiovascular risk.

While cognitive changes and mood instability are frequent symptoms reported by menopausal women, the degree to which the decline in estrogen production is responsible is not yet clear. Several lines of evidence suggest that estrogen may produce its effects on cognition and mood through modulation of serotonergic function. To test this hypothesis, we used the tryptophan depletion (TD) paradigm to lower central serotonin levels and pharmacologically manipulated estrogen levels in healthy menopausal women. We examined the individual and combined effects of estradiol and serotonin on working memory, emotion processing and task-related brain activation. Eight healthy predominantly early postmenopausal women underwent TD or sham depletion followed by functional magnetic resonance imaging (fMRI) both before and after short-term transdermal estradiol 75-150 ug/d administration. There was an estradiol treatment by TD interaction for brain activation during performance on both the N-back Task (working memory) and Emotion Identification Task (affective processing). During the 2-back condition, TD attenuated activation prior to, but not after, estradiol treatment in the right and left dorsal lateral prefrontal and middle frontal/cingulate gyrus. During emotion identification, TD heightened activation in the orbital frontal cortex and bilateral amygdala, and this effect was attenuated by estradiol treatment. These results provide preliminary evidence that serotonergic effects directly mediate the impact of estrogen on brain activation during working memory and affective processing.